bluuebunny/crossref_metadata_2025 huggingface dataset:
The Craniofacial Collaboration UK: Developmental Outcomes in 5-Year-Old Children With Metopic Synostosis
Authors: Edwards-Bailey Laura , Piggott Katie , Dalton Louise , Horton Jo , Parks Christopher , Wright Gillian , Kearney Anna
Published: November 2022

The Craniofacial Collaboration (CC-UK) was setup in 2015 as a joint initiative between the Psychology teams attached to the 4 highly specialized craniofacial centers in the United Kingdom. The CC-UK aims to address key limitations in the existing craniofacial literature by applying strict exclusion criteria and collating clinical data on a homogenous sample of children. This article reports the fourth wave of data collection from the CC-UK, with the analysis of developmental and behavioral outcomes for children with metopic synostosis at 5 years old. Previous data for sagittal synostosis at 3 and 5 years, and metopic synostosis at 3 years, have been presented. This paper offers the first analysis of developmental and behavioral parent-report measures at school age for metopic synostosis. All children in the current data set had primary corrective surgery. Findings highlight similar patterns to that of previous research among children with single-suture craniosynostosis, as well as earlier CC-UK analyses, with the majority falling within 1 standard deviation of the normative mean. However, differences across key behavioral and emotional domains, with some areas reporting heightened concerns compared with those detected among sagittal groups, may suggest that subtle differences between individual diagnostic groups are present. This further highlights the importance of utilizing homogenous samples within the field of craniofacial research. To further build upon this work, and to provide a greater understanding of how these difficulties and concerns may develop, or diminish, over time, further consideration to longitudinal outcomes is needed for individual diagnostic groups. Through this collaboration, the authors seek to achieve this goal in their future work.
Spatial Optimization to Improve COVID-19 Vaccine Allocation
Authors: Goodson Justin , Scroggins Stephen , Afroze Tasnova , Shacham Enbal
Published: November 2022

Early distribution of COVID-19 vaccines was largely driven by population size and did not account for COVID-19 prevalence nor location characteristics. In this study, we applied an optimization framework to identify distribution strategies that would have lowered COVID-19 related morbidity and mortality. Optimized vaccine allocation would have decreased case incidence by 8% with 5,926 fewer COVID-19 cases, 106 fewer deaths, and 4.5 million dollars in healthcare cost saved during the first half of 2021. As COVID-19 variants continue to be identified, and the likelihood of future pandemics remains high, application of resource optimization should be a priority for policy makers.
A qualitative evaluation of a multi-modal cancer prehabilitation programme for colorectal, head and neck and lung cancers patients
Authors: Bingham Sharon Linsey , Small Sarah , Semple Cherith
Published: November 2022

Background Growing evidence indicates patients’ survivorship outcomes can be enhanced through active engagement in a  multi-modal cancer prehabilitation programme (MCPP), although this intervention is not uniformly embedded as a standard of care.  MCPP aims to optimise patients physiologically and psychologically for cancer treatments, shorten recovery time, reduce complications, promote healthier lifestyles and improve quality of life.  South Eastern Health and Social Care Trust (SET) developed and evaluated a  system-wide collaborative approach  to MMCP across three tumour groups (colorectal, lung, head and neck cancer).  Addressing the lack of qualitative evaluation of MCPPs, this paper explores mechanisms promoting feasibility and acceptability of MCPP from patients’ and interdisciplinary professionals’ perspectives. Methods Semi-structured virtual one-to-one interviews were conducted with 24 interdisciplinary professionals and nine patients.  Transcripts were recorded, transcribed verbatim and themes developed using Framework Analysis.   Results Analysis of findings identified four themes providing an in-depth understanding of key elements required to develop and deliver a MCPP:   1) Planning: Building the team, 2) Shared vision to develop and tailor the MCPP to meet patient needs, 3) Delivering the MCPP and 4) Moving forward - improving the MCPP. Conclusion The system-wide collaborative approach to developing a MCPP at SET was deemed both feasible and acceptable.  Success was attributed to visionary leadership, alongside a diverse group of interdisciplinary professionals being engaged, motivated and committed to improving patient outcomes.  Iterative, responsive troubleshooting during delivery facilitated successful implementation.  Greater adherence to provision of prescriptive high intensity exercise within the programme may further promote enhanced patient outcomes.
Fine-scale variability in coral bleaching and mortality during a marine heatwave
Authors: Yadav Shreya , Roach Ty NF , McWilliam Michael J , Caruso Carlo , de Souza Mariana Rocha , Foley Catherine , Allen Corinne , Dilworth Jenna , Huckeba Joel , Santoro Erika P , Wold Renee , Simpson Jacqueline , Miller Spencer , Hancock Joshua R , Drury Crawford , Madin Joshua S
Published: November 2022

