bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Biologically Interpretable Multimodal Deep Learning Model for Cancer Prognosis Prediction
Authors: Azher Zarif L. , Vaickus Louis J. , Salas Lucas A. , Christensen Brock C. , Levy Joshua J. 
Published: November 2021

ABSTRACTRobust cancer prognostication can enable more effective patient care and management, which may potentially improve health outcomes. Deep learning has proven to be a powerful tool to extract meaningful information from cancer patient data. In recent years it has displayed promise in quantifying prognostication by predicting patient risk. However, most current deep learning-based cancer prognosis prediction methods use only a single data source and miss out on learning from potentially rich relationships across modalities. Existing multimodal approaches are challenging to interpret in a biological or medical context, limiting real-world clinical integration as a trustworthy prognostic decision aid. Here, we developed a multimodal modeling approach that can integrate information from the central modalities of gene expression, DNA methylation, and histopathological imaging with clinical information for cancer prognosis prediction. Our multimodal modeling approach combines pathway and gene-based sparsely coded layers with patch-based graph convolutional networks to facilitate biological interpretation of the model results. We present a preliminary analysis that compares the potential applicability of combining all modalities to uni- or bi-modal approaches. Leveraging data from four cancer subtypes from the Cancer Genome Atlas, results demonstrate the encouraging performance of our multimodal approach (C-index=0.660 without clinical features; C-index=0.665 with clinical features) across four cancer subtypes versus unimodal approaches and existing state-of-the-art approaches. This work brings insight to the development of interpretable multimodal methods of applying AI to biomedical data and can potentially serve as a foundation for clinical implementations of such software. We plan to follow up this preliminary analysis with an in-depth exploration of factors to improve multimodal modeling approaches on an in-house dataset.
Explaining heterogeneity in medial entorhinal cortex with task-driven neural networks
Authors: Nayebi Aran , Attinger Alexander , Campbell Malcolm G. , Hardcastle Kiah , Low Isabel I.C. , Mallory Caitlin S. , Mel Gabriel C. , Sorscher Ben , Williams Alex H. , Ganguli Surya , Giocomo Lisa M. , Yamins Daniel L.K. 
Published: November 2021

AbstractMedial entorhinal cortex (MEC) supports a wide range of navigational and memory related behaviors. Well-known experimental results have revealed specialized cell types in MEC — e.g. grid, border, and head-direction cells — whose highly stereotypical response profiles are suggestive of the role they might play in supporting MEC functionality. However, the majority of MEC neurons do not exhibit stereotypical firing patterns. How should the response profiles of these more “heterogeneous” cells be described, and how do they contribute to behavior? In this work, we took a computational approach to addressing these questions. We first performed a statistical analysis that shows that heterogeneous MEC cells are just as reliable in their response patterns as the more stereotypical cell types, suggesting that they have a coherent functional role. Next, we evaluated a spectrum of candidate models in terms of their ability to describe the response profiles of both stereotypical and heterogeneous MEC cells. We found that recently developed task-optimized neural network models are substantially better than traditional grid cell-centric models at matching most MEC neuronal response profiles — including those of grid cells themselves — despite not being explicitly trained for this purpose. Specific choices of network architecture (such as gated nonlinearities and an explicit intermediate place cell representation) have an important effect on the ability of the model to generalize to novel scenarios, with the best of these models closely approaching the noise ceiling of the data itself. We then performed in silico experiments on this model to address questions involving the relative functional relevance of various cell types, finding that heterogeneous cells are likely to be just as involved in downstream functional outcomes (such as path integration) as grid and border cells. Finally, inspired by recent data showing that, going beyond their spatial response selectivity, MEC cells are also responsive to non-spatial rewards, we introduce a new MEC model that performs reward-modulated path integration. We find that this unified model matches neural recordings across all variable-reward conditions. Taken together, our results point toward a conceptually principled goal-driven modeling approach for moving future experimental and computational efforts beyond overly-simplistic single-cell stereotypes.
Hybridization and Low Genetic Diversity in the Endangered Alabama Red-Bellied Turtle (Pseudemys alabamensis)
Authors: Moreno Nickolas , Heaton Andrew , Bruening Kaylin , Milligan Emma , Nelson David , Glaberman Scott , Chiari Ylenia 
Published: November 2021

