bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring cellular and molecular processes in single-cell data with non-negative matrix factorization using Python, R, and GenePattern Notebook implementations of CoGAPS
Authors: Johnson Jeanette , Tsang Ashley , Mitchell Jacob T. , Davis-Marcisak Emily , Sherman Thomas , Liefeld Ted , Loth Melanie , Goff Loyal A , Zimmerman Jacquelyn , Kinny-Köster Ben , Jaffee Elizabeth , Tamayo Pablo , Mesirov Jill P. , Reich Michael , Fertig Elana J. , Stein-O’Brien Genevieve L. 
Published: July 2022

AbstractNon-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. Still, inferring biological processes requires additional post hoc statistics and annotation for interpretation of features learned from software packages developed for NMF implementation. Here, we aim to introduce a suite of computational tools that implement NMF and provide methods for accurate, clear biological interpretation and analysis. A generalized discussion of NMF covering its benefits, limitations, and open questions in the field is followed by three vignettes for the Bayesian NMF algorithm CoGAPS (Coordinated Gene Activity across Pattern Subsets). Each vignette will demonstrate NMF analysis to quantify cell state transitions in public domain single-cell RNA-sequencing (scRNA-seq) data of malignant epithelial cells in 25 pancreatic ductal adenocarcinoma (PDAC) tumors and 11 control samples. The first uses PyCoGAPS, our new Python interface for CoGAPS that we developed to enhance runtime of Bayesian NMF for large datasets. The second vignette steps through the same analysis using our R CoGAPS interface, and the third introduces two new cloud-based, plug-and-play options for running CoGAPS using GenePattern Notebook and Docker. By providing Python support, cloud-based computing options, and relevant example workflows, we facilitate user-friendly interpretation and implementation of NMF for single-cell analyses.
On Non-Kolmogorov turbulence in blood flow and its possible role in mechanobiological stimulation
Authors: Saqr Khalid M. , Zidane Iham F. 
Published: July 2022

ABSTRACTThe study of turbulence in physiologic blood flow is important due to its strong relevance to endothelial mechanobiology and vascular disease. Recently, Saqr et al (Sci Rep 10, 15492, 2020) discovered non-Kolmogorov turbulence in physiologic blood flow in vivo, traced its origins to the Navier-Stokes equation and demonstrated some of its properties using chaos and hydrodynamic-stability theories. The present work extends these findings and investigates some inherent characteristics of non-Kolmogorov turbulence in monoharmonic and multiharmonic pulsatile flow under ideal physiologic conditions. The purpose of this work is to propose a conjecture for the origins for picoNewton forces that are known to regulate endothelial cells’ functions. The new conjecture relates these forces to physiologic momentum-viscous interactions in the near-wall region of the flow. Here, we used high-resolution large eddy simulation (HRLES) to study pulsatile incompressible flow in a straight pipe of L/D = 20. The simulations presented Newtonian and Carreau-Yasuda fluid flows, at Reynolds number of 256 and 228, respectively, each represented by one, two and three boundary harmonics. Comparison was established based on maintaining constant time-averaged mass flow rate in all simulations. First, we report the effect of primary harmonics on the global power budget using primitive variables in phase space. Second, we describe the non-Kolmogorov turbulence in frequency domain. Third, we investigate the near-wall coherent structures in time, space and frequency domains. Finally, we propose a new conjecture for the role of turbulence in endothelial cells’ mechanobiology. The proposed conjecture correlates near-wall turbulence to a force field of picoNewton scale, suggesting possible relevance to endothelial cells mechanobiology.
Identification and targeting of a unique NaV1.7 domain driving chronic pain
Authors: Gomez Kimberly , Stratton Harrison J. , Duran Paz , Loya Santiago , Tang Cheng , Calderon-Rivera Aida , François-Moutal Liberty , Khanna May , Madura Cynthia L. , Luo Shizhen , Ran Dongzhi , Boinon Lisa , Perez-Miller Samantha , Moutal Aubin , Khanna Rajesh 
Published: July 2022

