bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Fitness Prediction is Impacted by the Interplay of Language Models, Ensemble Learning, and Sampling Methods
Authors: Mardikoraem Mehrsa , Woldring Daniel 
Published: February 2023

AbstractAdvances in machine learning (ML) and the availability of protein sequences via high-throughput sequencing techniques have transformed our ability to design novel diagnostic and therapeutic proteins. ML allows protein engineers to capture complex trends hidden within protein sequences that would otherwise be difficult to identify in the context of the immense and rugged protein fitness landscape. Despite this potential, there persists a need for guidance during the training and evaluation of ML methods over sequencing data. Two key challenges for training discriminative models and evaluating their performance include handling severely imbalanced datasets (e.g., few high-fitness proteins among an abundance of non-functional proteins) and selecting appropriate protein sequence representations. Here, we present a framework for applying ML over assay-labeled datasets to elucidate the capacity of sampling methods and protein representations to improve model performance in two different datasets with binding affinity and thermal stability prediction tasks. For protein sequence representations, we incorporate two widely used methods (One-Hot encoding, physiochemical encoding) and two language-based methods (next-token prediction, UniRep; masked-token prediction, ESM). Elaboration on performance is provided over protein fitness, length, data size, and sampling methods. In addition, an ensemble of representation methods is generated to discover the contribution of distinct representations to the final prediction score. Within the context of these datasets, the synthetic minority oversampling technique (SMOTE) outperformed undersampling while encoding sequences with One-Hot, UniRep, and ESM representations. In addition, ensemble learning increased the predictive performance of the affinity-based dataset by 4% compared to the best single encoding candidate (F1-score = 97%), while ESM alone was rigorous enough in stability prediction (F1-score = 92%).
A “Four Core Genotypes” rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases
Authors: Arnold Arthur P. , Chen Xuqi , Grzybowski Michael N. , Ryan Janelle M. , Sengelaub Dale R. , Mohanroy Tara , Furlan V. Andree , Grisham William , Malloy Lynn , Takizawa Akiko , Wiese Carrie B. , Vergnes Laurent , Skaletsky Helen , Page David C. , Reue Karen , Harley Vincent R. , Dwinell Melinda R. , Geurts Aron M. 
Published: February 2023

AbstractBackgroundWe have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype.MethodsXY rats were produced with an autosomal transgene ofSry, the testis-determining factor gene, which were fathers of XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females that have XX and XY progeny with ovaries. These groups can be compared to detect sex differences caused by sex chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries).ResultsWe have measured numerous phenotypes to characterize this model, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Numerous phenotypes previously found to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.ConclusionThe results establish a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.
CPA-Perturb-seq: Multiplexed single-cell characterization of alternative polyadenylation regulators
Authors: Kowalski Madeline H. , Wessels Hans-Hermann , Linder Johannes , Choudhary Saket , Hartman Austin , Hao Yuhan , Mascio Isabella , Dalgarno Carol , Kundaje Anshul , Satija Rahul 
Published: February 2023

ABSTRACTMost mammalian genes have multiple polyA sites, representing a substantial source of transcript diversity that is governed by the cleavage and polyadenylation (CPA) regulatory machinery. To better understand how these proteins govern polyA site choice we introduce CPA-Perturb-seq, a multiplexed perturbation screen dataset of 42 known CPA regulators with a 3’ scRNA-seq readout that enables transcriptome-wide inference of polyA site usage. We develop a statistical framework to specifically identify perturbation-dependent changes in intronic and tandem polyadenylation, and discover modules of co-regulated polyA sites exhibiting distinct functional properties. By training a multi-task deep neural network (APARENT-Perturb) on our dataset, we delineate acis-regulatory code that predicts responsiveness to perturbation and reveals interactions between distinct regulatory complexes. Finally, we leverage our framework to re-analyze published scRNA-seq datasets, identifying new regulators that affect the relative abundance of alternatively polyadenylated transcripts, and characterizing extensive cellular heterogeneity in 3’ UTR length amongst antibody-producing cells. Our work highlights the potential for multiplexed single-cell perturbation screens to further our understanding of post-transcriptional regulationin vitroandin vivo.
Exploring the consequences of redirecting an exocytic Rab onto endocytic vesicles
Authors: Li Xia , Liu Dongmei , Griffis Eric , Novick Peter 
Published: February 2023