Coral bleaching and mortality can show significant spatial and taxonomic heterogeneity at local scales, highlighting the need to understand the fine-scale drivers and impacts of thermal stress. In this study, we used structure-from-motion photogrammetry to track coral bleaching, mortality, and changes in community composition during the 2019 marine heatwave in Kāne‘ohe Bay, Hawai‘i. We surveyed 30 shallow reef patches every 3 weeks for the duration of the bleaching event (August-December) and one year after, resulting in a total of 210 large-area, high-resolution photomosaics that enabled us to follow the fate of thousands of coral colonies through time. We also measured environmental variables such as temperature, sedimentation, depth, and wave velocity at each of these sites, and extracted estimates of habitat complexity (rugosity R and fractal dimension D) from digital elevation models to better understand their effects on patterns of bleaching and mortality. We found that up to 80% of corals experienced moderate to severe bleaching in this period, with peak bleaching occurring in October when heat stress (DHW) reached its maximum. Mortality continued to accumulate as bleaching levels dropped, driving large declines in more heat-susceptible species (77% loss ofPocilloporacover) and moderate declines in heat-tolerant species (19% and 23% forPorites compressaandMontipora capitata, respectively). Declines in live coral were accompanied by a rapid increase in algal cover across the survey sites. Spatial differences in bleaching were significantly linked to habitat complexity and coral species composition, with reefs that were dominated byPocilloporaexperiencing the most severe bleaching. Mortality was also influenced by species composition, fractal dimension, and site-level differences in thermal stress. Our results show that spatial heterogeneity in the impacts of bleaching are driven by a mix of environmental variation, habitat complexity, and differences in assemblage composition.
TreeTerminus - Creating transcript trees using inferential replicate counts
Authors: Singh Noor Pratap , Love Michael I. , Patro Rob
Published: November 2022

The accuracy and robustness of many types of analyses performed using RNA-seq data are directly impacted by the quality of the transcript and gene abundance estimates inferred from this data. However, a certain degree of uncertainty is always associated with the transcript abundance estimates. This uncertainty may make many downstream analyses, such as differential testing, difficult for certain transcripts. Conversely, gene-level analysis, though less ambiguous, is often too coarse-grained. To circumvent this problem, methods have proposed grouping transcripts together into distinct inferential units that should be used as a base unit for analysis. However, these methods don’t take downstream analysis into account.

We introduceTreeTerminus, a data-driven approach for grouping transcripts into a tree structure where leaves represent individual transcripts and internal nodes represent an aggregation of a transcript set.TreeTerminusconstructs trees such that, on average, the inferential uncertainty decreases as we ascend the tree topology. The tree provides the flexibility to analyze data at nodes that are at different levels of resolution in the tree and can be tuned depending on the analysis of interest. To obtain fixed groups for the downstream analysis, we provide a dynamic programming (DP) approach that can be used to find a cut through the tree that optimizes one of several different objectives.

We evaluatedTreeTerminuson two simulated and two experimental datasets, and observed an improved performance compared to transcripts (leaves) and other methods under several different metrics.
Memory for a day: Olfactory place episodic-like memory for dung droppings by the domestic horse (Equus ferus caballus)
Authors: Guyonnet Audrey EM , Whishaw Ian Q
Published: November 2022

