bluuebunny/crossref_metadata_2025 huggingface dataset:
Swim bladder resonance enhances hearing in crucian carp (Carassius auratus)
Authors: Li Hongquan , Gao Zhanyuan , Song Zhongchang , Su Yingnan , Ou Wenzhan , Zhang Jinhu , Zhang Yu
Published: August 2022

Sound sensing is vital for fish and more effort is necessary to address the hearing mechanism in fish. Here, we performed auditory evoked potentials (AEP) measurement, micro-computed tomography (Micro-CT) scanning, and numerical simulation to investigate the resonance of swim bladder and its influence on auditory sensitivity in crucian carp (Carassius auratus). The AEP results showed that at the tested frequency range up to 1000 Hz, the mean auditory thresholds of control fishes with an intact swim bladder were lower than that of treated fishes with a deflated swim bladder by 0.38–30.52 dB re 1 μPa. At the high frequency end, control fishes had a high but measurable auditory threshold. Correspondingly, numerical simulations showed that the intact swim bladder had a mean resonance frequency of 826±13.6 Hz, ranging from 810 to 840 Hz while the deflated swim bladder had no predominant resonance peak below 1000 Hz. The amplitude of received sound pressure at the resonance frequency for a sample in control group was 34.3 dB re 1 μPa higher than that for a treated sample, and the acceleration at the asteriscus of the control fish was higher than the treat fish by 43.13 dB re 1 m s-2. Both AEP experiment and modeling results showed that hearing sensitivity is enhanced through resonance of swim bladder in crucian carp and provided additional understandings on hearing mechanism in fish.

Summary statement

We used AEP measurement, Micro-CT scanning, and numerical simulation to demonstrate that the resonance of swim bladder can enhance hearing in crucian carp.
Global Protein-Turnover Quantification inEscherichia coliReveals Cytoplasmic Recycling under Nitrogen Limitation
Authors: Gupta Meera , Johnson Alex , Cruz Edward , Costa Eli , Guest Randi , Li Sophia Hsin-Jung , Hart Elizabeth M , Nguyen Thao , Stadlmeier Michael , Bratton Benjamin P. , Silhavy Thomas J. , Wingreen Ned S. , Gitai Zemer , Wühr Martin
Published: August 2022

Protein turnover is critical for proteostasis, but turnover quantification is challenging, and even in well-studiedE. coli, proteome-wide measurements remain scarce. Here, we quantify the degradation rates of ∼3.2kE. coliproteins under 12 conditions by combining heavy isotope labeling with complement reporter ion quantification and find that cytoplasmic proteins are recycled when nitrogen is limited. We use knockout experiments to assign substrates to the known cytoplasmic ATP-dependent proteases. Surprisingly, none of these proteases are responsible for the observed cytoplasmic protein degradation in nitrogen limitation, suggesting that a major proteolysis pathway inE. coliremains to be discovered. Lastly, we show that protein degradation rates are generally independent of cell division rates. Thus, we introduce broadly applicable technology for protein turnover measurements and provide a rich resource for protein half-lives and protease substrates inE. coli, complementary to genomics data, that will allow researchers to decipher the control of proteostasis.
The genomic landscape ofSaccharomyces paradoxusintrogression in geographically diverseSaccharomyces cerevisiaestrains
Authors: Clark Anne , Dunham Maitreya J. , Akey Joshua M.
Published: August 2022

Natural hybrids between many pairs of theSaccharomycesspecies have been observed. Hybridization can allow for rapid adaptation to new environments, and when followed by repeated backcrossing can lead to small pieces of introgressed sequence from an individual of one species remaining in the genome of an individual of another species. Introgressed sequences that persist over time are interesting both because they provide evidence of past hybridization events and because they may contribute to functional and phenotypic diversity. Previous studies have identified some examples of introgressed sequences inS. cerevisiae, but we sought to gain a more comprehensive understanding of the landscape of introgression in this species. We developed a simple, flexible approach based on a hidden Markov model to identify introgression in yeast genomes. We used our method to look for introgression in 93 diverseS. cerevisiaegenomes from its closest relative,S. paradoxus. We found evidence of introgression in all strains we considered, but the amount and location of introgression varied widely. We show that introgression contributes substantially to the total genetic diversity within these strains, and has the potential to confound inferences of their evolutionary relationships. Further characterizing introgression across diverseSaccharomycesspecies may help us better understand their evolution and the role that hybridization has played in adaptation to new environments.
Comparative genomics of tarakihi (Nemadactylus macropterus) and five New Zealand fish species: assembly contiguity affects the identification of genic features but not transposable elements
Authors: Papa Yvan , Wellenreuther Maren , Morrison Mark A. , Ritchie Peter A.
Published: August 2022

