bluuebunny/crossref_metadata_2025 huggingface dataset:
Bivalent mRNA vaccine improves antibody-mediated neutralization of many SARS-CoV-2 Omicron lineage variants
Authors: Jiang Nannan , Wang Li , Hatta Masato , Feng Chenchen , Currier Michael , Lin Xudong , Hossain Jaber , Cui Dan , Mann Brian R. , Kovacs Nicholas A. , Wang Wei , Atteberry Ginger , Wilson Malania , Chau Reina , Lacek Kristine A. , Paden Clinton R. , Hassell Norman , Rambo-Martin Benjamin , Barnes John R. , Kondor Rebecca J. , Self Wesley H. , Rhoads Jillian P. , Baughman Adrienne , Chappell James D. , Shapiro Nathan I. , Gibbs Kevin W. , Hager David N. , Lauring Adam S. , Surie Diya , McMorrow Meredith L. , Thornburg Natalie J. , Wentworth David E. , Zhou Bin
Published: January 2023

The early Omicron lineage variants evolved and gave rise to diverging lineages that fueled the COVID-19 pandemic in 2022. Bivalent mRNA vaccines, designed to broaden protection against circulating and future variants, were authorized by the U.S. Food and Drug Administration (FDA) in August 2022 and recommended by the U.S. Centers for Disease Control and Prevention (CDC) in September 2022. The impact of bivalent vaccination on eliciting neutralizing antibodies against homologous BA.4/BA.5 viruses as well as emerging heterologous viruses needs to be analyzed. In this study, we analyze the neutralizing activity of sera collected after a third dose of vaccination (2-6 weeks post monovalent booster) or a fourth dose of vaccination (2-7 weeks post bivalent booster) against 10 predominant/recent Omicron lineage viruses including BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BN.1, BQ.1, BQ.1.1, XBB, and XBB.1. The bivalent booster vaccination enhanced neutralizing antibody titers against all Omicron lineage viruses tested, including a 10-fold increase in neutralization of BQ.1 and BQ.1.1 viruses that predominated in the U.S. during the last two months of 2022. Overall, the data indicate the bivalent vaccine booster strengthens protection against Omicron lineage variants that evolved from BA.5 and BA.2 progenitors.
Novel artificial selection method improves function of simulated microbial communities
Authors: Vessman Björn , Guridi-Fernández Pablo , Arias-Sánchez Flor Inés , Mitri Sara
Published: January 2023

There is increasing interest in artificially selecting or breeding microbial communities, but experiments have reported modest success and it remains unclear how to best design such a selection experiment. Here, we develop computational models to simulate two previously known selection methods and compare them to a new “disassembly” method that we have developed. Our method relies on repeatedly competing different communities of known species combinations against one another, and sometimes changing the species combinations. Our approach significantly outperformed previous methods that could not maintain enough between-community diversity for selection to act on. Instead, the disassembly method allowed many species combinations to be explored throughout a single selection experiment. Nevertheless, selection at the community level in our simulations did not counteract selection at the individual level. Species in our model can mutate, and we found that they evolved to invest less into community function and more into growth. Increased growth compensated for reduced investment, however, and overall community performance was barely affected by within-species evolution. Our work provides important insights that will help design community selection experiments.
Dietary Trends and Dementia - A Multi-Country Ecological Analysis
Authors: Reed Robert
Published: January 2023

Background

This research evaluates the association between increased animal product consumption and population-level dementia incidence.

Design/methodology/approach

Publicly available data from 54 countries across a 10-year span was used to conduct a multivariate panel data regression to determine significant relationships between dietary changes and rates of dementia. Fixed effects analysis controls for the effect of omitted time-invariant differences between countries.

Findings

Excess calorie consumption is associated with a significant increase in dementia whereas fish consumption appears protective. On a population-level basis, increases in milk and egg consumption were associated with an increase in dementia rates. Meat, as a broadly defined category, was found to have no significant effect.

Practical Implications

This study supports the well-documented benefits of calorie control and fish consumption to protect against dementia, but indicates that egg and milk consumption is associated with increased population-level dementia incidence.

Originality/value

This research expands current literature by using an updated data set, evaluating considerably more countries, and utilizing a regression model that controls for the effects of time-invariant sources of heterogeneity in the data.
Combined severe-to-profound hearing and vision impairment – experiences of daily life and need of support, an interview study
Authors: Turunen-Taheri Satu , Hagerman Sirelius Annica , Hellström Sten , Skjönsberg Åsa , Backenroth Gunnel
Published: January 2023

Objectives

The purpose of the present study was to describe experiences of disabilities and factors affecting daily life from the perspective of adult persons with severe-to-profound hearing impairment in combination with severe vision impairment. Furthermore, the study also investigated which kind of support individuals with dual sensory loss received, and their experiences as citizens in the society.