The domestic horse (Equus ferus caballus) makes dung deposits to form “stud-piles” and investigates dung droppings more generally, suggesting that dung contains species-relevant communicative information. This natural behavior provides a behavior with which to examine a species-typical form of memory used by horses in relation to their social behavior. Horses were video recorded in indoor and outdoor riding arenas as they were lightly taken on a lead line to experimenter-determined objects or dung-piles. Frame-by-frame video analysis was used to measure sniffing duration and spatial memory of dung dropping visitations. Horses readily approached and sniffed dung for longer durations than they sniffed other objects. They always approached dung at new locations, made head movements across the extent of dung-piles as they sniffed, showed no preference in the nostril directed to the target, and might blink during sniffing and always blinked when disengaging from sniffing. Horses did remember dung visited withing a day by reducing visits and sniff duration but displayed little retention between days. The results are discussed in relation to the idea that this form of episodic-like memory is time limited because it competes with safety-related behavior related to horse movement within foraging areas.
When should coevolution among competitors promote coexistence versus exclusion?
Authors: Nell Lucas A. , Phillips Joseph S. , Ives Anthony R.
Published: November 2022

Coevolution of competitors can lead to niche partitioning promoting coexistence or to heightened conflicts promoting competitive exclusion. If both are possible, when should coevolution favor coexistence versus exclusion? We investigated this question with a general eco-evolutionary model in which species can reduce the interspecific competition they experience through evolutionary investments in two types of competitive traits: partitioning traits that promote coexistence and conflict traits that promote exclusion. We found that communities were generally mixed, consisting of species investing in both trait types or mixtures of species specializing in one type. For each species, its competitors’ abundances and investments determined its experienced competition, and stronger competition begot greater competitive trait investment. Species investing in conflict traits strengthened competition for other species both directly and indirectly, whereas partitioning traits only weakened competition via direct effects. Conflict traits were therefore the stronger driver of community-wide investments in all traits. However, species investing most in conflict traits experienced less competition, so they ultimately evolved least investment, making them most likely to be excluded by the next invader. Thus, coevolution may provide an open door for species that play nice and a revolving door of exclusion for those that do not.
Is exposure to chemical pollutants associated with sleep outcomes? A systematic review
Authors: Wallace Danielle A. , Gallagher Jayden Pace , Peterson Shenita R. , Ndiaye-Gueye Seyni , Fox Kathleen , Redline Susan , Johnson Dayna A.
Published: November 2022

Background

Sleep disruption is a public health concern and environmental exposures that influence the biological processes underpinning sleep may contribute to impaired sleep health. However, the contributions of environmental chemical pollutants to sleep health have not been systematically investigated.

Objectives

This systematic literature review sought to identify, evaluate, summarize, and synthesize the existing evidence between environmental chemical pollutant exposure and dimensions of sleep health in humans. We sought to evaluate potential mechanisms underlying exposure-outcome relationships and recommend areas for future research.

Methods

Databases were searched for peer-reviewed published research on chemical environmental pollutants and sleep health and disorders with no date restriction up to the last search date of April 2021 (registered protocol PROSPERO # CRD42021256918), resulting in 9,918 records. Two reviewers independently screened identified records against inclusion and exclusion criteria, extracted study information, and performed risk of bias assessments.

Results

We identified 204 studies of exposure to air pollution, exposures related to the Gulf War and other conflicts, endocrine disruptors, metals, pesticides, and solvents with dimensions of sleep health (architecture, duration, quality, timing) and sleep disorders (sleeping pill use, insomnia, sleep-disordered breathing) for inclusion in this review. Metals were the most frequently evaluated pollutants, while sleep maintenance/insomnia and quality were the most reported sleep outcomes. Synthesis of the evidence suggests mechanisms related to cholinergic signaling, neurotransmission, and inflammation as the most shared pathways.

Discussion

Evidence indicates that exposure to particulate matter, secondhand smoke, dioxins and dioxin- like compounds, lead, mercury, pesticides, solvents, and exposures related to the Gulf War are associated with worse sleep health and disorders. Chemical pollutants are likely key environmental determinants of sleep health and disorders; thus, there is a need to improve measurement of pollutants and sleep, study rigor, and determine the populations most vulnerable to the effects of exposure.
Identification of an early hippocampal recognition system using intracerebral evoked potentials in humans
Authors: López-Madrona Víctor J. , Trébuchon Agnès , Mindruta Ioana , Barbeau Emmanuel J. , Barborica Andrei , Pistol Costi , Oane Irina , Alario F. Xavier , Bénar Christian G.
Published: November 2022