Comparative analysis of whole-genome sequences can provide valuable insights into the evolutionary patterns of diversification and adaptation of species, including the genome contents and the regions under selection. However, such studies are lacking for fishes in New Zealand. To supplement the recently sequenced genome of tarakihi (Nemadactylus macropterus), the genomes of five additional percomorph species native to New Zealand (king tarakihi (Nemadactylus n.sp.), blue moki (Latridopsis ciliaris), butterfish (Odax pullus), barracouta (Thyrsites atun), and kahawai (Arripis trutta)) were determined and assembled using Illumina sequencing. While the proportion of repeat elements was highly correlated with the genome size (R2 = 0.97, P < 0.01), most of the metrics for the genic features (e.g. number of exons or intron length) were significantly correlated with assembly contiguity (| R2| = 0.79–0.97). A phylogenomic tree including eight additional high-quality fish genomes was reconstructed from sequences of shared gene families. The radiation of Percomorpha was estimated to have occurred c. 112 mya (mid-Cretaceous), while the Latridae have diverged from true Perciformes c. 83 mya (late Cretaceous). Evidence of positive selection was found in 65 genes in tarakihi and 209 genes in Latridae: the largest portion of these are involved in the ATP binding pathway and the integral structure of membranes. These results and the de novo genome sequences can be used to (1) inform future studies on both the strength and shortcomings of scaffold-level assemblies for comparative genomics and (2) provide insights into the evolutionary patterns and processes of genome evolution in bony fishes.
Genomic selection in organisms with biphasic lifecycles: a Saccharina latissima (sugar kelp) case study
Authors: Huang Mao , Robbins Kelly R , Li Yaoguang , Umanzor Schery , Marty-Rivera Michael , Bailey David , Aydlett Margaret , Schmutz Jeremy , Grimwood Jane , Yarish Charles , Lindell Scott , Jannink Jean-Luc
Published: August 2022

Sugar kelp (Saccharina latissima) has a biphasic life cycle, allowing selection on both the diploid sporophytes (SPs) and haploid gametophytes (GPs). We trained a genomic selection (GS) model from farm-tested SP phenotypic data and used a mixed-ploidy additive relationship matrix to predict GP breeding values. Top-ranked GPs were used to make crosses for further farm evaluation. The relationship matrix included 866 individuals: a) founder SPs sampled from the wild; b) progeny GPs from founders; c) Farm-tested SPs crossed from b); and d) progeny GPs from farm-tested SPs. The complete pedigree-based relationship matrix was estimated for all individuals. A subset of founder SPs (n = 58) and GPs (n = 276) were genotyped with Diversity Array Technology and whole genome sequencing, respectively. We evaluated GS prediction accuracy via cross validation on farm-tested SPs in two years using a basic GBLUP model. We also estimated the general combining ability (GCA) and specific combining ability (SCA) variances of parental GPs. A total of 11 yield-related and morphology traits were evaluated. The cross validation accuracies for dry weight per meter (r ranged from 0.16 to 0.35) and wet weight per meter (r ranged 0.19 to 0.35) were comparable to GS accuracy for yield traits in terrestrial crops. For morphology traits, cross validation accuracy exceeded 0.18 in all scenarios except for blade thickness in the second year. Accuracy in a third validation year for dry weight per meter over a confirmation set of 87 individuals was 0.31.
High interest in Long-Acting Injectable PrEP among Filipina Transfeminine Adults
Authors: Restar Arjee Javellana , Quilantang Ma Irene , Wickersham Jeffrey , Adia Alex , Guigayoma John , Bermudez Amiel Nazer , Galárraga Omar , Flores Dalmacio Dennis , Cu-Uvin Susan , Nazareno Jennifer , Operario Don , Sison Olivia
Published: August 2022