ABSTRACTPseudemys alabamensis is one of the most endangered turtle species in the United States due to its small population size and restricted geographic distribution in coastal Alabama and Mississippi. Increased urbanization and climate change impacts in the region further threaten this species. Populations of P. alabamensis are geographically isolated from one another by land and salt water, which could act as barriers to intraspecific gene flow. It is currently unknown how differentiated these isolated populations are from one another or whether they have experienced reductions in population size. Previous work found morphological differences between Alabama and Mississippi populations, suggesting that they may be evolutionarily distinct. Other Pseudemys turtles such as P. concinna and P. floridana occur within the same geographic area as P. alabamensis and are known to hybridize with each other. These more abundant species could further threaten the unique genetic identity of P. alabamensis through introgression. In order to evaluate the endangered status of P. alabamensis and the level of hybridization with other species, we used the mitochondrial (mtDNA) control region and nuclear microsatellite markers to assess genetic variation within and among populations of this species throughout its range and estimate admixture with co-occurring Pseudemys species. Genetic diversity of P. alabamensis was lower than expected at both markers (no variation in mtDNA and excess of homozygosity in microsatellites). We found evidence of genetic differentiation between Alabama and Mississippi populations as well as two populations (Fowl River, Alabama and Biloxi, Mississippi) with low estimated breeding sizes and signs of inbreeding. Finally, we found evidence of admixture of P. alabamensis with P. concinna/P. floridana and Pseudemys peninsularis (a species not native to Alabama or Mississippi). Our results indicate that P. alabamensis is highly endangered throughout its range and threatened by both low population sizes and hybridization. In order to improve the species’ chances of survival, focus should be placed on habitat preservation, maintenance of genetic diversity within both Mississippi and Alabama populations, and regular population monitoring activities such as nest surveillance and estimates of recruitment.
Diversity, function and evolution of marine invertebrate genomes
Authors: Zhang Yaolei , Wang Jiahao , Lv Meiqi , Gao Haoyang , Meng LingFeng , Yunga A , Seim Inge , Zhang He , Liu Shanshan , Zhang Linlin , Liu Xin , Xu Xun , Yang Huanming ,   M10K+ Consortium, Fan Guangyi 
Published: November 2021

AbstractInvertebrates, animals (metazoans) without backbones, encompass ∼97% of all animal yet remains understudied. They have provided insights into molecular mechanisms underlying fundamentally identical mechanisms in phylogenetically diverse animals, including vertebrates. Marine invertebrates have long fascinated researchers due to their abundance, diversity, adaptations, and impact on ecosystems and human economies. Here, we report a compendium and appraisal of 190 marine invertebrate genomes spanning 21 phyla, 43 classes, 92 orders, and 134 families. We identify a high proportion and long unit size of tandem repeats, likely contributing to reported difficulties in invertebrate genome assembly. A well-supported phylogenetic tree of marine invertebrates from 974 single-copy orthologous genes resolved topological controversies. We show that Ctenophora is at the basal phylum and Porifera is the sister group of Parahoxozoa; that Xenacoelomorpha is within Bilateria and is the sister group to Protostomia, rejecting three out of four hypotheses in the field; and that Bryozoa is at the basal position of Lophotrochozoa, not grouped into Lophophorata. We also present insights into the genetic underpinnings of metazoans from Hox genes, innate immune gene families, and nervous system gene families. Our marine invertebrate genome compendium provides a unified foundation for studies on their evolution and effects on ecological systems and human life.
Dysconnectivity between auditory-cognitive network associated with auditory GABA and glutamate levels in presbycusis patients
Authors: Li Ning , Ma Wen , Ren Fuxin , Li Xiao , Li Fuyan , Zong Wei , Wu Lili , Dai Zongrui , Hui Steve C.N. , Edden Richard A.E. , Li Muwei , Gao Fei 
Published: November 2021