AbstractDespite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition of a small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered a 15 amino acid CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight voltage-gated sodium channel isoforms decreased tetrodotoxin-sensitive NaV1.7 currents in rodent sensory neurons. A cell-penetrant version of NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 localization, reduced spinal neurotransmitter release, and reversed mechanical allodynia in a rat spared nerve injury model of neuropathic pain. Interfering with NaV1.7-CRMP2 coupling did not produce motor impairment and spared thermal, inflammatory, and post-surgical nociception. As proof-of-concept for NaV1.7-targeted gene therapy, we found that NaV1.7-CRS packaged into an adeno-associated virus recapitulated the effects on NaV1.7 function in both rodent and rhesus macaque sensory neurons and both reversed and prevented the development of mechanical allodynia in a neuropathic pain model in male and female rodents.One Sentence SummaryA novel regulatory domain on the voltage gated sodium channel NaV1.7 that can be targeted to produce analgesia.
The crosstalk between microbial sensors ELMO1 and NOD2 shape intestinal immune responses
Authors: Sharma Aditi , Achi Sajan Chandrangadhan , Ibeawuchi Stella-Rita , Anandachar Mahitha Shree , Gementera Hobie , Chaudhury Uddeep , Usmani Fatima , Vega Kevin , Sayed Ibrahim M , Das Soumita 
Published: July 2022

ABSTRACTMicrobial sensors play an essential role in maintaining cellular homeostasis. Our knowledge is limited on how microbial sensing helps in differential immune response and its link to inflammatory diseases. Recently, we have shown that cytosolic sensor ELMO1 (Engulfment and Cell Motility Protein-1) binds to effectors from pathogenic bacteria and controls intestinal inflammation. Here, we show that ELMO1 interacts with another sensor, NOD2 (Nucleotide-binding oligomerization domain-containing protein 2), that recognizes bacterial cell wall component muramyl dipeptide (MDP). The polymorphism of NOD2 is linked to Crohn’s disease (CD) pathogenesis. Interestingly, we found that overexpression of ELMO1 and mutant NOD2 (L1007fs) were not able to clear the CD-associated adherent invasive E. coli (AIEC-LF82). To understand the interplay of microbial sensing of ELMO1-NOD2 in epithelial cells and macrophages, we used enteroid-derived monolayers (EDMs) from ELMO1 and NOD2 KO mice and ELMO1 and NOD2-depleted murine macrophage cell lines. The infection of murine EDMs with AIEC-LF82 showed higher bacterial load in ELMO1-KO, NOD2 KO EDMs, and ELMO1 KO EDMs treated with NOD2 inhibitors. The murine macrophage cells showed that the downregulation of ELMO1 and NOD2 is associated with impaired bacterial clearance that is linked to reduced pro-inflammatory cytokines and reactive oxygen species. Our results indicated that the crosstalk between microbial sensors in enteric infection and inflammatory diseases impacts the fate of the bacterial load and disease pathogenesis.
Structure-Preserving Visualization for Single-cell RNA-Seq Profiles Using Deep Manifold Transformation with Batch-Correction
Authors: Xu Yongjie , Zang Zelin , Xia Jun , Tan Cheng , Geng Yulan , Li Stan Z. 
Published: July 2022

ABSTRACTDimensionality reduction and visualization play an important role in biological data analysis, such as data interpretation of single-cell RNA sequence (scRNA-seq). It is desired to have a visualization method that can not only be applicable to various application scenarios, including cell clustering and trajectory inference, but also satisfy a variety of technical requirements, especially the ability to preserve inherent structure of data and handle with batch effects. However, no existing methods can accommodate these requirements in a unified framework. In this paper, we propose a general visualization method, deep visualization (DV), that possesses the ability to preserve inherent structure of data and handle batch effects and is applicable to a variety of datasets from different application domains and dataset scales. The method embeds a given dataset into a 2- or 3-dimensional visualization space, with either a Euclidean or hyperbolic metric depending on a specified task type with typestatic(at a time point) ordynamic(at a sequence of time points) scRNA-seq data, respectively. Specifically, DV learns a structure graph to describe the relationships between data samples, transforms the data into visualization space while preserving the geometric structure of the data and correcting batch effects in an end-to-end manner. The experimental results on nine datasets in complex tissue from human patients or animal development demonstrate the competitiveness of DV in discovering complex cellular relations, uncovering temporal trajectories, and addressing complex batch factors. We also provide a preliminary attempt to pre-train a DV model for visualization of new incoming data.
End-to-End deep structure generative model for protein design
Authors: Lai Boqiao , McPartlon Matt , Xu Jinbo 
Published: July 2022

