bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic evaluation revealed that detecting translated non-canonical ORFs from ribosome profiling data remains challenging
Authors: Lei Tianyu , Chang Yue , Yao Chao , Zhang Hong 
Published: December 2022

AbstractNon-canonical open reading frames (ORFs), which are ORFs that are not included in reference genome annotations, are gaining more and more research interest in recent years. While vast numbers of non-canonical ORFs have been identified with ribosome profiling (Ribo-Seq) by various state-of-the-art computational methods, the performance of these methods has not been assessed systematically. To this end, we evaluated the four most popular methods for translated non-canonical ORF prediction using various public datasets. We found that non-canonical ORFs predicted by different methods differ substantially and are not saturated at typical sequence depths. Furthermore, the precision and accuracy of all four methods are not satisfactory, especially for ORFs with near-cognate start codons. Based on these results, we suggest that improved sequence depth, biological repetitions, and translation initiation site profiling should be considered to obtain a high-quality catalog of translated non-canonical ORFs in future studies.
THE STATE OF CURRENT MANAGEMENT OF THE HEIGHTENED RISK FOR ATHEROSCLEROTIC CARDIOVASCULAR EVENTS IN AN ESTABLISHED COHORT OF PATIENTS WITH LUPUS ERYTHEMATOSUS
Authors: Zhao Megan , Feng Rui , Werth Victoria P. , Williams Kevin Jon 
Published: December 2022

AbstractBackgroundPatients with lupus erythematosus (LE) are at a heightened risk for clinical events, chiefly heart attacks and strokes, caused by atherosclerotic cardiovascular disease (ASCVD). We recently proposed new guidelines to categorize levels of risk for future ASCVD events specifically in LE patients, with recommendations for management. Here, we assessed the state of current management of ASCVD event risk in light of these new recommendations.MethodsWe studied our entire UPenn Longitudinal Lupus Cohort of patients with cutaneous LE, without or with concurrent systemic LE, for whom we had full access to medical records (n=370, LE-ASCVD Study Cohort, years 2007-2021).ResultsOf our LE-ASCVD Study Cohort, 336/370 (90.8%) had a designated primary-care physician. By the new guidelines, the most recent plasma LDL cholesterol levels were above goal for 252/370 (68.1%) of the Cohort. Two hundred sixty-six (71.9%) had hypertension, which was under- or un-treated in 198/266 (74.4%). Of current smokers, 51/63 (81.0%) had no documented smoking cessation counseling or referrals. Diabetes was generally well-managed, and hypertriglyceridemia was uncommon. Of the Cohort, 254 patients qualified for two widely used online calculators in primary prevention that estimate the risk of an ASCVD event in the next 10 years: the ACC-ASCVD Risk Estimator Plus and QRisk3. We also stratified these 254 patients into the categories of ASCVD event risk we recently defined specifically for LE. Surprisingly, these three methods for estimating ASCVD event risk showed clinically meaningful agreement for only 100/254 (39.4%), i.e., discordance for over 60% that could affect clinical management. The documented rate of ASCVD events in the first 10 years after enrollment was 22.3% (95% CI 16.9%, 27.4%), indicating a high-risk population despite a preponderance of women and a median age at enrollment of only 47 years.ConclusionCutaneous LE patients are under-treated compared with the new guidelines and, accordingly, they experience a substantial burden of ASCVD events. Moreover, it is unclear how to accurately assess future ASCVD event risk in these patients – except that it is high – and this uncertainty may complicate clinical management. Efforts are underway to improve ASCVD event risk estimation and guideline implementation in lupus patients.
A subnational family planning estimation tool (SFPET) for estimating contraceptive use and unmet need by subnational areas and demographic subgroups
Authors: Kong David , Claps Emily , Kirkman Clark , Enriquez Minerva , Ressler Bryan , Mercer Laina D. , Buxton Sam , Izzo Mandy , Proctor Joshua L. 
Published: December 2022