Methods

Semi-structured qualitative interviews were performed, analyzed, and categorized using content analysis.

Results

Fourteen interviews were performed, with equal number of both sexes. Mean age was 70.1 years (47-81 years). Analysis of the data resulted in 22 categories, six sub-themes and two main themes. Two main themes emerged asIsolationandThe Ability to control one’s own daily life. Surprisingly, most of the participants did not think of their vision and hearing impairment as a combined disability. The interviews showed various kind of strategies to handle daily life. The Deafblind-team unit was reported to offer excellent health care. Companion services for persons with disabilities proved to have become more difficult to get support from and created lack of independence and control over their own lives. However, it was also obvious that the participants felt a positive outlook on life and more solution-oriented in order to adjust their everyday life to their life-situation.

Conclusions

The combination of vision and hearing impairment demonstrated isolation, and the respondents in the study have a need of support in everyday lives. At the same time, they struggle to have the ability to control their own lives.
The effect of emotion regulation on emotional eating among undergraduate students in China: the chain mediating role of impulsivity and depressive symptoms
Authors: Yang Huimin , Zhou Xinyi , Xie Longjiao , Sun Jing
Published: January 2023

This study aimed to examine the relationship between difficulties in emotion regulation and emotional eating and the role of impulsivity and depressive symptoms in mediating this chain. Four hundred ninety-four undergraduate students participated in the study. A self-designed questionnaire was used in the survey from February 6 to 13, 2022, to finish our purpose, including the Emotional Eating Scale (EES-R), Depression Scale (CES-D), the Short Version of the Impulsivity Behavior Scale (UPPS-P) and Difficulties in Emotion Regulation Scale (DERS). Results showed that 1) There was a positive correlation between difficulties in emotion regulation, impulsivity, depressive symptoms, and emotional eating, respectively.2) Impulsivity and depressive symptoms mediated the relationship between emotion regulation and emotional eating separately. 3) Impulsivity and depressive symptoms played the mediating chain role between emotion regulation and emotional eating.
Research on the mental health status of frontline medical staff during the normalization of the COVID-19 pandemic
Authors: Sun Ning , Li Laiyou , Xu Jinmei , zhou Shuping , Fan Chaoyan , Li Hongyu , Yang Shuang
Published: January 2023

Objective

This study aimed to investigate the relationship between personality characteristics and psychological health of hospitals’ frontline medical staff and provide a basis and reference for targeted psychological health education for frontline medical staff and for the staff of related departments to formulate relevant policies.

Methods

The self-evaluation scale of symptoms (SCL-90) was used to investigate the mental health status of 150 first-line medical staff in Zhejiang Province in response to the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.

Results

The average scores of SCL-90 and somatization, obsessive-compulsive, depression, anxiety, hostility, terror, and psychotic factors were significantly higher than those of the normal sample in the first-aid medical staff of Aihu Hubei. The degree of influence on the mental health status of the frontline medical staff in service in Hubei is as follows, from high to low: the degree of suspicion that they may have been infected when new coronavirus pneumonia-related symptoms occur, the degree of fear of being infected and thus bring the infection to their families, and whether they have received a medical check-up recently, as well as a high level of education (bothP<0.05).

Conclusion

The psychological health level of the frontline medical staff is lower than the national norm. In the context of the increasing number of confirmed cases and the new type of coronavirus pneumonia in the absence of any specific curative treatments, the frontline medical staff is under great psychological pressure. It is necessary to institute targeted mental health promotion to relieve the psychological pressure endured by the frontline medical staff, promote their physical and mental health, and better respond to the pandemic in China.
Integration of chromatin accessibility and gene expression data with cisREAD reveals a switch from PU.1/SPIB-driven to AP-1-driven gene regulation during B cell activation
Authors: Emmett Amber M.L. , Saadi Amel , Care Matthew A. , Doody Gina M. , Tooze Reuben M. , Westhead David R.
Published: January 2023

Human B cell differentiation into antibody secreting plasma cells is a critical process in the adaptive immune response, whose regulation at the genetic level remains incompletely understood. To reveal the temporal sequence of transcription factor driven cellular changes we generated chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data fromin vitrodifferentiation of human B cells into plasma cells using a published protocol for differentiation up to the plasma cell stage. Using a new computational method, cisREAD (cis-Regulatory Elements Across Differentiation), we defined a core set ofcis-regulatory elements that are confidently linked to dynamic transcription factor binding and changes in gene expression across the mature B lineage. Here we describe how cisREAD identifies regulatory element ‘communities’, based on chromatin accessibility and transcription factor co-occupancy, and prioritizes those whose accessibility predicts differential gene expression through regularized regression models. Through downstream analyses of cisREAD-predicted regulation, we show how transcription factors reshape B cell epigenomes and transcriptomes in response to differentiation stimuli. Our results confirm roles for OCT2, IRF4 and PRDM1 in plasma cell differentiation, and reveal that a shift from PU.1/SPIB-driven to AP-1-driven gene regulation is a key determinant of B cell activation.