The role of the hippocampal formation in memory recognition has been well studied in animals, with different pathways and structures linked to specific memory processes. In contrast, the hippocampus is commonly analyzed as a unique responsive area in most electrophysiological studies in humans, and the specific activity of its subfields remains unexplored. We combined intracerebral electroencephalogram recordings from epileptic patients with independent component analysis (ICA) during a memory recognition task involving the recognition of old and new images to disentangle the activities of multiple neuronal sources within the hippocampus. We identified two sources with different responses emerging from the hippocampus: a fast one (maximum at ∼250 ms) that could not be directly identified from raw recordings, and a later one, peaking at ∼400 ms. The earliest component was found in 12 out of 15 electrodes, with different amplitudes for old and new items in half of the electrodes. The latter component, identified in 13 out of 15 electrodes, had different delays for each condition, with a faster activation (∼290 ms after stimulus onset) for recognized items. We hypothesize that both sources represent two steps of hippocampal memory recognition, the faster reflecting the input from other structures and the latter the hippocampal internal processing. Recognized images evoking early activations would facilitate neural computation in the hippocampus, accelerating memory retrieval of complementary information. Overall, our results suggest that hippocampal activity is composed by several sources, including an early system for memory recognition, that can be disentangled with ICA methods.

SIGNIFICANCE STATEMENT

In the human memory circuit, the hippocampus is considered as a relatively late structure, associated to the retrieval of elaborated memories. In most electrophysiological studies, it is analyzed as a unique responsive area, and the specific activity of its subfields remains unexplored. In this work, we combined intracerebral recordings with independent component analysis to separate the electrophysiological activity from two different substructures of the hippocampus. We analyzed the responses of both sources in a memory task involving the recognition of old and new images. Our results revealed new hippocampal dynamics associated to different subfields, with memory recognition occurring much faster than previously reported. Importantly, we confirmed the potential of independent component analysis, which can be extended to other brain areas.
Imaging the Neural Substrate of Trigeminal Neuralgia Pain Using Deep Learning
Authors: Liang Yun , Zhao Qing , Hu Zhenhong , Bo Ke , Meyyappan Sreenivasan , Neubert John K. , Ding Mingzhou
Published: November 2022

Trigeminal neuralgia (TN) is a severe and disabling facial pain condition and is characterized by intermittent, severe, electric shock-like pain in one (or more) trigeminal subdivisions. This pain can be triggered by an innocuous stimulus or can be spontaneous. Presently available therapies for TN include both surgical and pharmacological management; however, the lack of a known etiology for TN contributes to the unpredictable response to treatment and the variability in long-term clinical outcomes. Given this, a range of peripheral and central mechanisms underlying TN pain remain to be understood. We acquired functional magnetic resonance imaging (fMRI) data from TN patients who (1) rested comfortably in the scanner during a resting state session and (2) rated their pain levels in real time using a calibrated tracking ball-controlled scale in a pain tracking session. Following data acquisition, the data was analyzed using the conventional correlation analysis and two artificial intelligence (AI)-inspired deep learning methods: convolutional neural network (CNN) and graph convolutional neural network (GCNN). Each of the three methods yielded a set of brain regions related to the generation and perception of pain in TN. There were six regions that were identified by all three methods, including the superior temporal cortex, the insula, the fusiform, the precentral gyrus, the superior frontal gyrus, and the supramarginal gyrus. Additionally, 17 regions, including dorsal anterior cingulate cortex(dACC) and the thalamus, were identified by at least two of the three methods. Collectively, these 23 regions represent signature centers of TN pain and provide target areas for future studies relating to central mechanisms of TN.
Single-cell multi-omics decodes regulatory programs during development of mouse secondary palate
Authors: Yan Fangfang , Suzuki Akiko , Iwaya Chihiro , Pei Guangsheng , Chen Xian , Yoshioka Hiroki , Yu Meifang , Simon Lukas M. , Iwata Junichi , Zhao Zhongming
Published: November 2022

The abnormal perturbation in gene regulation during palatogenesis may lead to cleft palate, a major congenital birth defect in humans and mice. However, a comprehensive multi-omic map of the developing secondary palate at single-cell resolution is lacking. In this study, we performed single-cell multiome sequencing and profiled chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. Application of optimal transport reconstructed five trajectories, representing continuous differentiation of multipotent cells into different subpopulations in later stages. By linking open chromatin signals to gene expression changes, we discovered a list of lineage-determining transcription factors, such as Shox2 for the anterior and Dlx1/2 for the posterior palatal mesenchymal trajectories. In conclusion, this study charted epigenetic and transcriptional dynamics during palatogenesis, which provides a valuable resource for the community and facilitate future research in cleft palate.