AbstractBackgroundAccess to safe, effective, and voluntary family planning (FP) is a fundamental human right and is an important step toward achieving gender equality and economic autonomy. Global organizations have set ambitious goals to create universal access to FP services but assessing progress can be challenging, especially at the local geographic scale. Here, we present a quantitative visualization tool called the subnational family planning estimation tool (SFPET) that can be used by policy makers to monitor programmatic success at subnational levels and gain insight into trends within demographic subgroups.MethodsThe visualization tool builds on the statistical methods and analyses presented in earlier research to generate model-based estimates of FP indicators for 25 sub-Saharan countries at administrative units one and two. Here, we have extended this modeling approach to more demographic and geographic subgroups, integrated recently released survey data, and constructed a web-based dashboard to navigate survey and model-based estimates.FindingsSignificant heterogeneity in the levels and trends of FP indicators exist at subnational levels and across demographic subgroups. This tool provides the ability to efficiently navigate these model-based estimates across local regions within countries and across demographic subgroups. The tool also helps highlight regions and groups that may be falling behind the national trends as well as identify exemplars that exceed the national average.InterpretationSFPET1is an interactive dashboard created to aid policymakers in assessing progress towards family planning goals by visualizing both model-based and direct survey estimates of family planning indicators at the subnational level. This framework provides insight into locations and population segments experiencing the greatest unmet need, enabling targeting and allocation of resources to achieve family planning goals.
A unifying theory explains seemingly contradicting biases in perceptual estimation
Authors: Hahn Michael , Wei Xue-Xin 
Published: December 2022

AbstractPerceptual biases are widely regarded as a window into the computational principles underlying human perception. To understand these biases, previous work has proposed a number of conceptually different and even seemingly contradicting ingredients, including attraction to a Bayesian prior, repulsion from the prior due to efficient coding, and central tendency effects on a bounded range. We present a unifying Bayesian theory of biases in perceptual estimation. We theoretically demonstrate an additive decomposition of perceptual biases into attraction to a prior, repulsion away from regions with high encoding precision, and regression away from the boundary. The results reveal a simple and universal rule for predicting the direction of perceptual biases. Our theory accounts for, and leads to new understandings of biases in the perception of a variety of stimulus attributes, including orientation, color, and magnitude.
Infer global, predict local: quantity-quality trade-off in protein fitness predictions from sequence data
Authors: Posani Lorenzo , Rizzato Francesca , Monasson Rémi , Cocco Simona 
Published: December 2022

AbstractPredicting the effects of mutations on protein function is an important issue in evolutionary biology and biomedical applications. Computational approaches, ranging from graphical models to deep-learning architectures, can capture the statistical properties of sequence data and predict the outcome of high-throughput mutagenesis experiments probing the fitness landscape around some wild-type protein. However, how the complexity of the models and the characteristics of the data combine to determine the predictive performance remains unclear. Here, based on a theoretical analysis of the prediction error, we propose descriptors of the sequence data, characterizing their quantity and quality relative to the model. Our theoretical framework identifies a trade-off between these two quantities, and determines the optimal subset of data for the prediction task, showing that simple models can outperform complex ones when inferred from adequately-selected sequences. We also show how repeated subsampling of the sequence data allows for assessing how much epistasis in the fitness landscape is not captured by the computational model. Our approach is illustrated on several protein families, as well as on in silico solvable protein models.Significance StatementIs more data always better? Or should one prefer fewer data, but of higher quality? Here, we investigate this question in the context of the prediction of fitness effects resulting from mutations to a wild-type protein. We show, based on theory and data analysis, that simple models trained on a small subset of carefully chosen sequence data can perform better than complex ones trained on all available data. Furthermore, we explain how comparing the simple local models obtained with different subsets of training data reveals how much of the epistatic interactions shaping the fitness landscape are left unmodeled.
Modelling Spontaneous Firing Activity of the Motor Cortex in a Spiking Neural Network with Random and Local Connectivity
Authors: Haggie Lysea , Besier Thor , McMorland Angus 
Published: December 2022

