bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer learning to leverage larger datasets for improved prediction of protein stability changes
Authors: Dieckhaus Henry , Brocidiacono Michael , Randolph Nicholas , Kuhlman Brian 
Published: July 2023

AbstractAmino acid mutations that lower a protein’s thermodynamic stability are implicated in numerous diseases, and engineered proteins with enhanced stability are important in research and medicine. Computational methods for predicting how mutations perturb protein stability are therefore of great interest. Despite recent advancements in protein design using deep learning,in silicoprediction of stability changes has remained challenging, in part due to a lack of large, high-quality training datasets for model development. Here we introduce ThermoMPNN, a deep neural network trained to predict stability changes for protein point mutations given an initial structure. In doing so, we demonstrate the utility of a newly released mega-scale stability dataset for training a robust stability model. We also employ transfer learning to leverage a second, larger dataset by using learned features extracted from a deep neural network trained to predict a protein’s amino acid sequence given its three-dimensional structure. We show that our method achieves competitive performance on established benchmark datasets using a lightweight model architecture that allows for rapid, scalable predictions. Finally, we make ThermoMPNN readily available as a tool for stability prediction and design.
Genetic Architectures of Medical Images Revealed by Registration and Fusion of Multiple Modalities
Authors: Friedman Sam Freesun , Moran Gemma Elyse , Rakic Marianne , Phillipakis Anthony 
Published: July 2023

AbstractThe advent of biobanks with vast quantities of medical imaging and paired genetic measurements creates huge opportunities for a new generation of genotype-phenotype association studies. However, disentangling biological signals from the many sources of bias and artifacts remains difficult. Using diverse types of medical imaging (i.e. MRIs, ECGs and DXAs), we develop registered and cross-modal generative models. In all cases, we show how registration, both spatial and temporal, guided by domain knowledge or learned de novo, uncovers rich biological information. Remarkably, our findings demonstrate that even extremely lossy transformations, such as registering images onto a single 1D curve (e.g. a circle), can yield robust signals. Conversely, we demonstrate that increasing data dimensionality by integrating multiple modalities can also result in richer representations. Through genome- and phenome-wide association studies (GWAS and PheWAS) of learned embeddings, we uncover significantly more associations with registered and fused modalities than with equivalently trained and sized representations learned from native coordinate spaces. Our findings systematically reveal the crucial role registration plays in enhancing the characterization of physiological states across a broad range of medical imaging data types.
Correlations reveal the hierarchical organization of networks with latent binary variables
Authors: Häusler Stefan 
Published: July 2023

AbstractDeciphering the functional organization of large biological networks is a major challenge for current mathematical methods. A common approach is to decompose networks into largely independent functional modules, but inferring these modules and their organization from network activity is difficult, given the uncertainties and incompleteness of measurements. Typically, some parts of the overall functional organization, such as intermediate processing steps, are latent. We show that the hidden structure can be determined from the statistical moments of observable network components alone, as long as the functional relevance of the network components lies in their mean values and the mean of each latent variable maps onto a scaled expectation of a binary variable. Whether the function of biological networks permits a hierarchical modularization can be falsified by a correlation-based statistical test that we derive. We apply the test to three biological networks at different spatial scales, i.e., gene regulatory networks, dendrites of pyramidal neurons, and networks of spiking neurons.
Clade-wise alignment integration improves co-evolutionary signals for protein-protein interaction prediction
Authors: Fang Tao , Szklarczyk Damian , Hachilif Radja , von Mering Christian 
Published: July 2023

AbstractBackgroundProtein-protein interactions play essential roles in almost all biological processes. The binding interfaces between interacting proteins impose evolutionary constraints, leading to co-evolutionary signals that have successfully been employed to predict protein interactions from multiple sequence alignments (MSAs). During the construction of MSAs for this purpose, critical choices have to be made: how to ensure the reliable identification of orthologs, how to deal with paralogs, and how to optimally balance the need for large alignments versus sufficient alignment quality.ResultsHere, we propose a divide-and-conquer strategy for MSA generation: instead of building a single, large alignment for each protein, multiple distinct alignments are constructed, each covering only a single clade in the tree of life. Co-evolutionary signals are searched separately within these clades, and are only subsequently integrated into a final interaction prediction using machine learning. We find that this strategy markedly improves overall prediction performance, concomitant with better alignment quality. Using the popular DCA algorithm to systematically search pairs of such alignments, a genome-wide all-against-all interaction scan in a bacterial genome is demonstrated.ConclusionsGiven the recent successes of AlphaFold in predicting protein-protein interactions at atomic detail, a discover-and-refine approach is proposed: our method could provide a fast and accurate strategy for pre-screening the entire genome, submitting to AlphaFold only promising interaction candidates - thus reducing false positives as well as computation time.
Actin-Driven Nanotopography Promotes Stable Integrin Adhesion Formation in Developing Tissue
Authors: Chen Tianchi , Huertas Fernández-Espartero Cecilia , Illand Abigail , Tsai Ching-Ting , Yang Yang , Klapholz Benjamin , Jouchet Pierre , Fabre Mélanie , Rossier Olivier , Cui Bianxiao , Lévêque-Fort Sandrine , Brown Nicholas H. , Giannone Grégory 
Published: July 2023