AbstractBidirectional vesicular traffic links compartments along the exocytic and endocytic pathways. Rab GTPases have been implicated in specifying the direction of vesicular transport because anterograde vesicles are marked with a different Rab than retrograde vesicles. To explore this proposal, we sought to redirect an exocytic Rab, Sec4, onto endocytic vesicles by fusing the catalytic domain of the Sec4 GEF, Sec2, onto the CUE localization domain of Vps9, a GEF for the endocytic Rab, Ypt51. The Sec2GEF-GFP-CUE construct was found to localize to bright puncta predominantly near sites of polarized growth and this localization was strongly dependent upon the ability of the CUE domain to bind to the ubiquitin moieties added to the cytoplasmic tails of proteins destined for endocytic internalization. Sec4 and Sec4 effectors were recruited to these puncta with varying efficiency. The puncta appeared to consist of clusters of 80 nm vesicles and although the puncta are largely static, FRAP analysis suggests that traffic into and out of these clusters continues. Cells expressing Sec2GEF-GFP-CUE grew surprisingly well and secreted protein at near normal efficiency, implying that Golgi derived secretory vesicles were delivered to polarized sites of cell growth, where they tethered and fused with the plasma membrane despite the misdirection of Sec4 and its effectors. In total, the results suggest that while Rabs play a critical role in regulating vesicular transport, cells are remarkably tolerant of Rab misdirection.
Plasmid-mediated colistin resistance among human clinicalEnterobacteralesisolates: National surveillance in the Czech Republic
Authors: Zelendova Marketa , Papagiannitsis Costas C. , Sismova Petra , Medvecky Matej , Pomorska Katarina , Palkovicova Jana , Nesporova Kristina , Jakubu Vladislav , Jamborova Ivana , Zemlickova Helena , Dolejska Monika ,   Working Group for Monitoring of Antibiotic Resistance
Published: February 2023

AbstractThe occurrence of colistin resistance has increased rapidly amongEnterobacteralesaround the world. We performed a national survey of plasmid-mediated colistin resistance in human clinical isolates by a retrospective analysis of samples from 2009-2017 and a prospective sampling in 2018-2020. The aim of this study was to identify and characterize isolates withmcrgenes from various regions of the Czech Republic using whole genome sequencing (WGS). Of all 1932 colistin-resistant isolates analyzed, 73 (3.8%) were positive formcrgenes. Most isolates carriedmcr-1(48/73) and were identified asEscherichia coli(n=44) andKlebsiella pneumoniae(n=4) of various sequence types (ST). Twenty-five isolates includingEnterobacterspp. (n=24) andCitrobacter freundii(n=1) carryingmcr-9gene were detected, three of them (Enterobacter kobeiST54) co-harbored themcr-4andmcr-9genes. Multi-drug resistance phenotype was a common feature ofmcrisolates and 14% (10/73) isolates also co-harboured clinically important beta-lactamases including 2 isolates with carbapenemases KPC-2 and OXA-48. Phylogenetic analysis ofE. coliST744, the dominant genotype in this study, with the global collection, showed Czech isolates belonged to two major clades, one containing isolates from Europe, while the second composed of isolates from diverse geographical areas. Themcr-1gene was carried by IncX4 (34/73, 47%), IncHI2/ST4 (6/73, 8%) and IncI2 (8/73, 11%) plasmid groups. Small plasmids belonging to the ColE10 group were associated withmcr-4in three isolates whilemcr-9was carried by IncHI2/ST1 plasmids (4/73, 5%) or the chromosome (18/73, 25%). We showed an overall low level of occurrence ofmcrgenes in colistin-resistant bacteria from human clinical samples in the Czech Republic.
Benchmarking Variational AutoEncoders on cancer transcriptomics data
Authors: Eltager Mostafa , Abdelaal Tamim , Charrout Mohammed , Mahfouz Ahmed , Reinders Marcel J.T. , Makrodimitris Stavros 
Published: February 2023

AbstractDeep generative models, such as variational autoencoders (VAE), have gained increasing attention in computational biology due to their ability to capture complex data manifolds which subsequently can be used to achieve better performance in downstream tasks, such as cancer type prediction or subtyping of cancer. However, these models are difficult to train due to the large number of hyperparameters that need to be tuned. To get a better understanding of the importance of the different hyperparameters, we examined six different VAE models when trained on TCGA transcriptomics data and evaluated on the downstream task of cluster agreement with cancer subtypes. We studied the effect of the latent space dimensionality, learning rate, optimizer and initialization on the quality of subsequent clustering of the TCGA samples. We foundβ-TCVAE and DIP-VAE to have a good performance, on average, despite being more sensitive to hyperparameters selection. Based on these experiments, we derived recommendations for selecting the different hyperparameters settings. In addition, we examined whether the learned latent spaces capture biologically relevant information. Hereto, we correlated the different representations with various data characteristics such as age, days to metastasis, immune infiltration, and mutation signatures. We found that for all models the latent factors, in general, do not uniquely correlate with one of the data characteristics even for models specifically designed for disentanglement.
Impact of Peripheral Auditory Structure on the Development of Auditory-Language Network in Children with Profound Sensorineural Hearing Loss
Authors: Wang Yaoxuan , Jiang Mengda , Zhu Yuting , Xue Lu , Shu Wenying , Li Xiang , Chen Hongsai , Chu Yinghua , Song Yang , Tao Xiaofeng , Wang Zhaoyan , Wu Hao 
Published: February 2023

