bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning for histopathological subtyping and grading of lung adenocarcinoma
Authors: Lami Kris , Ota Noriaki , Yamaoka Shinsuke , Bychkov Andrey , Matsumoto Keitaro , Uegami Wataru , Attanoos Richard , Berezowska Sabina , Brcic Luka , Cavazza Alberto , English John C. , Fabro Alexandre Todorovic , Ishida Kaori , Kashima Yukio , Kitamura Yuka , Larsen Brandon T. , Marchevsky Alberto M. , Miyazaki Takuro , Morimoto Shimpei , Ozasa Mutsumi , Roden Anja C. , Schneider Frank , Smith Maxwell L. , Tabata Kazuhiro , Takano Angela M. , Tanaka Tomonori , Tsuchiya Tomoshi , Nagayasu Takeshi , Sakanashi Hidenori , Fukuoka Junya 
Published: November 2022

ABSTRACTThe histopathological distinction of lung adenocarcinoma (LADC) subtypes is subject to high inter-observer variability, which can compromise the optimal assessment of the patient prognosis. Therefore, this study developed convolutional neural networks (CNNs) capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the LADC tumour grades established recently by the International Association for the Study of Lung Cancer pathology committee. Consensus LADC ground truth histopathological images were obtained from seventeen expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained with EfficientNet b3 architecture to predict eight different LADC classes (lepidic, acinar, papillary, micropapillary, solid, invasive mucinous adenocarcinoma, other carcinoma types, and no carcinoma cells). Furthermore, the trained models were tested on an independent cohort of 133 patients. The models achieved high precision, recall, and F1-scores exceeding 0.90 for most of the LADC classes. Clear stratification of the three LADC grades was reached in predicting the disease-specific survival by the two models. Moreover, the grading prediction of one of the trained models was more accurate than those of 14 out of 15 pulmonary pathologists involved in the study (p=0.0003). Both trained models showed high stability in the segmentation of each pair of predicted grades with low variation in the hazard ratio across 200 bootstrapped samples. These findings indicate that the trained CNNs improve the diagnostic accuracy of the pathologist, standardise LADC subtype recognition, and refine LADC grade assessment. Thus, the trained models are promising tools that may assist in the routine evaluation of LADC subtypes and grades in clinical practice.
Modeling the directed evolution of broad host range phages
Authors: Bull James J. , Wichman Holly A. , Krone Stephen M. 
Published: November 2022

AbstractBackgroundThe host ranges of individual phages tend to be narrow, yet many applications of phages would benefit from expanded host ranges. Empirical methods have been developed to direct the evolution of phages to attack new strains, but the methods have not been evaluated or compared for their consequences. In particular, how do different methods favor generalist (broad host range) phages over specialist phages? All methods involve exposing phages to two or more novel bacterial strains, but the methods differ in the order in which those hosts are presented through time: Parallel presentation, Sequential presentation, and Mixed presentation.MethodsWe use a combination of simple analytical methods and numerical analyses to study the effect of these different protocols on the selection of generalist versus specialist phages.ResultsThe three presentation protocols have profoundly different consequences for the evolution of generalist versus specialist phages. Sequential presentation favors generalist almost to the exclusion of specialists, whereas Parallel presentation does the least so. However, other protocol attributes (e.g. the nature of dilution between transfers of phages to new cultures) also have effects on selection and phage maintenance. It is also noted that protocols can be designed to enhance recombination to augment evolution and to reduce stochastic loss of newly-arisen mutants.
Apoptotic contraction drives target cell release by cytotoxic T cells
Authors: Sanchez Elisa E. , Tello-Lafoz Maria , Guo Aixuan J. , de Jesus Miguel , Winer Benjamin Y. , Budhu Sadna , Chan Eric , Rosiek Eric , Kondo Taisuke , DuSold Justyn , Taylor Naomi , Altan-Bonnet Gregoire , Olson Michael F. , Huse Morgan 
Published: November 2022