Highlights

The first report on building a single-cell multi-omics atlas with joint chromatin accessibility and gene expression measurements from the same cells during the development of mouse secondary palate.

Application of optimal transport calculated fate probabilities to different terminal states and recovered continuous landscapes during mouse secondary palate development.

By linkingcis-regulatory DNA elements to target genes, we characterized a series of transcription factors governing the differentiation of cranial neural crest-derived multipotent cells to the anterior and posterior palatal mesenchymal trajectories, respectively.

Transcription factors Shox2 and Dlx1/2 exhibited top regulatory roles for the anterior and posterior palatal mesenchymal trajectories, respectively, showing significant enrichment in both motif accessibility and gene expression.
Multisensory integration (MSI) by polymodal sensory neurons dictates larval settlement in a brainless cnidarian larva
Authors: Birch Sydney , Plachetzki David
Published: November 2022

Multisensory integration (MSI) combines information from more than one sensory modality to elicit behaviors distinct from unisensory behaviors. MSI is best understood in animals with complex brains and specialized centers for parsing sensory information, but the dispersive larvae of sessile marine invertebrates utilize multimodal environmental sensory stimuli to base irreversible settlement decisions on, and most lack complex brains. Here, we examined the sensory determinants of settlement in actinula larvae of the hydrozoanEctopleura crocea(Cnidaria), which possess a diffuse nerve net. A factorial settlement study revealed that photo-, chemo-, and mechano-sensory cues each influence the settlement response, which was complex and dependent on specific combinations of cues, therefore indicating MSI. Mechanosensory cues either inhibited or enhanced settlement rates depending on the presence or absence of chemical and light cues in the environment. Sensory gene expression over development peaked with developmental competence to settle, which in actinulae, requires cnidocyte discharge. Transcriptome analyses also highlighted several deep homological links between cnidarian and bilaterian mechano- chemo- and photo-sensory pathways. Fluorescentin situhybridization studies of candidate transcripts suggested cellular partitioning of sensory function among the few cell types that comprise the actinula nervous system, where ubiquitous polymodal sensory neurons with putative chemo- and photo-sensitivity interface with mechanoreceptive cnidocytes. We propose that a simple multisensory processing circuit, involving polymodal chemo/photosensory neurons and mechanoreceptive cnidocytes, is sufficient to explain MSI in actinulae settlement. Our study demonstrates that MSI is not exclusive to complex brains, but likely predated and contextualized their evolution.
Sashimi.py: a flexible toolkit for combinatorial analysis of genomic data
Authors: Zhang Yiming , Zhou Ran , Wang Yuan
Published: November 2022

Simultaneously visualizing how isoform expression, protein–DNA/RNA interactions, accessibility, and architecture of chromatin differs across condition and cell types could inform our understanding on regulatory mechanisms and functional consequences of alternative splicing. However, the existing versions of tools generating sashimi plots remain inflexible, complicated, and user-unfriendly for integrating data sources from multiple bioinformatic formats or various genomics assays. Thus, a more scalable visualization tool is necessary to broaden the scope of sashimi plots. Here, we introduce sashimi.py, a Python package for generating publication-quality visualization by a programmable and interactive web-based approach. Sashimi.py is a platform to visually interpret genomic data from a large variety of data sources including single-cell RNA-seq, protein–DNA/RNA interactions, long-reads sequencing data, and Hi-C data without any preprocessing, and also offers a broad degree of flexibility for formats of output files that satisfy the requirements of major journals. The Sashimi.py package is an open-source software which is freely available on Bioconda (https://anaconda.org/bioconda/sashimi-py), Docker, PyPI (https://pypi.org/project/sashimi.py/) and GitHub (https://github.com/ygidtu/sashimi.py), and a built-in web server for local deployment is also provided.
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

The 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

Background

The 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.

Methods

We 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.