AbstractAccumulating studies suggest an interaction between presbycusis (PC) and cognitive impairment, which may be explained by the cognitive-ear link to a large extent. However, the neurophysiological mechanisms underlying this link are largely unknown. Here, 51 PC patients and 51 well-matched healthy controls were recruited. We combined resting-state functional MRI and edited magnetic resonance spectroscopy to investigate changes of intra- and inter-network functional connectivity and their relationships with auditory gamma-aminobutyric acid (GABA) and glutamate (Glu) levels and cognitive impairment in PC. Our study confirmed the plastic model of cognitive-ear link at the level of the large-scale brain network, including the dysconnectivity within high-order cognitive networks and between the auditory-cognitive network and overactivation between cognitive networks dependent on hearing loss, which was closely related to the cognitive impairment of PC patients. Moreover, GABA and Glu levels in the central auditory processing were abnormal in patients with PC. Importantly, reduction of GABA-mediated inhibition plays a crucial role in a dysconnectivity between the auditory-cognitive network, which may be neurochemical underpinnings of functional remodeling of cognitive-ear link in PC. Modulation of GABA neurotransmission may enable the development of new therapeutic strategies for the cognitive impairment of PC patients.
Multiple and Dissociable Effects of Sensory History on Working-Memory Performance
Authors: Hajonides Jasper E. , van Ede Freek , Stokes Mark G. , Nobre Anna C. , Myers Nicholas E. 
Published: November 2021

AbstractBehavioural reports of sensory information are biased by stimulus history. The nature and direction of such serial-dependence biases can differ between experimental settings – both attractive and repulsive biases towards previous stimuli have been observed. How and when these biases arise in the human brain remains largely unexplored. They could occur either via a change in sensory processing itself and/or during post-perceptual processes such as maintenance or decision-making. To address this, we analysed behavioural and magnetoencephalographic data from a working-memory task in which participants were sequentially presented with two randomly oriented gratings, one of which was cued for recall at the end of the trial. Behavioural responses showed evidence for two distinct biases: 1) a within-trial repulsive bias away from the previously encoded orientation on the same trial, and 2) a between-trial attractive bias towards the task-relevant orientation on the previous trial. Multivariate classification of stimulus orientation revealed that neural representations during stimulus encoding were biased away from the previous grating orientation, regardless of whether we considered the within- or between-trial prior orientation – despite opposite effects on behaviour. These results suggest that repulsive biases occur at the level of sensory processing and can be overridden at post-perceptual stages to result in attractive biases in behaviour.
Understanding gene regulatory mechanisms based on gene classification
Authors: Tian Hao , He Yueying , Xue Yue , Gao Yi Qin 
Published: November 2021

AbstractThe CpG dinucleotide and its methylation play vital roles in gene regulation as well as 3D genome organization. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites (TSS) and found that housekeeping genes tend to possess high CpG density while tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around TSS, the human genes are clearly divided into different categories. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, and correlation patterns between expression level and CpG/TpG density. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes, such as their CpG density distribution.
Phylogeography of the desert scorpionMesobuthus mongolicusilluminates a route out of Central Asia and Junggar Basin as a corridor for faunal exchange between Central and East Asia
Authors: Shi Cheng-Min , Zhang Xue-Shu , Liu Lin , Ji Ya-Jie , Zhang De-Xing 
Published: November 2021