AbstractMorphogenesis requires building stable macromolecular structures from highly dynamic proteins. Muscles are anchored by long-lasting integrin adhesions to resist contractile force. However, the mechanisms governing integrin diffusion, immobilization, and activation within developing tissues remain elusive. Here, we show that actin polymerisation-driven membrane protrusions form nanotopographies that enable strong adhesion at Drosophila muscle attachment sites (MAS). Super-resolution microscopy revealed that integrins assemble adhesive belts around Arp2/3-dependent actin protrusions, forming invadosome-like structures with membrane nanotopographies. Single protein tracking showed that, during MAS development, integrins became immobile and confined within diffusion traps formed by the membrane nanotopographies. Actin filaments also displayed restricted motion and confinement, indicating strong mechanical connection with integrins. Using isolated muscles cells, we show that substrate nanotopography, rather than rigidity, drives adhesion maturation by regulating actin protrusion, integrin diffusion and immobilization. These results thus demonstrate that actin-polymerisation driven membrane protrusions are essential for the formation of strong integrin adhesions sites in the developing embryo, and highlight the important contribution of geometry to morphogenesis.
The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK
Authors: Rautila Osma S. , Kaivola Karri , Rautila Harri , Hokkanen Laura , Launes Jyrki , Strandberg Timo E. , Laaksovirta Hannu , Palmio Johanna , Tienari Pentti J. 
Published: July 2023

AbstractThe C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of cases are sporadic. One possible explanation isde novoexpansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HST) with the novel haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE carriers and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA carriers, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.
Predictive microbial community changes across a temperature gradient
Authors: Sun Xin , Folmar Jacquelyn , Favier Ariel , Pyenson Nora , Sanchez Alvaro , Rebolleda-Gomez María 
Published: July 2023

AbstractA central challenge in community ecology is predicting the effects of abiotic factors on community assembly. In particular, microbial communities play a central role in the ecosystem, but we do not understand how changing factors like temperature are going to affect community composition or function. One of the challenges is that we do not understand the mechanistic impacts of temperature on different metabolic strategies, nor how this metabolic plasticity could impact microbial interactions. Dissecting the contribution of environmental factors on microbial interactions in natural ecosystems is hindered by our understanding of microbial physiology and our ability to disentangle interactions from sequencing data. Studying the self-assembly of multiple communities in synthetic environments, here we are able to predict changes in microbial community composition based on metabolic responses of each functional group along a temperature gradient. This research highlights the importance of metabolic plasticity and metabolic trade-offs in predicting species interactions and community dynamics across abiotic gradients.
Structure and function of bacterial YeeE-YeeD complex in thiosulfate uptake pathway
Authors: Ikei Mai , Miyazaki Ryoji , Monden Keigo , Naito Yusuke , Takeuchi Azusa , Takahashi Yutaro S. , Tanaka Yoshiki , Murata Keina , Mori Takaharu , Ichikawa Muneyoshi , Tsukazaki Tomoya 
Published: July 2023

AbstractUptake of thiosulfate ions as an inorganic sulfur source from the environment is important for bacterial sulfur assimilation. Recently, a selective thiosulfate uptake pathway involving a membrane protein YeeE (TsuA) inEscherichia coliwas characterized. YeeE-like proteins are conserved in some bacteria, archaea, and eukaryotes. However, the precise function of YeeE, along with its potential partner protein in the thiosulfate ion uptake pathway, remained unclear. Here, we assessed selective thiosulfate transport viaSpirochaeta thermophilaYeeE in vitro and characterizedE. coliYeeD (TsuB) as an adjacent and essential protein for YeeE-mediated thiosulfate uptake in vivo. We further showed thatS. thermophilaYeeD possesses thiosulfate decomposition activity and that a conserved cysteine in YeeD was modified to several forms in the presence of thiosulfate. Finally, the crystal structures ofS. thermophilaYeeE-YeeD fusion proteins at 3.34-Å and 2.60-Å resolutions revealed their interactions. The association was evaluated by a binding assay using purifiedS. thermophilaYeeE and YeeD. Based on these results, a model of the sophisticated uptake of thiosulfate ions by YeeE and YeeD is proposed.125-character sentenceThe structural study of the YeeE-YeeD membrane protein complex provides insight into the thiosulfate uptake and degradation mechanism.
Dynamic simulations of feeding and respiration of the early Cambrian periderm-bearing cnidarian polyps
Authors: Zhang Yiheng , Wang Xing , Han Jian , Xiao Juyue , Yong Yuanyuan , Yu Chiyang , Yue Ning , Sun Jie , He Kaiyue , Hao Wenjing , Zhang Tao , Wang Bin , Wang Deng , Yang Xiaoguang 
Published: July 2023