Results

The 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

Cytotoxic 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

Cell-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.
Gene expression signatures predict circadian rhythms in oncogenic pathways
Authors: Winkler Eleonora , Ananthasubramaniam Bharath , Herzel Hanspeter
Published: November 2022

Day-night environmental cycles together with our own adaptive rhythms in behavior and physiology lead to rhythmicity of various processes on the cellular level, including cell signaling. Despite many implications of such daily changes in signaling, the quantification of such rhythms and estimates of peak phases of pathway activities in various tissues are missing. Governed mainly by posttranslational modifications, a pathway activity might not be well quantified via the expression level of pathway components. Instead, a gene expression signatures approach can be used to score activity of various pathways. Here, we apply such gene expression signatures on circadian time series transcriptomics data to infer rhythmicity in cellular signaling. We show that, across multiple datasets, the gene expression signatures predict the presence of rhythmicity in EGFR, PI3K and p53 pathways in mouse liver. With the focus on EGFR pathway, we pinpoint the most influential signature genes for the overall rhythmicity in the activity scores for this pathway. These findings suggest that time of the day is an important factor to consider in studies on signaling. Simultaneously, this study provides a new paradigm to use circadian transcriptomics to get at temporal dynamics of pathway activation.
Mutation-induced infections of phage-plasmids
Authors: Shan Xiaoyu , Szabo Rachel E. , Cordero Otto X.
Published: November 2022

Phage-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

Certain 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 statement

Certain 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

Pervasive 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.
Infant low-frequency EEG cortical power, cortical tracking and phase-amplitude coupling predicts language a year later.
Authors: Attaheri Adam , Ní Choisdealbha Áine , Rocha Sinead , Brusini Perrine , Di Liberto Giovanni M. , Mead Natasha , Olawole-Scott Helen , Boutris Panagiotis , Gibbon Samuel , Williams Isabel , Grey Christina , Alfaro e Oliveira Maria , Brough Carmel , Flanagan Shelia , Goswami Usha
Published: November 2022

Cortical signals have been shown to track acoustic and linguistic properties of continuous speech. This phenomenon has been measured in both children and adults, reflecting speech understanding by adults as well as cognitive functions such as attention and prediction. Furthermore, atypical low-frequency cortical tracking of speech is found in children with phonological difficulties (developmental dyslexia). Accordingly, low-frequency cortical signals may play a critical role in language acquisition. A recent investigation with infants Attaheri et al., 2022 (1) probed cortical tracking mechanisms at the ages of 4, 7 and 11 months as participants listened to sung speech. Results from temporal response function (TRF), phase-amplitude coupling (PAC) and dynamic theta-delta power (PSD) analyses indicated speech envelope tracking and stimulus-related power (PSD) for delta and theta neural signals. Furthermore, delta- and theta-driven PAC was found at all ages, with theta phases displaying stronger PAC with high-frequency amplitudes than delta. The present study tests whether these previous findings replicate in the second half of the full cohort of infants (N = 122) who were participating in this longitudinal study (first half: N=61, (1); second half: N=61). In addition to demonstrating good replication, we investigate whether cortical tracking in the first year of life predicts later language acquisition for the full cohort (122 infants recruited, 113 retained) using both infant-led and parent-estimated measures and multivariate and univariate analyses. Increased delta cortical tracking in the univariate analyses, increased ~2Hz PSD power and stronger theta-gamma PAC in both multivariate and univariate analyses were related to better language outcomes using both infant-led and parent-estimated measures. By contrast, increased ~4Hz PSD power in the multi-variate analyses, increased delta-beta PAC and a higher theta/delta power ratio in the multi-variate analyses were related to worse language outcomes. The data are interpreted within a "Temporal Sampling" framework for developmental language trajectories.
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

Transitions 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

Genetic 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

Objectives

To identify existing DNA methylation-based prognostic biomarkers and prediction models for colorectal cancer (CRC) prognosis and to validate them in a large external cohort.

Design

Systematic review and external validation study.

Data source

Systematic 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 measures

Overall survival (OS) in CRC patients.

Results

We 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.

Conclusions

Only 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 box

What is already known on this topic

Several 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 validation

Many CpG sites associated with CRC prognosis and prognostic models based on these CpGs have been proposed

An independent study to validate these biomarkers and prediction models is essential for assessing their utility in clinical practice, but has not yet performed

What this study adds

This external validation study verified the prognostic relevance of a fraction of existing DNA methylation-based prognostic biomarkers for CRC

Published 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