AbstractA comprehensive understanding of the ecological, evolutionary and genetic consequences of climate changes requires integration of information from different geographic regions and ecosystems. However, a clear knowledge gap exists in arid biota of Asian drylands, where climate change and biological evolution demonstrate high regional specificity. We report here our phylogeographic study on the desert scorpionMesobuthus mongolicus, attempting to narrow the gap. Range wide samples for one mitochondrial gene and three nuclear loci were subjected to phylogenetic inferences, molecular dating, Bayesian phylogeographic and demographic reconstructions, and population genetic analyses. Ecological niche modeling was employed to generate models of potential distribution range at present and during the last glacial maximum (LGM). Our results revealed thatM. mongolicusrepresents a single coherent lineage that diverged with its most closely related lineage from Central Asia about 1.36 Ma and underwent radiation ever since. Bayesian phylogeographic reconstruction suggested the ancestral population ofM. mongolicusdispersed gradually eastward through the Junngar Basin to the Gobi region during the late Pleistocene, strengthening the view that the Junggar Basin has constituted an important corridor for faunal exchange between Central Asian and East Asia. We found that the desert scorpion underwent demographic expansion while experiencing range contraction during the LGM. Development of sandy deserts in northwest China incurred by Eurasian aridification might have opened up substantial empty niches that sustained population expansion during the LGM. Our results suggested that organisms’ ecological adaptations have acted as an important determinant for their phylogeographic and demographic responses to past climate changes.
Germinal centre-driven maturation of B cell response to SARS-CoV-2 vaccination
Authors: Kim Wooseob , Zhou Julian Q. , Sturtz Alexandria J. , Horvath Stephen C. , Schmitz Aaron J. , Lei Tingting , Kalaidina Elizaveta , Thapa Mahima , Alsoussi Wafaa B. , Haile Alem , Klebert Michael K. , Suessen Teresa , Parra-Rodriguez Luis , Mudd Philip A. , Middleton William D. , Teefey Sharlene A. , Pusic Iskra , O’Halloran Jane A. , Presti Rachel M. , Turner Jackson S. , Ellebedy Ali H. 
Published: November 2021

AbstractGerminal centres (GC) are lymphoid structures where vaccine-responding B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells (BMPCs)1–4. Induction of the latter is a hallmark of durable immunity after vaccination5. SARS-CoV-2 mRNA vaccination induces a robust GC response in humans6–8, but the maturation dynamics of GC B cells and propagation of their progeny throughout the B cell diaspora have not been elucidated. Here we show that anti-SARS-CoV-2 spike (S)-binding GC B cells were detectable in draining lymph nodes for at least six months in 10 out of 15 individuals who had received two doses of BNT162b2, a SARS-CoV-2 mRNA vaccine. Six months after vaccination, circulating S-binding MBCs were detected in all participants (n=42) and S-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of single-cell RNA sequencing of responding blood and lymph node B cells from eight participants and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1540 S-specific B cell clones. SHM accumulated along the B cell differentiation trajectory, with early blood plasmablasts showing the lowest frequencies, followed by MBCs and lymph node plasma cells whose SHM largely overlapped with GC B cells. By three months after vaccination, the frequency of SHM within GC B cells had doubled. Strikingly, S+ BMPCs detected six months after vaccination accumulated the highest level of SHM, corresponding with significantly enhanced anti-S polyclonal antibody avidity in blood at that time point. This study documents the induction of affinity-matured BMPCs after two doses of SARS-CoV-2 mRNA vaccination in humans, providing a foundation for the sustained high efficacy observed with these vaccines.
Sequence anticipation and spike-time-dependent-plasticity emerge from a predictive learning rule
Authors: Saponati Matteo , Vinck Martin 
Published: November 2021