AbstractDesigning protein with desirable structure and functional properties is the pinnacle of computational protein design with unlimited potentials in the scientific community from therapeutic development to combating the global climate crisis. However, designing protein macromolecules at scale remains challenging due to hard-to-realize structures and low sequence design success rate. Recently, many generative models are proposed for protein design but they come with many limitations. Here, we present a VAE-based universal protein structure generative model that can model proteins in a large fold space and generate high-quality realistic 3-dimensional protein structures. We illustrate how our model can enable robust and efficient protein design pipelines with generated conformational decoys that bridge the gap in designing structure conforming sequences. Specifically, sequences generated from our design pipeline outperform native fixed backbone design in 856 out of the 1,016 tested targets(84.3%) through AF2 validation. We also demonstrate our model’s design capability and structural pre-training potential by structurally inpainting the complementarity-determining regions(CDRs) in a set of monoclonal antibodies and achieving superior performance compared to existing methods.
Parent co-Designed Drug Information for parents and Guardians Taking Neonates home (PADDINGToN) a mixed method approach to defining and evaluating information resources
Authors: Gill Andrea , Bracken Louise , Barker Catrin , Caldwell Neil , Cleary Brian , McCallion Naomi , Morris Stephen , Neary Elaine , Turner Mark , Peak Matthew , O’Brien Fiona 
Published: July 2022

AbstractBackgroundA study of premature babies, less than 32 weeks gestation, found that the median number of medicines per patient at discharge was 2.5 (range 2 to 7), with 28% of babies discharged on more than 3 medicines (1). Medication administration to infants can cause anxiety and concern for parents/carers who worry about making mistakes. A systematic review of carers for all ages has estimated the administration error rate at home to be between 2 and 33% (2) while a rate of 66.3% was recorded in medication administered to premature infants where parents were responsible for administration (3). It has also been reported that up to 90% of carers will administer a medicine incorrectly at some point (2).The aim of this study is to work with healthcare professionals (HCPs) and parents/carers to co-design resources aimed at improving medication safety and reducing parental anxiety for those giving medications to neonates at home.MethodsWork Package 1: Project management and co-ordination phase: preparation of protocols and survey material and ethics approval applications.Work Package 2: Stakeholder engagement phase, e-surveys and focus groups: An electronic-survey (e-survey) will be developed by a multi-disciplinary study management group (SMG).This will be circulated to HCPs involved in the care of neonates and parents/carers whose babies had recently been discharged from hospital. A small number of parents/carers will be invited to take part in focus groups.Work Package 3: Co-design of resources and quantitative evaluation: Parents/carers willing to co-design educational and information resources to support safe administration of medicines to neonates following discharge will be recruited. A quantitative evaluation of the effect of the resource will be conducted with a new group of caregivers to measure specific outcome(s).DiscussionThis study aims to co-develop, with healthcare professionals (HCPs) and parents/carers, resources aimed at improving medication safety and reducing parental anxiety for those giving medications to neonates at home. Co-development of resources with HCPs and parents, ensures that the project outcomes are relevant and useful, leading to a reduction in parental anxiety.Trial registrationISRCTN registry Ref 17332620
baseLess: lightweight detection of sequences in raw MinION data
Authors: Noordijk Ben , Nijland Reindert , Carrion Victor J. , Raaijmakers Jos M. , de Ridder Dick , de Lannoy Carlos 
Published: July 2022

AbstractWith its candybar form factor and low initial investment cost, the MinION brought affordable portable nucleic acid analysis within reach. However, translating the electrical signal it outputs into a sequence of bases still requires high-end computer hardware, which remains a caveat when aiming for deployment of many devices at once or usage in remote areas. For applications focusing on detection of a target sequence, such as infectious disease or GMO monitoring, the computational cost of analysis may be reduced by directly detecting the target sequence in the electrical signal instead. Here we present baseLess, a computational tool that enables such target-detection-only analysis. BaseLess makes use of an array of small neural networks, each of which efficiently detects a fixed-size subsequence of the target sequence directly from the electrical signal. We show that baseLess can accurately determine the identity of reads between three closely related fish species and can classify sequences in mixtures of twenty bacterial species, on an inexpensive single-board computer.AvailabilitybaseLess and all code used in data preparation and validation is available on Github at https://github.com/cvdelannoy/baseLess, under an MIT license. Used validation data and scripts can be found at https://doi.org/10.4121/20261392, under an MIT license.
Mitochondrial Derived Vesicles retain membrane potential and contain a functional ATP synthase
Authors: Hazan (Ben-Menachem) Reut , Lintzer Dvora , Ziv Tamar , Das Koyeli , Rosenhek-Goldian Irit , Porat Ziv , Ben Ami Pilo Hila , Karniely Sharon , Saada Ann , Regev-Rudzki Neta , Pines Ophry 
Published: July 2022