GRAPHICAL ABSTRACT

Integration of epigenomic and transcriptomic datasets with the cisREAD method, followed by clustering and network analysis, reveals that gene regulation shifts from PU.1/SPIB to AP-1 upon B cell activation.
Single Molecule Mechanics and Kinetics of Cardiac Myosin Interacting with Regulated Thin Filaments
Authors: Clippinger Schulte Sarah R. , Scott Brent , Barrick Samantha K. , Stump W. Tom , Blackwell Thomas , Greenberg Michael J.
Published: January 2023

The cardiac cycle is a tightly regulated process wherein the heart generates force to pump blood to the body during systole and then relaxes during diastole. Disruption of this finely tuned cycle can lead to a range of diseases including cardiomyopathies and heart failure. Cardiac contraction is driven by the molecular motor myosin, which pulls regulated thin filaments in a calcium-dependent manner. In some muscle and non-muscle myosins, regulatory proteins on actin tune the kinetics, mechanics, and load dependence of the myosin working stroke; however, it is not well understood whether or how thin filament regulatory proteins tune the mechanics of the cardiac myosin motor. To address this critical gap in knowledge, we used single-molecule techniques to measure the kinetics and mechanics of the substeps of the cardiac myosin working stroke in the presence and absence of thin filament regulatory proteins. We found that regulatory proteins gate the calcium-dependent interactions between myosin and the thin filament. At physiologically relevant ATP concentrations, cardiac myosin’s mechanics and unloaded kinetics are not affected by thin filament regulatory proteins. We also measured the load-dependent kinetics of cardiac myosin at physiologically relevant ATP concentrations using an isometric optical clamp, and we found that thin filament regulatory proteins do not affect either the identity or magnitude of myosin’s primary load-dependent transition. Interestingly, at low ATP concentrations, thin filament regulatory proteins have a small effect on actomyosin dissociation kinetics, suggesting a mechanism beyond simple steric blocking. These results have important implications for both disease modeling and computational models of muscle contraction.

Significance Statement

Human heart contraction is powered by the molecular motor β-cardiac myosin, which pulls on thin filaments consisting of actin and the regulatory proteins troponin and tropomyosin. In some muscle and non-muscle systems, these regulatory proteins tune the kinetics, mechanics, and load dependence of the myosin working stroke. Despite having a central role in health and disease, it is not well understood whether the mechanics or kinetics of β-cardiac myosin are affected by regulatory proteins. We show that regulatory proteins do not affect the mechanics or load-dependent kinetics of the working stroke at physiologically relevant ATP concentrations; however, they can affect the kinetics at low ATP concentrations, suggesting a mechanism beyond simple steric blocking. This has important implications for modeling of cardiac physiology and diseases.
Thermal plasticity of wing spot size inDrosophila guttifera: investigating the relevance to Wingless morphogen
Authors: Fukutomi Yuichi , Takahashi Aya , Koshikawa Shigeyuki
Published: January 2023

Thermal plasticity of animal color patterns has been studied to investigate the molecular mechanisms of phenotypic plasticity. There are examples in which the formation of color patterns is controlled by a morphogen. The extracellular distribution of a morphogen can be plastic with temperature change. Whether alteration of morphogen distribution with temperature change produces thermal plasticity in color patterns has not been studied. To address this question, polka-dotted wing spots ofDrosophila guttifera, whose inducer iswinglessmorphogen, can be a suitable model system. In this study, we rearedD. guttiferaat different temperatures to test whether wing spots show thermal plasticity. We found that wing size becomes larger and spot size adjusted with wing size becomes smaller at lower temperatures. We also changed the rearing temperature in the middle of the pupal period and found that the most sensitive developmental period for wing size and spot size is different. The results suggest that developmental mechanisms for the thermal plasticity of wing size and spot size are different. We also found that the most sensitive stage for spot size was part of the pupal period including stages at whichwinglessis expressed in the polka-dotted pattern. Therefore, it is suggested that temperature change might affect the process of specifying spot areas by Wingless in the extracellular region.
A field-capable rapid plant DNA extraction protocol using microneedle patches for botanical survey and monitoring
Authors: Selz Jonathan , Adam Nicolas R. , Magrini Céline E. M. , Montandon Fulvia Malvido , Buerki Sven , Maerkl Sebastian J.
Published: January 2023

Premise

A novel protocol for rapid plant DNA extractions using microneedles is proposed, which supports botanic surveys, taxonomy and systematics. This protocol can be conducted in the field with limited laboratory skills and equipment. The protocol is validated by conducting sequencing and comparing results with Qiagen spin-column DNA extractions using BLAST analyses.