AbstractIntelligent behavior depends on the brain’s ability to anticipate future events. However, the learning rules that enable neurons to predict and fire ahead of sensory inputs remain largely unknown. We propose a plasticity rule based on predictive processing, where the neuron learns a low-rank model of the synaptic input dynamics in its membrane potential. Neurons thereby amplify those synapses that maximally predict other synaptic inputs based on their temporal relations, which provide a solution to an optimization problem that can be implemented at the single-neuron level using only local information. Consequently, neurons learn sequences over long timescales and shift their spikes towards the first inputs in a sequence. We show that this mechanism can explain the development of anticipatory signalling and recall in a recurrent network. Furthermore, we demonstrate that the learning rule gives rise to several experimentally observed STDP (spike-timing-dependent plasticity) mechanisms. These findings suggest prediction as a guiding principle to orchestrate learning and synaptic plasticity in single neurons.
Tissue homeostasis in sponges: quantitative analysis of cell proliferation and apoptosis
Authors: Melnikov Nikolai P. , Bolshakov Fyodor V. , Frolova Veronika S. , Skorentseva Ksenia V. , Ereskovsky Alexander V. , Saidova Alina A. , Lavrov Andrey I. 
Published: November 2021

AbstractBackgroundTissues of multicellular animals are maintained due to a tight balance between cell proliferation and programmed cell death. Phylum Porifera is an early branching group of metazoans essential to understanding the key mechanisms of tissue homeostasis. This paper is dedicated to the comparative analysis of proliferation and apoptosis in intact tissues of two sponges belonging to distinct Porifera lineages, Halisarca dujardinii (class Demospongiae) and Leucosolenia variabilis (class Calcarea).ResultsLabeled nucleotides EdU and anti-phosphorylated histone 3 antibodies reveal a considerable number of cycling cells in intact tissues of both species. The main type of cycling cells are choanocytes - flagellated cells of the aquiferous system. The rate of proliferation remains constant in areas containing choanoderm. Cell cycle distribution assessed by the quantitative DNA stain reveals the classic cell cycle distribution curve. During EdU pulse-chase experiments conducted in H. dujardinii, the contribution of the choanocytes to the total amount of EdU-positive cells decreases, while contribution of the mesohyl cells increases. These findings could indicate that the proliferation of the choanocytes is not solely limited to the renewal of the choanoderm, and that choanocytes may participate in the general cell turnover through migration. The number of apoptotic cells in intact tissues of both species is insignificant. In vivo studies in both species with TMRE and CellEvent Caspase-3/7 indicate that apoptosis might be independent of mitochondrial outer membrane permeabilization.ConclusionsA combination of confocal laser scanning microscopy and flow cytometry provides a quantitative description of cell turnover in intact sponge tissues. Intact tissues of H. dujardinii (Demospongiae) and L. variabilis (Calcarea) are highly proliferative, indicating either high rates of growth or cell turnover. Although the number of apoptotic cells is low, apoptosis could still be involved in the regular cell turnover.
Vertex protein PduN tunes encapsulated pathway performance by dictating bacterial metabolosome morphology
Authors: Mills Carolyn E. , Waltmann Curt , Archer Andre G. , Kennedy Nolan W. , Abrahamson Charlotte H. , Jackson Alexander D. , Roth Eric W. , Shirman Sasha , Jewett Michael C. , Mangan Niall M. , de la Cruz Monica Olvera , Tullman-Ercek Danielle 
Published: November 2021

AbstractEngineering subcellular organization in microbes shows great promise in addressing bottlenecks in metabolic engineering efforts; however, rules guiding selection of an organization strategy or platform are lacking. Here, we study compartment morphology as a factor in mediating encapsulated pathway performance. Using the 1,2-propanediol utilization microcompartment (Pdu MCP) system from Salmonella enterica serovar Typhimurium LT2, we find that we can shift the morphology of this protein nanoreactor from polyhedral to tubular by removing vertex protein PduN. Analysis of the metabolic function between these Pdu microtubes (MTs) shows that they provide a diffusional barrier capable of shielding the cytosol from a toxic pathway intermediate, similar to native MCPs. However, kinetic modeling suggests that the different surface area to volume ratios of MCP and MT structures alters encapsulated pathway performance. Finally, we report a microscopy-based assay that permits rapid assessment of Pdu MT formation to enable future engineering efforts on these structures.