AbstractComputational models of cortical activity can provide in-sight into the mechanisms of higher-order processing in the human brain including planning, perception and the control of movement. Activity in the cortex is ongoing even in the absence of sensory input or discernible movements and is thought to be linked to the topology of the underlying cortical circuitry [1]. However, the connectivity and its functional role in the generation of spatio-temporal firing patterns and cortical computations are still unknown.Movement of the body is a key function of the brain, with the motor cortex the main cortical area implicated in the generation of movement. We built a spiking neural network model of the motor cortex which incorporates a laminar structure and circuitry based on a previous cortical model by Potjans and Diesmann [2]. A local connectivity scheme was implemented to introduce more physiological plausibility to the cortex model, and the effect on the rates, distributions and irregularity of neuronal firing was compared to the original random connectivity method and experimental data. Local connectivity increased the distribution of and overall rate of neuronal firing. It also resulted in the irregularity of firing being more similar to those observed in experimental measurements, and a reduction in the variability in power spectrum measures.The larger variability in dynamical behaviour of the local connectivity model suggests that the topological structure of the connections in neuronal population plays a significant role in firing patterns during spontaneous activity. This model took steps towards replicating the macroscopic network of the motor cortex, replicating realistic spatiotemporal firing to shed light on information coding in the cortex. Large scale computational models such as this one can capture how structure and function relate to observable neuronal firing behaviour, and investigates the underlying computational mechanisms of the brain.
Biomechanical influence of plate configurations on mandible subcondylar fracture fixation: a finite element study
Authors: Gupta Anoushka , Dutta Abir , Dutta Kaushik , Mukherjee Kaushik 
Published: December 2022

AbstractMandible subcondylar fractures have very high complication rate, yet there is no consensus in a suitable plate design for optimal patient outcomes. The present study is aimed at understanding the subcondylar fracture fixation by comparing load transfer in intact and reconstructed fractured mandibles with five different plates: single mini, trapezoid, lambda, strut, and double-mini plates under the complete mastication cycle. Under contralateral molar occlusion (LMOL), the single mini plate resulted in the highest strains. On the contrary, during ipsilateral molar clenching (RMOL), the tensile and compressive strain distributions were found to be reversed, with the tensile strains at the posterior border resulting in lesser strain in reconstructed mandible with single mini plate. Owing to the reduced strains in the reconstructed mandibles, the contralateral molar clenching task is preferred during the immediate post-surgery period for patients. Under this contralateral molar clenching, the peak von Mises stresses in the plate decreased with increase in the number of screws. Furthermore, the presence of two arms seems beneficial to neutralise the tensile and compressive strains across load cases. Consequently, double mini and trapezoid plates were found to perform better as compared to single mini plate during the entire mastication cycle for subcondylar fracture fixation.
Evaluating hippocampal replay without a ground truth
Authors: Takigawa M. , Huelin Gorriz M. , Tirole M. , Bendor D. 
Published: December 2022

AbstractDuring rest and sleep, memory traces replay in the brain. The dialogue between brain regions during replay is thought to stabilize labile memory traces for long-term storage. However, because replay is an internally-driven, spontaneous phenomenon, it does not have a ground truth - an external reference that can validate whether a memory has truly been replayed. Instead, replay detection is based on the similarity between the sequential neural activity comprising the replay event and the corresponding template of neural activity generated during active locomotion. If the statistical likelihood of observing such a match by chance is sufficiently low, the candidate replay event is inferred to be replaying that specific memory. However, without the ability to evaluate whether replay detection methods are successfully detecting true events and correctly rejecting non-events, the evaluation and comparison of different replay methods is challenging. To circumvent this problem, we present a new framework for evaluating replay, tested using hippocampal neural recordings from rats exploring two novel linear tracks. Using this two-track paradigm, our framework selects replay events based on their temporal fidelity (sequence-based detection), and applies a cross-validation using each event’s trajectory discriminability, where sequenceless decoding across both tracks is used to quantify whether the track replaying is also the most likely track being reactivated.
A multifunctional Wnt regulator underlies the evolution of coat pattern in African striped mice
Authors: Johnson Matthew R. , Li Sha , Guerrero-Juarez Christian F. , Miller Pearson , Brack Benjamin J. , Mereby Sarah A. , Feigin Charles , Gaska Jenna , Nie Qing , Rivera-Perez Jaime A. , Ploss Alexander , Shvartsman Stanislav Y. , Mallarino Ricardo 
Published: December 2022