AbstractProfound congenital sensorineural hearing loss (SNHL) prevents children from developing spoken language. Cochlear implantation and auditory brainstem implantation can provide hearing sensation, but language development outcomes can vary, particularly for patients with inner ear malformations and/or cochlear nerve deficiency (IEM&CND). Currently, the peripheral auditory structure is evaluated through visual inspection of clinical imaging, but this method is insufficient for surgical planning and prognosis. The central auditory pathway is also challenging to examine in vivo due to its delicate subcortical structures. Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to deaf patients. In this study, we developed a new pipeline for mapping the auditory pathway using structural and diffusional MRI. We used a fixel-based approach to investigate the structural development of the auditory-language network for profound SNHL children with normal peripheral structure and those with IEM&CND under six years old. Our findings indicate that the language pathway is more sensitive to peripheral auditory condition than the central auditory pathway, highlighting the importance of early intervention for profound SNHL children to provide timely speech inputs. We also propose a comprehensive pre-surgical evaluation extending from the cochlea to the auditory-language network, which has promising clinical potential.
Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice
Authors: López-Pérez Ana , Remeseiro Silvia , Hörnblad Andreas 
Published: February 2023

AbstractBackground & AimsThis study aimed to provide a comprehensive understanding of the regulatory and transcriptional landscape in liver tumours from DIAMOND mice, a mouse model that mimics human hepatocellular carcinoma (HCC) in the context of metabolic associated fatty liver disease (MAFLD).MethodsRNA-sequencing and ChIP-sequencing were used to study the gene expression and regulatory changes in DIAMOND liver tumours. RNAin situhybridisation splice variant analysis was used to study β-catenin exon 3 exclusion in tumours at cellular resolution. Sequencing data on β-catenin exon 3 splicing in DIAMOND tumours was compared to data from human patients and cell lines.ResultsThe study found an increase in Wnt/β-catenin-signalling accompanied by rewiring of the Wnt/β-catenin regulatory network in DIAMOND tumours. Changes include switching in the expression of the canonical TCF/LEF downstream effectors and associated chromatin remodelling. In addition, a large subset of DIAMOND tumours showed aberrant splicing of β-catenin, which generate an mRNA isoform that encodes an oncogenic protein. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples.ConclusionsThis study provides evidence that western diet induces aberrant genome-wide splicing in DIAMOND livers, and in particular of the β-catenin gene in a subset of DIAMOND liver tumours. This mechanism is distinct from previously reported activation of β-catenin in HCC and mouse models, since it is independent on mutations in the locus. Our data suggests that metabolic input modulates gene regulatory network responses to active Wnt-signalling, which will be an important consideration also in the human setting.Lay summarySequencing data generated in this study highlights the effect of diet in modulating oncogenic gene expression and underscores an alternative mutation-independent mechanism leading to constitutive activation of β-catenin, a well-known driver of liver cancer.
Exploring the Knowledge of An Outstanding Protein to Protein Interaction Transformer
Authors: Yang Sen , Feng Dawei , Cheng Peng , Liu Yang , Wang Shengqi 
Published: February 2023

AbstractProtein-to-protein interaction (PPI) prediction aims to predict whether two given proteins interact or not. Compared with traditional experimental methods of high cost and low efficiency, the current deep learning based approach makes it possible to discover massive potential PPIs from large-scale databases. However, deep PPI prediction models perform poorly on unseen species, as their proteins are not in the training set. Targetting on this issue, the paper first proposes PPITrans, a Transformer based PPI prediction model that exploits a language model pre-trained on proteins to conduct binary PPI prediction. To validate the effectiveness on unseen species, PPITrans is trained with Human PPIs and tested on PPIs of other species. Experimental results show that PPITrans significantly outperforms the previous state-of-the-art on various metrics, especially on PPIs of unseen species. For example, the AUPR improves 0.339 absolutely on Fly PPIs. Aiming to explore the knowledge learned by PPITrans from PPI data, this paper also designs a series of probes belonging to three categories. Their results reveal several interesting findings, like that although PPITrans cannot capture the spatial structure of proteins, it can obtain knowledge of PPI type and binding affinity, learning more than binary PPI.
The effect of hypoxia onDaphnia magnaperformance and its associated microbial and bacterioplankton community: a scope for Genotype x Microbial community interactions upon environmental stress ?
Authors: Coone Manon , Vanoverberghe Isabel , Houwenhuyse Shira , Verslype Chris , Decaestecker Ellen 
Published: February 2023