Methods and Results

Two sets of DNA extractions were conducted on 13 species spanning various leaf anatomies and phylogenetic lineages: i) fresh leaves were punched with custom polymeric microneedle patches to recover genomic DNA ii) Qiagen DNA extractions. Three plastid (matK,rbcL,trnH-psbA) and one nuclear ribosomal (ITS) DNA regions were amplified, and Sanger or Nanopore sequenced. The proposed method reduced the extraction to 1 min and yielded the same DNA sequences as Qiagen.

Conclusions

Our drastically faster and simpler method is compatible with Nanopore sequencing and suitable for multiple applications including high-throughput DNA-based species identification and monitoring.
Parental care shapes the evolution of molecular genetic variation
Authors: Mashoodh R , Trowsdale A , Manica A , Kilner RM
Published: January 2023

Cooperative social behaviours, such as parental care, have long been hypothesized to relax selection leading to the accumulation of genetic variation in populations. Although the idea has been discussed for decades, there has been relatively little experimental work to investigate how social behaviour contributes to genetic variation in populations. Here, we investigate how parental care can shape molecular genetic variation in the subsocial insectNicrophorus vespilloides. Using whole genome sequencing of populations that had evolved in the presence or absence of parental care for 30 generations, we show that parental care maintains levels of standing genetic variation. In contrast, under a harsh environment without care, strong directional selection caused a reduction in genetic variation. Furthermore, we show that adaptation to the loss of care is associated with genetic divergence between populations at loci related to stress, morphological development and transcriptional regulation. These data reveal how social behaviour is linked to the genetic processes that shape and maintain genetic diversity within populations, and provides rare empirical evidence for an old hypothesis.

Lay Summary

Social behaviours, such as parental care, have long been hypothesized to result in the accumulation of genetic variation in populations. Here, we investigate how parental care can shape molecular genetic variation in a species that perform biparental care,Nicrophorus vespilloides. Using genome sequencing of populations that had evolved in the presence or absence of parental care for 30 generations, we show that parental care maintains levels of standing genetic variation. In contrast, under a harsh environment without care, populations lost genetic variation. Furthermore, we show that adaptation to the loss of care is associated with genetic divergence between populations at genes related to stress, morphological development and transcriptional regulation. These data reveal how social behaviour is linked to the genetic processes that shape and maintain genetic diversity within populations.
Missing data in amortized simulation-based neural posterior estimation
Authors: Wang Zijian , Hasenauer Jan , Schälte Yannik
Published: January 2023

Amortized simulation-based neural posterior estimation provides a novel machine learning based approach for solving parameter estimation problems. It has been shown to be computationally efficient and able to handle complex models and data sets. Yet, the available approach cannot handle the in experimental studies ubiquitous case of missing data, and might provide incorrect posterior estimates. In this work, we discuss various ways of encoding missing data and integrate them into the training and inference process. We implement the approaches in the BayesFlow methodology, an amortized estimation framework based on invertible neural networks, and evaluate their performance on multiple test problems. We find that an approach in which the data vector is augmented with binary indicators of presence or absence of values performs the most robustly. Accordingly, we demonstrate that amortized simulation-based inference approaches are applicable even with missing data, and we provide a guideline for their handling, which is relevant for a broad spectrum of applications.
Odd-even disparity in the population of slipped hairpins in RNA repeat sequences with implications for phase separation
Authors: Maity Hiranmay , Nguyen Hung T. , Hori Naoto , Thirumalai D.
Published: January 2023

Low complexity nucleotide repeat sequences, which are implicated in several neurological disorders, undergo liquid-liquid phase separation (LLPS) provided the number of repeat units,n, exceeds a critical value. Here, we establish a link between the folding landscapes of the monomers of trinucleotide repeats and their propensity to self-associate. Simulations using a coarse-grained Self-Organized Polymer (SOP) model for (CAG)nrepeats in monovalent salt solutions reproduce experimentally measured melting temperatures, which are available only for smalln. By extending the simulations to largen, we show that the free energy gap, ΔGS, between the ground state (GS) and slipped hairpin (SH) states is a predictor of aggregation propensity. The GS for evennis a perfect hairpin (PH) whereas it is a SH whennis odd. The value of ΔGS(zero for oddn) is larger for evennthan for oddn. As a result, the rate of dimer formation is slower in (CAG)30relative to (CAG)31, thus linking ΔGSto RNA-RNA association. The yield of the dimer decreases dramatically, compared to the wild type, in mutant sequences in which the population of the SH is decreases substantially. Association between RNA chains is preceded by a transition to the SH even if the GS is a PH. The finding that the excitation spectra, which depends on the exact sequence,n, and ionic conditions, is a predictor of self-association, should also hold for other RNAs (mRNA for example) that undergo LLPS.
Distinct Functional cerebral Hypersensitivity networks during incisional and inflammatory pain in rats
Authors: Kreitz S. , Pradier B. , Segelcke D. , Amirmohseni S. , Hess A. , Faber C. , Pogatzki-Zahn E.
Published: January 2023