AbstractAnimal pigment patterns are excellent models to elucidate mechanisms of biological organization. Although theoretical simulations, such as Turing reaction-diffusion systems, recapitulate many animal patterns, they are insufficient to account for those showing a high degree of spatial organization and reproducibility. Here, we compare the coats of the African striped mouse (Rhabdomys pumilio) and the laboratory mouse (Mus musculus) to study the molecular mechanisms controlling stripe pattern formation. By combining transcriptomics, mathematical modeling, and mouse transgenics, we show thatSfrp2regulates the distribution of hair follicles and establishes an embryonic prepattern that foreshadows pigment stripes. Moreover, by developing and employingin vivogene editing experiments in striped mice, we find thatSfrp2knockout is sufficient to alter the stripe pattern. Strikingly, mutants also exhibit changes in coat color, revealing an additional function ofSfrp2in regulating hair color. Thus, a single factor controls coat pattern formation by acting both as an orienting signaling mechanism and a modulator of pigmentation. By uncovering a multifunctional regulator of stripe formation, our work provides insights into the mechanisms by which spatial patterns are established in developing embryos and the molecular basis of phenotypic novelty.
Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity
Authors: Kriukov Dmitrii , Khrameeva Ekaterina E. , Gladyshev Vadim N. , Dmitriev Sergey E. , Tyshkovskiy Alexander 
Published: December 2022

AbstractPartial somatic cell reprogramming has been touted as a promising rejuvenation strategy. However, its association with mechanisms of aging and longevity at the molecular level remains unclear. We identified a robust transcriptomic signature of reprogramming in mouse and human cells that revealed co-regulation of genes associated with reprogramming and response to lifespan-extending interventions, including those related to DNA repair and inflammation. We found that age-related gene expression changes were reversed during reprogramming, as confirmed by transcriptomic aging clocks. The longevity and rejuvenation effects induced by reprogramming in the transcriptome were mainly independent of pluripotency gain. Decoupling of these processes allowed predicting interventions mimicking reprogramming-induced rejuvenation (RIR) without affecting somatic cell identity, including an anti-inflammatory compound osthol,ATG5overexpression, andC6ORF223knockout. Overall, we revealed specific molecular mechanisms associated with RIR at the gene expression level and developed tools for discovering interventions that support the rejuvenation effect of reprogramming without posing the risk of neoplasia.
Extending eco-evolutionary theory with oligomorphic dynamics
Authors: Lion Sébastien , Sasaki Akira , Boots Mike 
Published: December 2022