AbstractAlthough fossil evidence suggests the existence of an early muscular system in the ancient cnidarian jellyfish from the early Cambrian Kuanchuanpu biota (ca.535 Ma), south China, the mechanisms underlying the feeding and respiration of the early jellyfish are conjectural. Recently, the polyp inside the periderm of olivooids was demonstrated to be a calyx-like structure, most likely bearing short tentacles and bundles of coronal muscles at the edge of the calyx, thus presumably contributing to feeding and respiration. Here, we simulate the contraction and expansion of the microscopic periderm-bearing olivooidQuadrapyrgitesvia the fluid-structure interaction computational fluid dynamics (CFD) method to investigate their feeding and respiratory activities. The simulations show that the rate of water inhalation by the polyp subumbrella is positively correlated with the rate of contraction and expansion of the coronal muscles, consistent with the previous feeding and respiration hypothesis. The dynamic simulations also show that the frequent inhalation/exhalation of water through the periderm polyp expansion/contraction conducted by the muscular system ofQuadrapyrgitesmost likely represents the ancestral feeding and respiration patterns of Cambrian sedentary medusozoans that predated the rhythmic jet-propelled swimming of the modern jellyfish. Most importantly for these Cambrian microscopic sedentary medusozoans, the increase of body size and stronger capacity of muscle contraction may have been indispensable in the stepwise evolution of active feeding and subsequent swimming in a higher flow (or higher Reynolds number) environment.Impact statementTo the best of our knowledge, our study is the first to simulate the feeding and respiration patterns ofQuadrapyrgitesby introducing a dynamic fluid-structure coupling method, revealing the relationship between the ancient medusozoans and modern jellyfish.
Circadian proteomics reveal rampant tuning of post-transcriptional apparatus byChlamydomonasclock
Authors: Jadhav Dinesh Balasaheb , Roy Sougata 
Published: July 2023

AbstractTiming of biological processes enable organisms to sustain the diurnal fluctuations resulting from earth’s rotation. Circadian clocks execute this temporal regulation by modulating temporal expression of genes. Clock regulation of mRNAs was envisioned as the primary driver of daily rhythms. However, mRNA oscillations often don’t concur with the downstream protein oscillations. To assess the contribution from post-transcriptional processes, we quantitatively probed theChlamydomonasproteome for two circadian cycles. Our study suggests rampant role of posttranscriptional processes in clock regulation ofChlamydomonasmetabolism. We quantified >1000 proteins, half of which demonstrate circadian rhythms. Among these rhythmic proteins, >40% originate from non-rhythmic mRNAs and > 90% peak around midday or midnight. Accumulation rhythms of proteins rather than their encoding mRNAs shows extreme coordination. We uncovered new rhythms and accounted for physiological rhythms whose mechanistic details remained undocumented from earlier transcriptomic studies. We envisage our study will refine and enrich the evaluation of temporal metabolic processes inChlamydomonas.Owing toChlamydomonas’sunique phylogeny this study can lead to new insights into evolution of clock regulation across kingdoms.
Fruitless mating with the exes: the irreversible parthenogenesis in a stick insect
Authors: Nozaki Tomonari , Chikami Yasuhiko , Yano Koki , Sato Ryuta , Suetsugu Kenji , Kaneko Shingo 
Published: July 2023

AbstractParthenogenetic lineages, common in many animals, have sparked debate about their evolutionary persistence. While asexuality is expected to ensure reproductive assurance and provide a demographic advantage, parthenogens should suffer from the lack of gene shuffling with other individuals. On the other hand, occasional sexual reproduction has been theoretically predicted to be enough to mitigate the long-term costs of parthenogenesis. Recent studies have revealed instances of cryptic sex in some old parthenogenetic lineages, which is most likely mediated by rarely occurring males. Unlike female traits that rapidly become vestigial under asexuality, traits in males have been predicted to slowly decay due to the accumulation of neutral mutations over long evolutionary times. In fact, rare males often retain sexual functions, raising questions about the asexuality of these long-standing parthenogenetic lineages. Here, we intensively examined the possibility of sexual reproduction in the Japanese common stick insect,Ramulus mikado, which was also suggested to be an old parthenogen in our previous work. While asexual female reproduction appears to be quite predominant throughout Japan, we fortunately obtained the rare males from the field. These males exhibited typical stick insect male morphology and engaged in mating behaviors with conspecific females. However, no paternal-specific alleles were detected in the offspring; all embryos showed genotypes identical to their mothers. Our histological observations on a few males revealed that they had no sperm in their reproductive organs, although the degree of decay may be different among the lineages. We also found that females have sexual organs with signs of degeneration. All these results demonstrate the irreversible asexual reproduction ofR. mikadoand indicate their long history as a parthenogenetic species. Our present study provides unique insights into the maintenance of parthenogenesis and degenerative evolution of sexual traits in ancient asexual lineages.
Heterogenous Biofilm Mass-Transport Model Replicates Periphery Sequestration of Antibiotics inP. aeruginosaPAO1 Microcolonies
Authors: Prince Joshua , Jones A-Andrew D. 
Published: July 2023