ABSTRACTCytotoxic T lymphocytes (CTLs) use immune synapses to destroy infected or transformed target cells. Although the mechanisms governing synapse assembly have been studied extensively, little is known about how this interface dissociates, which is a critical step that both frees the CTL to search for additional prey and enables the phagocytosis of target corpses. Here, we applied time-lapse imaging to explore the basis for synapse dissolution and found that it occurred concomitantly with the cytoskeletal contraction of apoptotic targets. Genetic and pharmacological disruption of apoptotic contraction indicated that it was necessary for CTL dissociation. Furthermore, acute stimulation of contractile forces triggered the release of live targets, demonstrating that contraction is sufficient to drive the response. Finally, mechanically amplifying apoptotic contractility promoted faster CTL detachment and serial killing. Collectively, these results establish a biophysical basis for synapse dissolution and highlight the importance of mechanosensory feedback in the regulation of cell-cell interactions.
Unraveling the coordinated dynamics of protein- and metabolite-mediated cell-cell communication
Authors: Armingol Erick , Larsen Reid O. , Cequeira Martin , Baghdassarian Hratch , Lewis Nathan E. 
Published: November 2022

AbstractCell-cell communication involves multiple classes of molecules, diverse interacting cells, and complex spatiotemporal dynamics. While this communication can be inferred from single-cell RNA-seq, no computational methods can account for both protein and metabolite ligands simultaneously, while also accounting for the temporal dynamics. We adapted Tensor-cell2cell here to study several time points simultaneously and jointly incorporate both ligand types. Our approach detects temporal dynamics of cell-cell communication during brain development, allowing for the detection of the concerted use of key protein and metabolite ligands by pertinent interacting cells.
Mutation-induced infections of phage-plasmids
Authors: Shan Xiaoyu , Szabo Rachel E. , Cordero Otto X. 
Published: November 2022

AbstractPhage-plasmids are extra-chromosomal elements that act both as plasmids and as phages, whose eco-evolutionary dynamics remain poorly constrained. Here, we show segregational drift and loss- of-function mutations play key roles in the infection dynamics of a cosmopolitan phage-plasmid, allowing it to create continuous productive infections in a population of marineRoseobacter. Recurrent loss-of-function mutations in the phage repressor that controls prophage induction led to constitutively lytic phage-plasmids that spread rapidly throughout the population. The entire phage-plasmid genome was packaged into virions, which were horizontally transferred by re-infecting lysogenized cells, leading to an increase in phage-plasmid copy number and to a heterozygous phage repressor locus within re-infected cells. While wild-type repressor variants prevented induction of phage-plasmids in a cell, the uneven apportionment of phage-plasmids after cell division (i.e., segregational drift) led to the production of offspring carrying only the constitutively lytic phage-plasmid, thus restarting the lysis-reinfection-segregation life-cycle. Mathematical models and experiments showed that these dynamics lead to a continuous productive infection of the bacterial population in which lytic and lysogenic phage-plasmids coexist. An analysis of marine bacterial genomes shows that the same plasmid backbone here described carries different phages in the environment and disseminates trans-continentally, suggesting that the phage-plasmid strategy is relevant and widespread in nature. Together, our study describes how the interplay between phage infection and plasmid genetics provide a unique eco-evolutionary strategy for phage-plasmids.
Unraveling the Intricate Cargo-BBSome Coupling Mechanism at the Ciliary Tip
Authors: Liu Yan-Xia , Li Wen-Juan , Zhang Rui-Kai , Sun Sheng-Nan , Fan Zhen-Chuan 
Published: November 2022