AbstractUnderstanding the interplay between ecological processes and the evolutionary dynamics of quantitative traits in natural systems remains a major challenge. Two main theoretical frameworks are used to address this question, adaptive dynamics and quantitative genetics, both of which have strengths and limitations and are often used by distinct research communities to address different questions. In order to make progress, new theoretical developments are needed that integrate these approaches and strengthen the link to empirical data. Here, we discuss a novel theoretical framework that bridges the gap between quantitative genetics and adaptive dynamics approaches. “Oligomorphic dynamics” can be used to analyse eco-evolutionary dynamics across different time scales and extends quantitative genetics theory to account for multimodal trait distributions, the dynamical nature of genetic variance, the potential for disruptive selection due to ecological feed-backs, and the non-normal or skewed trait distributions encountered in nature. Oligomorphic dynamics explicitly takes into account the effect of environmental feedback, such as frequency- and density-dependent selection, on the dynamics of multi-modal trait distributions and we argue it has the potential to facilitate a much tighter integration between eco-evolutionary theory and empirical data.
A study of the expression of germline-specific paralogs of the ubiquitously expressed NAC complex revealed their association with centrosomes
Authors: Mikhaleva Elena A. , Akulenko Natalia V. , Olenkina Oxana M. , Abramov Yuri A. , Lavrov Sergey A. , Leinsoo Thoomas A. , Kogan Galina L. , Gvozdev Vladimir A. 
Published: December 2022

AbstractProtein homeostasis involves the ubiquitously expressed heterodimeric protein NAC (ribosome associated nascent polypeptide complex), consisting of α- and β-subunits. We previously found inDrosophila melanogasterthe presence of germline-specific paralogous genes for NAC subunits (gNACs): unique for the α-subunit and several highly homologous amplified genes for the β-subunit, indistinguishable by the antibodies used, while they were detected as different phosphorylated isoforms in 2D electrophoresis with immunostaining. The distinct increase in gNAC expression in growing spermatocytes compared with their predecessors, gonioblasts, is accompanied by a clear presence of gNAC in the cytoplasm of dividing meiotic cells and spermatids. In oogenesis, gNAC expression is significantly lower than in the testis, but gNAC accumulation is found at the posterior pole of the mature oocyte, known as the germplasm region responsible for the germ cell formation in the offspring. gNAC-associated ribosomes from mature oocytes are enriched in mRNA sets encoding known germplasm and centrosome proteins. gNAC is also detected in a pericentriolar component of centrosomes: in syncytial dividing nuclei in the early embryos, in primordial germ cells and spermatocytes, including meiotic divisions stage. CRISPR/Cas9-mediated deficiency of the gNAC-alpha subunit causes female infertility. We propose the role of the gNAC phosphoregulatory paralog system as a component of the germline proteostasis network, coordinated with the centrosome functions. Here, we also extended our results by identifying cross-links between ubiquitous and germline-specific NAC-β paralogs, finding an additional case of functional cross-talk between heterodimeric ubNAC and gNAC α-subunit paralogs, which may maintain the robustness of proteostasis and fly fecundity.
Trivalent SARS-CoV-2 S1 Subunit Protein Vaccination Induces Broad Humoral Responses in BALB/c Mice
Authors: Khan Muhammad S. , Kim Eun , Huang Shaohua , Kenniston Thomas W. , Gambotto Andrea 
Published: December 2022

AbstractThis paper presents a novel approach for improving the efficacy of COVID-19 vaccines against emergent SARS-CoV-2 variants. We have evaluated the immunogenicity of unadjuvanted wild-type (WU S1-RS09cg) and variant-specific (Delta S1-RS09cg and OM S1-RS09cg) S1 subunit protein vaccines delivered either as a monovalent or a trivalent antigen in BALB/c mice. Our results show that a trivalent approach induced a broader humoral response with more coverage against antigenically distinct variants, especially when compared to monovalent Omicron-specific S1. This trivalent approach was also found to have increased or equivalent ACE2 binding inhibition, and increased S1 IgG endpoint titer at early timepoints, against SARS-CoV-2 spike variants when compared monovalent Wuhan, Delta, or Omicron S1. Our results demonstrate the utility of protein subunit vaccines against COVID-19 and provide insights into the impact of variant-specific COVID-19 vaccine approaches on the immune response in the current SARS-CoV-2 variant landscape. Particularly, our study provides insight into effects of further increasing valency of currently approved SARS-CoV-2 vaccines, a promising approach for improving protection to curtail emerging viral variants.