AbstractThe depletion of oxygen as a result of increased stratification and decreased oxygen solubility is one of the most significant chemical changes occurring in aquatic ecosystems as a result of global environmental change. Hence, more aquatic organisms will be exposed to hypoxic conditions over time. Deciphering the effects of hypoxia on strong ecological interactors in this ecosystem’s food web is critical for predicting how aquatic communities can respond to such an environmental disturbance. Here, (sub-)lethal effects of hypoxia and whether these are genotype specific inDaphnia, a keystone species of freshwater ecosystems, are studied. This is especially relevant upon studying genetic responses with respect to phenotypic switches (G x E interactions) upon environmental stress. Further, we investigated the effect of hypoxia on theDaphniamicrobial community to test if the microbiome plays a role in the phenotypic switch and tolerance to hypoxia. For this, twoDaphniagenotypes were exposed for two weeks to either hypoxia or normoxia and host performance was monitored together with changes in the host associated and free-living microbial community after this period. We found G x E interactions for some of the testedDaphniaperformance traits. The microbial community responded to hypoxia stress with responses in the bacterioplankton and in theDaphniaassociated microbial community with respect to species richness and community composition and structure. The latter response was different for the two genotypes suggesting that the microbiome plays an important role in G x E interactions with respect to hypoxia tolerance inDaphnia, but further testing (e.g. through microbiome transplants) is needed to confirm this.
Structural and functional classification of G-quadruplex families within the human genome
Authors: Neupane Aryan , Chariker Julia H. , Rouchka Eric C. 
Published: February 2023

ABSTRACTG quadruplexes are short secondary DNA structures located throughout genomic DNA and transcribed RNA. though G4 structures have been shown to formin vivo, no current search tools are known to exist to examine these structures based on previously identified G quadruplexes, much less filter them based on similar sequence, structure, and thermodynamic properties. We present a framework for clustering G quadruplex sequences into families using theCD-HIT, MeShClust and DNACLUSTmethods along with a combination ofStarcodeandBLAST. Utilizing this framework to filter and annotate clusters, 95 families of G quadruplex sequences were identified within the human genome. Profiles for each family were created using hidden Markov models to allow for identification of additional family members and generate homology probability scores. The thermodynamic folding energy properties, functional annotation of genes associated with the sequences, scores from different prediction algorithms and transcription factor binding and motif to the G4 region for the sequences within a family were used to annotate and compare the diversity within and across clusters. The resulting set of G quadruplex families can be used to further understand how different regions of the genome are regulated by factors targeting specific structures common to members of a specific cluster.
High Efficiency Rare Earth Element Biomining with Systems Biology Guided Engineering ofGluconobacter oxydans
Authors: Schmitz Alexa M. , Pian Brooke , Marecos Sabrina , Wu Mingming , Holycross Megan , Gazel Esteban , Reid Matthew C. , Barstow Buz 
Published: February 2023

AbstractThe global demand for critical rare earth elements (REE) is rising1with the increase in demand for sustainable energy technologies like wind turbines2,3, electric vehicles2,3, and high efficiency lighting4. Current processes for producing REE require high energy inputs and can produce disproportionate amounts of hazardous waste. Biological methods for REE production are a promising solution to this problem. In earlier work we identified the most important genetic mechanisms contributing to the REE-bioleaching capability ofGluconobacter oxydansB585. Here we have targeted two of these mechanisms to generate a high-efficiency bio-mining strain ofG. oxydans. Disruption of the phosphate-specific transport system through a clean deletion ofpstSconstitutively turns on the phosphate starvation response, yielding a much more acidic biolixiviant, and increasing bioleaching by up to 30%. Coupling knockout ofpstSwith the over-expression of themgdhmembrane-bound glucose dehydrogenase gene, results in up to 73% improvement of REE-bioleaching.
Labellable Phylogenetic Networks
Authors: Francis Andrew , Steel Mike 
Published: February 2023

AbstractPhylogenetic networks are mathematical representations of evolutionary history that are able to capture both tree-like evolutionary processes (speciations), and non-tree-like “reticulate” processes such as hybridization or horizontal gene transfer. The additional complexity that comes with this capacity, however, makes networks harder to infer from data, and more complicated to work with as mathematical objects.In this paper we define a new, large class of phylogenetic networks, that we calllabellable, and show that they are in bijection with the set of “expanding covers” of finite sets. This correspondence is a generalisation of the encoding of phylogenetic forests by partitions of finite sets. Labellable networks can be characterised by a simple combinatorial condition, and we describe the relationship between this large class and other commonly studied classes. Furthermore, we show that all phylogenetic networks have a quotient network that is labellable.