AbstractCertain ciliary transmembrane and membrane-tethered signaling proteins migrate from the ciliary tip to base via retrograde intraflagellar transport (IFT), essential for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. During this process, the BBSome functions as an adaptor between retrograde IFT trains and these signaling protein cargoes. The Arf-like 13 (ARL13) small GTPase resembles ARL6/BBS3 in facilitating these signaling cargoes to couple with the BBSome at the ciliary tip prior to loading onto retrograde IFT trains for transporting towards the ciliary base, while the molecular basis for how this intricate coupling event happens remains elusive. Here, we report thatChlamydomonasARL13 only in a GTP-bound form (ARL13GTP) anchors to the membrane for diffusing into cilia. Upon entering cilia, ARL13 undergoes GTPase cycle for shuttling between the ciliary membrane (ARL13GTP) and matrix (ARL13GDP). To achieve this goal, the ciliary membrane-anchored BBS3GTPbinds and activates the ciliary matrix-residing ARL13GDPas an ARL13 guanine nucleotide exchange factor. At the ciliary tip, ARL13GTPbinds and recruits the ciliary matrix-residing and post-remodeled BBSome as an ARL13 effector to anchor to the ciliary membrane. This makes the BBSome spatiotemporally become available for the ciliary membrane-tethered phospholipase D (PLD) to couple with. Afterward, ARL13GTPhydrolyzes GTP for releasing the PLD-laden BBSome to load onto retrograde IFT trains. According to this model, hedgehog signaling defects associated withARL13bandBBS3mutations in humans could be satisfactorily explained, providing us a mechanistic understanding behind BBSome-cargo coupling required for proper ciliary signaling.Significance statementCertain signaling proteins export in a BBSome-dependent manner from cilia via retrograde IFT. As IFT cargoes, their coupling with the BBSome is mediated by ARL13 and BBS3. Here, we report that ARL13 in a GTP-bound state binds the membrane for diffusing into cilia followed by running GTPase cycle with BBS3 acting as an ARL13-specific guanine nucleotide exchange factor. ARL13GTPrecruits the IFT-shed BBSome as its effector to anchor to the membrane of the ciliary tip, making it spatiotemporally available for the ciliary membrane-tethered PLD to bind. Afterward, ARL13 GTP hydrolysis releases the PLD-laden BBSome for retrograde IFT train loading. ARL13 and BBS3 facilitate the cargo-BBSome coupling in such a way providing a regulatory mechanism for signaling protein export from cilia.
Transcription is ubiquitously terminated in thousands of bidirectional termination zones in yeast
Authors: Zhen Gang , Kwon Buki 
Published: November 2022

AbstractPervasive transcription of eukaryotic genomes requires intricate mechanisms to delineate boundaries for each transcriptional unit. How transcription is efficiently terminated before invading neighboring genes remains an open question. Here, after dissecting the cleavage and polyadenylation landscape using a hybrid approach, we observed thousands of bidirectional termination zones in the genome ofSaccharomyces cerevisiae. These zones are ∼120 bp wide and terminate transcription from both sense and antisense strands in yeast. They are ubiquitously used as termination sites for both coding and non-coding genes. We suggest that the known transcription termination efficiency element, UAUAUA motifs, serves as the central elements in these zones. Notably, bidirectional termination zones are specifically nucleosome depleted, suggesting chromatin structure plays a key role in the formation of bidirectional termination zones in yeast. Finally, we provide evidence for transcriptional interference in these bidirectional termination zones, and expression level of each cleavage site is influenced by sequence contexts both upstream and downstream. We provide the first global fine-scale picture of transcription termination in a eukaryotic genome.
Genetic and phenotypic consequences of local transitions between sexual and parthenogenetic reproduction in the wild
Authors: Miller Soleille Morelli , Stuart Katarina C , Burke Nathan William , Rollins Lee Ann , Bonduriansky Russell 
Published: November 2022

AbstractTransitions from sexual to asexual reproduction have occurred in numerous lineages across the tree of life, but it remains unclear why asexual populations rarely persist. In facultatively parthenogenetic animals, all-female populations can arise when males are absent or become extinct, and such populations can give rise to obligately asexual species. Facultative parthenogens could therefore shed light on the initial stages of transitions to asexuality, and the factors that determine the success or failure of asexual populations. Here, we describe a novel spatial mosaic of mixed-sex and all-female populations of the facultatively parthenogenetic Australian phasmidMegacrania batesii, and use this system to investigate the consequences of reproductive mode variation in the wild. Analysis of single nucleotide polymorphisms (SNPs) indicated multiple, independent transitions between reproductive modes. As expected, all-female populations had drastically reduced heterozygosity and genetic diversity relative to mixed-sex populations. However, we found few consistent differences in fitness-related traits between population types. All-female populations exhibited more frequent and severe (non-functional) wing deformities, but did not show higher rates of appendage loss. All-female populations also harbored more parasites, but only in certain habitats. Reproductive mode explained little variation in female body size, fecundity, or egg hatch-rate. Our results confirm that transitions to parthenogenetic reproduction can lead to dramatic reductions in genetic diversity and heterozygosity. However, our findings also suggest that asexualM. batesiipopulations consist of high-fitness genotypes that might be able to thrive for many generations, perhaps until they encounter a drastic environmental change to which they are unable to adapt.
CauloKO: an ordered transposon mutant library inCaulobacter crescentus
Authors: Moore Gabriel M. , Ramos Justin G. , Bratton Benjamin P. , Gitai Zemer 
Published: November 2022