Although the pathophysiology of pain has been investigated tremendously, there are still many open questions, especially with regard to specific pain entities and their pain-related symptoms. To increase the translational impact of (preclinical) animal pain neuroimaging studies, the use of disease-specific pain models, as well as relevant stimulus modalities, are critical. Yet, the challenges of identifying neuroimaging signatures at a pain entity- and modality-specific level are manifold. Therefore, we developed a comprehensive framework for brain network analysis in disease-specific pain models combining functional MRI with graph-theory and data classification by linear discriminant analysis. This enabled us to expand our knowledge of stimulus (mechanical vs. electrical) modality processing under incisional (INC) and pathogen-induced inflammatory (CFA) pain entities compared to acute pain conditions. In short, graph-theoretical analyses revealed distinct Network Signatures of Pain Hypersensitivity (NSPH) for INC and CFA, resulting in impaired discrimination of stimulus modalities in both pain models compared to control conditions (CTR). Such specific neuroimaging signatures are an important step toward identifying novel pain biomarkers for certain diseases and relevant outcomes to evaluate target engagement of novel therapeutic options, which ultimately can be translated to the clinic.
Insights into the metabolic specificities of pathogenic strains from theRalstonia solanacearum species complex
Authors: Baroukh Caroline , Cottret Ludovic , Pires Emma , Peyraud Rémi , Guidot Alice , Genin Stéphane
Published: January 2023

All the strains grouped under the speciesRalstonia solanacearumrepresent a species complex which collectively constitute a devastating plant pathogen responsible of many diseases on agricultural crops throughout the world. The strains have different lifestyles and host range. Here we sought whether specific metabolic pathways contribute to strain diversification. To this end, we carried out systematic comparisons, followed by manual expertise on 11 strains representing the diversity of the species complex. We reconstructed the metabolic network of each strain from its genome sequence and looked for the metabolic pathways differentiating the different reconstructed networks and, by extension, the different strains. Finally, we conducted an experimental validation by determining the metabolic profile of each strain with the Biolog technology, also in a comparative approach. Results revealed that the metabolism is conserved between strains, with a core-metabolism composed of 82% of the pan-reactome. The 3 species composing the species complex could be distinguished according to the presence/absence of some metabolic pathways, in particular one implying salicylic acid degradation. Phenotypic assays revealed that the trophic preferences on organic acids and several amino acids such as glutamine, glutamate, aspartate and asparagine are conserved between strains. Finally, the generation and assessment of the transcription factorphcAregulating virulence in each specie showed that the faster growth compared to the WT strain was conserved acrossRalstonia solanacearumspecies complex.

Author summary

Ralstonia solanacearumis one of the most important threats to plant health worldwide, causing disease on a very large range of agricultural crops such as tomato or potato. Behind theRalstonia solanacearumname are hundreds of strains with different host range and lifestyle, classified into three species. Studying the differences between strain allows to better apprehend the biology of the pathogen and the specificity of some strains. None of the published genomic comparative studies have focused on the metabolism of the strains so far. We developed a new bioinformatic pipeline to build high-quality metabolic networks and used a combination of metabolic modeling and high-throughput phenotypic Biolog microplates to look for the metabolic differences between 11 strains across the three species. Our study revealed that genes encoding for enzymes are overall conserved, with few variations between strains. However, at the level of the phenotype, more variations were observed. These variations probably result from regulation rather than the presence or absence of enzymes in the genome.
AngioMT: An in silico platform for digital sensing of oxygen transport through heterogenous microvascular networks
Authors: Mathur Tanmay , Tronolone James J. , Jain Abhishek
Published: January 2023

Measuring the capacity of microvascular networks in delivering soluble oxygen and nutrients to its organs is essential in health, disease, and surgical interventions. Here, a finite element methodbased oxygen transport program, AngioMT, is designed and validated to predict spatial oxygen distribution and other physiologically relevant transport metrics within both the vascular network and the surrounding tissue. The software processes acquired images of microvascular networks and produces a digital mesh which is used to predict vessel and tissue oxygenation. The image-to-physics translation by AngioMT correlated with results from commercial software, however only AngioMT could provide predictions within the solid tissue in addition to vessel oxygenation. AngioMT predictions were sensitive and positively correlated to spatial heterogeneity and extent of vascularization of 500 different vascular networks formed with variable vasculogenic conditions. The predictions of AngioMT cross-correlate with experimentally-measured oxygen distributionsin vivo. The computational power of the software is increased by including calculations of higher order reaction mechanisms, and the program includes defining additional organ and tissue structures for a more physiologically relevant analysis of tissue oxygenation in complex co-cultured systems, orin vivo. AngioMT may serve as a digital performance measuring tool of vascular networks in microcirculation, experimental models of vascularized tissues and organs, and in clinical applications, such as organ transplants.
CrossTx: Cross-cell line Transcriptomic Signature Predictions
Authors: Chrysinas Panagiotis , Chen Changyou , Gunawan Rudiyanto
Published: January 2023