AbstractVesicular transport is a means of communication. While cells can communicate between each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, in particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here we show that functional mitochondria, isolated fromSaccharomyces cerevisiaerelease vesicles, independent of the fission machinery. We were then able for the first time to isolate these Mitochondrial Derived Vesicles (MDVs) and found that they are relatively uniform in size, of about 100nm and carry selective protein cargo including enrichment of ATP synthase subunits. Remarkably, we further found that these MDVs harbor a functional ATP synthase complex. Moreover, we demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP producing vesicles, which can potentially regenerate ATP deficient mitochondria and may participate in organelle to organelle communication.
Condensate functionalization with motors directs their nucleation in space and allows manipulating RNA localization
Authors: Cochard Audrey , Safieddine Adham , Combe Pauline , Benassy Marie-Noëlle , Weil Dominique , Gueroui Zoher 
Published: July 2022

ABSTRACTThe localization of RNAs in cells is critical for many cellular processes. Whereas motor-driven transport of RNP condensates plays a prominent role in RNA localization in cells, their studies remain limited by the scarcity of available tools allowing to manipulate condensates in a spatial manner. To fill this gap, we reconstitute in cellula a minimal RNP transport system based on bioengineered condensates which were functionalized with kinesins and dynein-like motors, allowing for their positioning at either the cell periphery or centrosomes. This targeting mostly occurs through the active transport of the condensate scaffolds, which leads to localized nucleation of phase-separated condensates. Then, programming the condensates to recruit specific mRNAs is able to shift the localization of these mRNAs towards the cell periphery or the centrosomes. Our method opens novel perspectives to examine the role of RNA localization as a driver of cellular functions.
Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats
Authors: Herbst Allen , Choi Solbie , Hoang Austin N. , Kim Chiye , Moreno Diana Martinez , McKenzie Debbie , Aiken Judd M. , Wanagat Jonathan 
Published: July 2022

AbstractRemdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir’s effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. For the 33-month-old control rats, the average mtDNA copy number per nucleus was 2567, 1100, and 1869 for heart, kidney, and quadriceps, respectively. MtDNA deletion mutation frequency was 2.6×10−4, 1.6×10−4 and 4.7×10−3for heart, kidney, and quadriceps, respectively. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.
Breast Cancer Reaction-Diffusion from Spectral-Spatial Analysis in Immunohistochemistry
Authors: Pasetto Stefano , Zahid Mohammad U. , Diaz Roberto , Montejo Michael , Rosa Marilin , Gatenby Robert , Enderling Heiko 
Published: July 2022

AbstractCancer is a prevalent disease, and while many significant advances have been made, the ability to accurately predict how an individual tumor will grow – and ultimately respond to therapy – remains limited. We use spatial-spectral analysis of 20 patients accrued to a phase II study of preoperative SABR with 9.5 x 3 Gy for early-stage breast cancer whose tissues were stained with multiplex immunofluorescence. We employ the reaction-diffusion framework to compare the data-deduced two-point correlation function and the corresponding spatial power spectral distribution with the theoretically predicted ones. A single histopathological slice suffices to characterize the reaction-diffusion equation dynamics through its power spectral density giving us an interpretative key in terms of infiltration and diffusion of cancer on a per-patient basis. This novel approach tackles model-parameter-inference problems for tumor infiltration and can immediately inform clinical treatments.
Carriage of three plasmids in a single human clinical isolate of Clostridioides difficile
Authors: Roseboom Anna M. , Ducarmon Quinten R. , Hornung B.V.H. , Harmanus C. , Crobach M.J.T. , Kuijper Ed J. , Vossen Rolf H.A.M. , Kloet Susan L. , Smits Wiep Klaas 
Published: July 2022

AbstractA subset of clinical isolates of Clostridioides difficile contains one or more plasmids and these plasmids can harbor virulence and antimicrobial resistance determinants. Despite their potential importance, C. difficile plasmids remain poorly characterized. Here, we describe a human clinical isolate that carries three plasmids from three different plasmid families that are therefore compatible. For two of these, we identify a region capable of sustaining plasmid replication in C. difficile. Together, our data advance our understanding of C. difficile plasmid biology.HighlightsThe complete circular genome sequence is provided for a C. difficile isolate harboring three plasmidsThese three plasmids (pJMR5-1, pJMR5-4 and pJRM5-W) are therefore compatible in a single strainSequence analysis suggest a modular nature of plasmid families to which the pJMR-plasmids belongA functional replicon was cloned from pJMR5-1 (pCD-ECE1 family) and pJMR5-W (pCD-WTSI1 family) and plasmids carrying this replicon are compatible with plasmid pCD630