AbstractGenetic screens are powerful approaches to unveiling new biological insight and ordered redundant transposon libraries have emerged as a primary tool for performing screens of known genetic saturation. Newer sequencing methods based on combinatorial pooling have lowered the cost and time required to generate these libraries.Caulobacter crescentusis a gramnegative bacterium that has served as a model for understanding bacterial physiology with a myriad of genetic tools. To add to this collection of tools, we created CauloKO - the first ordered, transposon library inC. crescentus. CauloKO includes insertion mutants in 86% of all non-essential genes and 77% of all open reading frames of strain CB15. CauloKO insertion mutants were validated using Sanger sequencing. We also present phenotypic analysis of the CauloKO library using a crystal violet screen for biofilm mutants, which both confirmed previous results and identified new mutants for future studies. This combined approach revealed that the CauloKO library shows promise for screening applications, particularly for phenotypes that require monoclonal populations of cells.
DNA methylation-based biomarkers and prediction models for the survival of patients with colorectal cancer: systematic review and external validation study
Authors: Yuan Tanwei , Edelmann Dominic , Kather Jakob N. , Fan Ziwen , Tagscherer Katrin E. , Roth Wilfried , Bewerunge-Hudler Melanie , Brobeil Alexander , Kloor Matthias , Bläker Hendrik , Burwinkel Barbara , Brenner Hermann , Hoffmeister Michael 
Published: November 2022

ABSTRACTObjectivesTo identify existing DNA methylation-based prognostic biomarkers and prediction models for colorectal cancer (CRC) prognosis and to validate them in a large external cohort.DesignSystematic review and external validation study.Data sourceSystematic search in PubMed and Web of Science until October 2022 to identify epigenome-wide studies reporting methylation at CpG sites (CpGs) associated with survival among CRC patients. Validation data were drawn from the 2310 CRC patients of the DACHS study recruited from 22 hospitals in the Rhine-Neckar region in the southwest of Germany.Main outcome measuresOverall survival (OS) in CRC patients.ResultsWe identified 200 unique CpGs and 10 CpG-based prognostic models derived from 15 studies. In the external validation analysis, 1252 of 2310 patients died during follow-up (median 10.4 years). Thirty-nine CpGs (20%) and five prognostic models (50%) were independently associated with overall survival after adjustment for clinical variables. The five models had unsatisfactory discrimination ability, with area under the receiver operating characteristic curves at five years ranging from 0.54 to 0.60. The calibration accuracy of the five models using recalibrated baseline survival was also poor, and no relevant added prognostic value to traditional clinical variables was observed. Based on the Prediction Model Risk of Bias Assessment Tool, all models were rated as high risk of bias.ConclusionsOnly 20% of published CpGs associated with survival in CRC patients could be externally validated. So far derived published CpG-based prognostic models for CRC do not seem to be useful for clinical practice.Summary boxWhat is already known on this topicSeveral studies have suggested that DNA methylation biomarkers could have the potential to improve prognostic accuracy for patients with colorectal cancer (CRC), but these studies mostly did not include large-scale external validationMany CpG sites associated with CRC prognosis and prognostic models based on these CpGs have been proposedAn independent study to validate these biomarkers and prediction models is essential for assessing their utility in clinical practice, but has not yet performedWhat this study addsThis external validation study verified the prognostic relevance of a fraction of existing DNA methylation-based prognostic biomarkers for CRCPublished CpG-based prognostic models all performed poorly in our external validation and were rated as at high risk of bias, so they do not seem to be useful for clinical practice
Comparing 3D, 2.5D, and 2D Approaches to Brain Image Segmentation
Authors: Avesta Arman , Hossain Sajid , Lin MingDe , Aboian Mariam , Krumholz Harlan M. , Aneja Sanjay 
Published: November 2022