Motivation

Predicting the cell response to chemical compounds is central to drug discovery, drug repurposing, and personalized medicine. To this end, large datasets of drug response signatures have been curated, most notably the Connectivity Map (CMap) from the Library of Integrated Network-based Cellular Signatures (LINCS) project. A multitude ofin silicoapproaches have also been formulated to leverage drug signature data for accelerating novel therapeutics. However, the majority of the available data are from immortalized cancer cell lines. Cancer cells display markedly different responses to compounds, not only when compared to normal cells, but also among cancer types. Strategies for predicting drug signatures in unseen cells—cell lines not in the reference datasets—are still lacking.

Results

In this work we developed a computational strategy, called CrossTx, for predicting drug transcriptomic signatures of an unseen target cell line using drug transcriptome data of reference cell lines and background transcriptome data of the target cells. Our strategy involves the combination of predictor and corrector steps. Briefly, the Predictor applies averaging (mean) or linear regression model to the reference dataset to generate cell line-agnostic drug signatures. The Corrector generates target-specific drug signatures by projecting cell line-agnostic signatures from the Predictor onto the transcriptomic latent space of the target cell line using Principal Component Analysis (PCA) and/or an Autoencoder (AE). We tested different combinations of Predictor-Corrector algorithms in an application to the CMap dataset to demonstrate the performance of our approach.

Conclusion

CrossTx is an efficacious and generalizable method for predicting drug signatures in an unseen target cell line. Among the combinations tested, we found that the best strategy is to employ Mean as the Predictor and PCA followed by AE (PCA+AE) as the Corrector. Still, the combination of Mean and PCA (without AE) is an attractive strategy because of its computationally efficiency and simplicity, while offering only slightly less accurate drug signature predictions than the best performing combination.

Availability and implementation

http://www.github.com/cabsel/crosstx

Contact

rgunawan@buffalo.edu
HOGVAX: Exploiting Peptide Overlaps to Maximize Population Coverage in Vaccine Design with Application to SARS-CoV-2
Authors: Schulte Sara C. , Dilthey Alexander T. , Klau Gunnar W.
Published: January 2023

Peptide vaccines present a safe and cost-efficient alternative to traditional vaccines. Their efficacy depends on the peptides included in the vaccine and the ability of major histocompatibility complex (MHC) molecules to bind and present these peptides. Due to the high diversity of MHC alleles, their diverging peptide binding specificities, and physical constraints on the maximum length of peptide vaccine constructs, choosing a set of peptides that effectively achieve immunization across a large proportion of the population is challenging.

Here, we present HOGVAX, a combinatorial optimization approach to select peptides that maximize population coverage. The key idea behind HOGVAX is to exploit overlaps between peptide sequences to include a large number of peptides in limited space and thereby also cover rare MHC alleles. We formalize the vaccine design task as a theoretical problem, which we call the Maximum Scoring k-Superstring Problem (MSKS). We show that MSKS is NP-hard, reformulate it into a graph problem using the hierarchical overlap graph (HOG), and present a haplotype-aware variant of MSKS to take linkage disequilibrium between MHC loci into account. We give an integer linear programming formulation for the graph problem and provide an open source implementation.

We demonstrate on a SARS-CoV-2 case study that HOGVAX-designed vaccine formulations contain significantly more peptides than vaccine sequences built from concatenated peptides. We predict over 98% population coverage and high numbers of per-individual presented peptides, leading to robust immunity against new pathogens or viral variants.
Six3acts independently ofPax6to provide an essential contribution to lens development
Authors: Manohar Sumanth , Nakayama Takuya , Fisher Marilyn , Grainger Robert M.
Published: January 2023

The Six3 transcription factor is essential for forebrain and eye development, andSIX3mutations cause the congenital disorder holoprosencephaly. We created asix3mutant inXenopus tropicaliswith a mild holoprosencephaly phenotype, and unlike mouseSix3mutants that are headless/eyeless, theXenopusmutant forms some eye structures, allowing direct study of Six3 function in eye formation. We focus here on striking deficits in lens formation. Early lens induction occurs normally in the mutant, e.g., the essential eye genepax6, is activated in lens ectoderm, persisting in the eye to a late developmental stage, but in many embryos the lens fails to form. We found thatbmp4, bmp7.1, smad7, dll1, dlc, mab21l1and/ormab21l2, previously unknown assix3eye targets, are downregulated in the mutant. We show thatsix3is required for lens formation, acting primarily in developing retina during neurulation through BMP and Notch signaling, and thatmab21l1/mab21l2regulate(s) this BMP activity. This work reveals previously unrecognized essential roles forsix3in eye development, identifying its key role in signaling needed for lens formation, and acting independently ofpax6activity.