1AbstractA spatiotemporal model for antibiotic accumulation in bacterial biofilm microcolonies which leverages heterogenous porosity and attachment site profiles replicated the periphery sequestration phenomena reported in prior experimental studies onPseudomonas aeruginosa PAO1biofilm cell clusters. TheseP. aeruginosacell clusters arein vitromodels of the chronicP. aeruginosainfections found in adult cystic fibrosis patients, which display resistance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics are unable to penetrate biofilm cell clusters. The underlying physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena was able to better fit observed periphery sequestration data compared to previous models.
Global Pannexin 1-deletion increases tumor-infiltrating lymphocytes in the BRAF/Pten mouse melanoma model
Authors: Sanchez-Pupo Rafael E. , Finch Garth A. , Johnston Danielle E. , Craig Heather , Abdo Rober , Barr Kevin , Kerfoot Steven , Dagnino Lina , Penuela Silvia 
Published: July 2023

ABSTRACTImmunotherapies for malignant melanoma seek to boost the anti-tumoral response of CD8+T cells but have a limited patient response rate, in part due to limited tumoral immune cell infiltration. Genetic or pharmacological inhibition of Pannexin 1 (PANX1) channel-forming protein is known to decrease melanoma cell tumorigenic propertiesin vitroandex vivo. Here, we crossedPanx1knockout (Panx1−/−) mice with the inducible melanoma model:BrafCA,PtenloxP,Tyr::CreERT2(BPC). We found that deleting thePanx1gene in mice does not reduce BRAF(V600E)/Pten-driven primary tumor formation or improve survival. However, BPC-Panx1−/-mice tumors exhibited a significant increase in infiltration of CD8+T lymphocytes with no changes in the expression of early T cell activation marker CD69, LAG-3 checkpoint receptor or PD-L1 in tumors when compared to BPC-Panx1+/+genotype. Our results suggest that although aPanx1deletion does not overturn the aggressiveBRAF/Pten-driven melanoma progressionin vivo, it does increase the infiltration of effector immune T cell populations in the tumor microenvironment. We propose that PANX1-targeted therapy could be explored as a strategy to increase tumor-infiltrating lymphocytes to boost anti-tumor immunity.
Look4LTRs: A Long terminal repeat retrotransposon detection tool capable of cross species studies and discovering recently nested repeats
Authors: Garza Anthony B. , Lerat Emmanuelle , Girgis Hani Z. 
Published: July 2023

AbstractPlant genomes include large numbers of transposable elements. One particular type of these elements is flanked by two Long Terminal Repeats (LTRs) and can translocate using RNA. Such elements are known as LTR-retrotransposons; they are the most abundant type of transposons in plant genomes. They have many important functions involving gene regulation and the rise of new genes and pseudo genes in response to severe stress. Additionally, LTR-retrotransposons have several applications in biotechnology. Due to the abundance and the importance of LTR-retrotransposons, multiple computational tools have been developed for their detection. However, none of these tools take advantages of the availability of related genomes; they process one chromosome at a time. Further, recently nested LTR-retrotransposons (multiple elements of the same family are inserted into each other) cannot be annotated accurately — or cannot be annotated at all — by the currently available tools. Motivated to overcome these two limitations, we builtLook4LTRs, which can annotate LTR-retrotransposons in multiple related genomes simultaneously and discover recently nested elements. The methodology ofLook4LTRsdepends on techniques imported from the signal-processing field, graph algorithms, and machine learning with a minimal use of alignment algorithms. Four plant genomes were used in developingLook4LTRsand eight plant genomes for evaluating it in contrast to three related tools.Look4LTRsis the fastest while maintaining better or comparable F1 scores (the harmonic average of recall and precision) to those obtained by the other tools. Our results demonstrate the added benefit of annotating LTR-retrotransposons in multiple related genomes simultaneously and the ability to discover recently nested elements. Expert human manual examination of six elements — not included in the ground truth — revealed that three elements belong to known families and two elements are likely from new families. With respect to examining recently nested LTR-retrotransposons, three out of five were confirmed to be valid elements.Look4LTRs— with its speed, accuracy, and novel features — represents a true advancement in the annotation of LTR-retrotransposons, opening the door to many studies focused on understanding their functions in plants.