AbstractDeep-learning methods for auto-segmenting brain images either segment one slice of the image (2D), five consecutive slices of the image (2.5D), or an entire volume of the image (3D). Whether one approach is superior for auto-segmenting brain images is not known.We compared these three approaches (3D, 2.5D, and 2D) across three auto-segmentation models (capsule networks, UNets, and nnUNets) to segment brain structures. We used 3430 brain MRIs, acquired in a multi-institutional study, to train and test our models. We used the following performance metrics: segmentation accuracy, performance with limited training data, required computational memory, and computational speed during training and deployment.3D, 2.5D, and 2D approaches respectively gave the highest to lowest Dice scores across all models. 3D models maintained higher Dice scores when the training set size was decreased from 3199 MRIs down to 60 MRIs. 3D models converged 20% to 40% faster during training and were 30% to 50% faster during deployment. However, 3D models require 20 times more computational memory compared to 2.5D or 2D models.This study showed that 3D models are more accurate, maintain better performance with limited training data, and are faster to train and deploy. However, 3D models require more computational memory compared to 2.5D or 2D models.
A permissive role for dopamine in the production of vigorous movements
Authors: Liu Haixin , Melani Riccardo , Sankaramanchi Akhila , Zeng Ruoheng , Maltese Marta , Martin Jenna R. , Tritsch Nicolas X. 
Published: November 2022

AbstractDopamine is essential for the production of vigorous movements, but how dopamine modifies the gain of motor commands remains unclear. Here, we developed a dexterous motor task in which head-restrained mice self-initiate fast and large-amplitude lever pushes with their left forelimb to earn rewards. We show that this task is goal-directed and depends on cortico-striatal circuits in the hemisphere contralateral to the limb used to push the lever. We find that unilateral loss of midbrain dopamine neurons reduces the speed and amplitude of lever pushes, and that levodopa treatment rapidly restores motor vigor, consistent with parkinsonian bradykinesia. Photometry recordings of striatal dopamine levels indicate that the therapeutic efficacy of levodopa does not require phasic dopamine release. In dopamine-intact mice, optogenetic stimulation of midbrain dopamine neurons calibrated to mimic transients evoked by rewards is also insufficient to increase the speed and amplitude of forelimb movements. Together, our data show that phasic dopamine transients are unlikely to specify the vigor of forelimb movements online as they are being executed, and suggest instead that dopamine plays a permissive role in the selection and production of vigorous movements. Our findings have important implications for our understanding of how the basal ganglia contribute to motor control under physiological conditions and in Parkinson’s disease.
Contrast detection is enhanced by non-stochastic, high-frequency transcranial alternating current stimulation with triangle and sine waveform
Authors: Potok Weronika , van der Groen Onno , Sivachelvam Sahana , Bächinger Marc , Fröhlich Flavio , Kish Laszlo B. , Wenderoth Nicole 
Published: November 2022

AbstractStochastic Resonance (SR) describes a phenomenon where an additive noise (stochastic carrier-wave) enhances the signal transmission in a nonlinear system. In the nervous system, nonlinear properties are present from the level of single ion channels all the way to perception and appear to support the emergence of SR. For example, SR has been repeatedly demonstrated for visual detection tasks, also by adding noise directly to cortical areas via transcranial random noise stimulation (tRNS). We mathematically show that high-frequency, non-stochastic, periodic signals can yield resonance-like effects with linear transfer and infinite signal-to-noise ratio at the output. Here we tested this prediction empirically and investigated whether non-random, high-frequency, transcranial alternating current stimulation (hf-tACS) applied to visual cortex could induce resonance-like effects and enhance performance on a visual detection task. We demonstrated in 28 participants that applying 80 Hz triangular-waves or sine-waves with hf-tACS reduced visual contrast detection threshold for optimal brain stimulation intensities. The influence of hf-tACS on contrast sensitivity was equally effective to tRNS-induced modulation, demonstrating that both hf-tACS and tRNS can reduce contrast detection thresholds. Our findings suggest that a resonance-like mechanism can also emerge when non-stochastic electrical waveforms are applied via hf-tACS.New & NoteworthyOur findings extend our understanding of neuromodulation induced by noninvasive electrical stimulation. We provide first evidence showing acute online benefits of hf-tACStriangleand hf-tACSsinetargeting the primary visual cortex (V1) on visual contrast detection in accordance with the resonance-like phenomenon. The ‘non-stochastic’ hf-tACS and ‘stochastic’ hf-tRNS are equally effective in enhancing visual contrast detection.