SUMMARY STATEMENT

This study identifies thesix3transcription factor as the mediator of key inductive signals driving lens formation, acting independently ofpax6in early phases of lens formation.
Simultaneous interneuron labeling reveals population-level interactions among parvalbumin, somatostatin, and pyramidal neurons in cortex
Authors: Potter Christian , Bassi Constanza , Runyan Caroline A.
Published: January 2023

Cortical interneurons shape network activity in cell type-specific ways, and are also influenced by interactions with other cell types. These specific cell-type interactions are understudied, as transgenic labeling methods typically restrict labeling to one neuron type at a time. Although recent methods have enabled post-hoc identification of cell types, these are not available to many labs. Here, we present a method to distinguish between two red fluorophoresin vivo, which allowed imaging of activity in somatostatin (SOM), parvalbumin (PV), and putative pyramidal neurons (PYR) in mouse association cortex. We compared population events of elevated activity and observed that the PYR network state corresponded to the ratio between mean SOM and PV neuron activity, demonstrating the importance of simultaneous labeling to explain dynamics. These results extend previous findings in sensory cortex, as activity became sparser and less correlated when the ratio between SOM and PV activity was high.
HYENA detects oncogenes activated by distal enhancers in cancer
Authors: Yu Anqi , Yesilkanal Ali E. , Thakur Ashish , Wang Fan , Yang Yang , Phillips William , Wu Xiaoyang , Muir Alexander , He Xin , Spitz Francois , Yang Lixing
Published: January 2023

Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm “HYENA” to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNATOB1-AS1is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression ofTOB1-AS1can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
Polyploid yeast are dependent on elevated levels of Mps1 for successful chromosome segregation
Authors: Meyer Régis E , Sartin Ashlea , Gish Madeline , Harsha Jillian , Wilkie Emily , Haworth Dawson , LaVictoire Rebecca , Alberola Isabel , Chuong Hoa H , Gorbsky Gary J , Dawson Dean S
Published: January 2023

Tumor cell lines with elevated chromosome numbers frequently have correlated elevations of Mps1 expression and these tumors are more dependent on Mps1 activity for their survival than control cell lines. Mps1 is a conserved kinase involved in controlling aspects of chromosome segregation in mitosis and meiosis. The mechanistic explanation for the Mps1-addiction of aneuploid cells is unknown. To address this question, we explored Mps1-dependence in yeast cells with increased sets of chromosomes. These experiments revealed that in yeast, increasing ploidy leads to delays and failures in orienting chromosomes on the mitotic spindle. Yeast cells with elevated numbers of chromosomes proved vulnerable to reductions of Mps1 activity. Cells with reduced Mps1 activity exhibit an extended prometaphase with longer spindles and delays in orienting the chromosomes. One known role of Mps1 is in recruiting Bub1 to the kinetochore in meiosis. We found that the Mps1-addiction of polyploid yeast cells is due in part to its role in Bub1 recruitment. Together, the experiments presented here demonstrate that increased ploidy renders cells more dependent on Mps1 for orienting chromosomes on the spindle. The phenomenon described here may be relevant in understanding why hyper-diploid cancer cells exhibit elevated reliance on Mps1 expression for successful chromosome segregation.

Author summary

Losing or gaining chromosomes during cell division leads to aneuploidy (an abnormal number of chromosomes) and can contribute to cancer and other diseases. Indeed, most cells in solid tumors carry abnormally elevated numbers of chromosomes. Mps1 is a regulator of the machinery that distributes chromosomes to daughter cells. In tumors with elevated chromosome numbers the expression of Mps1 is often also elevated. In some aneuploid tumor cell lines these elevated Mps1 levels have been shown to be critical for survival tumor survival. To determine how cells with higher ploidy become dependent on Mps1, we explored Mps1-dependence in yeast cells with increased numbers of chromosomes. We report that yeast cells with elevated chromosome number are sensitive to reductions Mps1 expression. In cells with high ploidy and reduced levels of Mps1, the progression of the cell cycle is delayed and the ability of the cells to properly orient and segregate their chromosomes on the spindle is greatly reduced.
Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
Authors: Bai Nan , Adeshina Yusuf , Bychkov Igor , Xia Yan , Gowthaman Ragul , Miller Sven A. , Gupta Abhishek K. , Johnson David K. , Lan Lan , Golemis Erica A. , Makhov Petr B. , Xu Liang , Pillai Manoj M. , Boumber Yanis , Karanicolas John
Published: January 2023

RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of “hotspots” from protein-protein complexes to protein-RNA complexes, supports the “druggability” of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins.
A Cellular Platform for Production of C4Monomers
Authors: Davis Matthew A. , Yu Vivian Yaci , Fu Beverly , Wen Miao , Koleski Edward J. , Silverman Joshua , Berdan Charles A. , Nomura Daniel K. , Chang Michelle C. Y.
Published: January 2023

Living organisms carry out a wide range of remarkable functions, including the synthesis of thousands of simple and complex chemical structures for cellular growth and maintenance. The manipulation of this reaction network has allowed for the genetic engineering of cells for targeted chemical synthesis, but it remains challenging to alter the program underlying their fundamental chemical behavior. By taking advantage of the unique ability of living systems to use evolution to find solutions to complex problems, we have achieved ~95% theoretical yield of three C4commodity chemicals,n-butanol, 1,3-butanediol, and 4-hydroxy-2-butanone. Genomic sequencing of the evolved strains identifiedpcnBandrpoBCas two gene loci that are able to alter carbon flow by remodeling the transcriptional landscape of the cell, highlighting the potential of synthetic pathways as a tool to identify metabolic control points.
Early rise and persistent inhibition of electromyography during failed stopping
Authors: Fisher Mitchell , Trinh Hoa , O’Neill Jessica , Greenhouse Ian
Published: January 2023

Reactively canceling movements is a vital feature of the motor system to ensure safety. This behavior can be studied in the laboratory using the stop signal task. There remains ambiguity about whether a “point-of-no-return” exists, after which a response cannot be aborted. A separate question concerns whether motor system inhibition associated with attempted stopping persists when stopping is unsuccessful. We address these two questions using electromyography (EMG) in two stop signal task experiments. Experiment 1 (n = 24) involved simple right and left index finger responses in separate task blocks. Experiment 2 (n = 28) involved a response choice between the right index and pinky fingers. To evaluate the approximate point-of-no-return, we measured EMG in responding fingers during the 100 ms preceding the stop signal and observed significantly greater EMG amplitudes during failed than successful stop trials in both experiments. Thus, EMG differentiated failed from successful stopping prior to the stop signal, regardless of whether there was a response choice. To address whether motor inhibition persists after failed stopping, we assessed EMG peak-to-offset durations and slopes (i.e., the rate of EMG decline) for go, failed stop, and successful stop (partial response EMG) trials. EMG peak-to-offset was shorter and steeper in failed stop trials compared to go and successful stop partial response EMG trials, suggesting motor inhibition persists even when failing to stop. These findings indicate EMG is sensitive to a point at which participants can no longer successfully stop an ongoing movement and suggest the peak-to-offset time of response-related EMG activity during failed stopping reflects stopping-related inhibition.
DNA G-quadruplex is a transcriptional control device that regulates memory
Authors: Marshall Paul R. , Zhao Qiongyi , Davies Joshua , Liau Wei-Siang , Lee Yujin , Basic Dean , Periyakaruppiah Ambika , Zajaczkowski Esmi L. , Leighton Laura J. , Madugalle Sachithrani U. , Musgrove Mason , Kielar Marcin , Gong Hao , Ren Haobin , Kaczmarczyk Lech , Jackson Walker S. , Chen Alon , Spitale Robert C. , Bredy Timothy W.
Published: January 2023

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here we report that DNA G-quadruplex (G4-DNA) accumulates in neurons in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation.

One-Sentence Summary

G4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.
The role of catalytic and regulatory domains of human PrimPol in DNA binding and synthesis
Authors: Boldinova Elizaveta O. , Baranovskiy Andrey G. , Gagarinskaya Diana I. , Makarova Alena V. , Tahirov Tahir H.
Published: January 2023

Human PrimPol possesses DNA primase and DNA polymerase activities and restarts stalled replication forks protecting cells against DNA damage in nuclei and mitochondria. The zinc-binding motif (ZnFn) of the C-terminal domain (CTD) of PrimPol is required for DNA primase activity but the mechanism is not clear. In this work, we biochemically demonstrate that PrimPol initiatesde novoDNA synthesis incis-orientation, when the N-terminal catalytic domain (NTD) and the CTD of one molecule take part in catalysis. The modeling studies revealed that PrimPol uses a similar mode of initiating NTP coordination as the human primase. The ZnFn motif residue Arg417 is required for binding the 5’-triphosphate group that stabilizes the PrimPol complex with a DNA template-primer. We found that PrimPol is able to efficiently initiate DNA synthesis in the absence of the link between the two domains. The ability of the NTD alone to prime DNA synthesis and a regulatory role of the RPA-binding motif in the modulation of PrimPol binding to DNA are also demonstrated.