Transfeminine adults are impacted by the HIV epidemic in the Philippines, and newly approved modalities of pre-exposure prophylaxis (PrEP), including long-acting injectable (LAI-PrEP), could be beneficial for this group. We utilized secondary data from the #ParaSaAtin survey that sampled Filipina transfeminine adults (n=139) and conducted a series of multivariable logistic regressions with lasso selection to explore factors independently associated with PrEP outcomes, including awareness, discussion with trans friends, and interest in LAI-PrEP. Overall, 53% of Filipina transfeminine respondents were aware of PrEP, 39% had discussed PrEP with their trans friends, and 73% were interested in LAI-PrEP. PrEP awareness was associated with being non-Catholic, having previously been HIV tested, discussing HIV services with a provider, and having high HIV knowledge (p<0.05). Discussing PrEP with friends was associated with older age, having experienced healthcare discrimination due to transgender identity, having HIV tested, and having discussed HIV services with a provider (p<0.05). Interest in LAI-PrEP was associated with living in Central Visayas, having discussed HIV services with a provider, and having discussed HIV services with a sexual partner were associated (p<0.05). Implementing LAI-PrEP in the Philippines requires addressing systemic improvements across personal, interpersonal, social, and structural levels in healthcare access, including efforts to create healthcare settings and environments with providers who are trained and competent in transgender health and can address the social and structural drivers of trans health inequities, including HIV and barriers to LAI-PrEP.
Fast and Accurate Maximum-Likelihood Estimation of Multi-Type Birth-Death Epidemiological Models from Phylogenetic Trees
Authors: Zhukova Anna , Hecht Frédéric , Maday Yvon , Gascuel Olivier
Published: August 2022

Multi-type birth-death (MTBD) models are phylodynamic analogies of compartmental models in classical epidemiology. They serve to infer such epidemiological parameters as the average number of secondary infectionsReand the infectious time from a phylogenetic tree (a genealogy of pathogen sequences). The representatives of this model family focus on various aspects of pathogen epidemics. For instance, the birth-death exposed-infectious (BDEI) model describes the transmission of pathogens featuring an incubation period (when there is a delay between the moment of infection and becoming infectious, as for Ebola and SARS-CoV-2), and permits its estimation along with other parameters.

With constantly growing sequencing data, MTBD models should be extremely useful for unravelling information on pathogen epidemics. However, existing implementations of these models in a phylodynamic framework have not yet caught up with the sequencing speed. Computing time and numerical instability issues limit their applicability to medium data sets (≤500 samples), while the accuracy of estimations should increase with more data.

We propose a new highly parallelizable formulation of ordinary differential equations for MTBD models. We also extend them to forests to represent situations when a (sub-)epidemic started from several cases (e.g., multiple introductions to a country). We implemented it for the BDEI model in a maximum likelihood framework using a combination of numerical analysis methods for efficient equation resolution. Our implementation estimates epidemiological parameter values and their confidence intervals in two minutes on a phylogenetic tree of 10 000 samples. Comparison to the existing implementations on simulated data shows that it is not only much faster, but also more accurate. An application of our tool to the 2014 Ebola epidemic in Sierra-Leone is also convincing, with very fast calculation and precise estimates. As MTBD models are closely related to Cladogenetic State Speciation and Extinction (ClaSSE)-like models, our findings could also be easily transferred to the macroevolution domain.
Does sugar control arrest complications in type 2 diabetes? Examining rigor in statistical and causal inference in clinical trials
Authors: Ojha Akanksha , Vidwans Harshada , Watve Milind
Published: August 2022

In contrast with type 1 diabetes mellitus (T1DM), in type 2 (T2DM) the success of intensive glucose normalization in arresting diabetic complications is marginal and inconsistent across multiple clinical trials. However, glucose regulation still largely remains the main target of treatment for T2DM in clinical practice. We examine the scientific rigor behind the design, conduct and inferences of 6 major clinical trials targeting glucose normalization and following up for diabetic complications and mortality. We find and discuss multiple flaws in reporting the results, their statistical treatment and clinically useful recommendations. The most serious flaw is the inability to recognize the limitations of statistical inferences when multiple comparisons are involved. Further we show using simulations that when different outcomes are not independent of each other, significance gets overestimated. We also suggested alternative ways to assess the effect of antihyperglycemic treatment, if any. Using more sound and elaborate statistical methods and inferential logic we find no support to the prevalent belief that intensive glucose normalization has any benefit in terms of reducing the frequency of any of the complications. Furthermore, alternative interpretations of the results have not been considered and evaluated in any of the clinical trials or their meta-analysis so far. Because of failure to show consistent significant benefit across multiple trials, we should now treat the hypothesis that glucose normalization prevents complications in T2DM as decisively falsified. This necessitates rethinking about some of the fundamental beliefs about the pathophysiology of diabetic complications and facilitate novel alternative lines of research.
Continuously perfusable, customisable and matrix-free vasculature on a chip platform
Authors: Chesnais Francois , Joel Jordan , Hue Jonas , Shakib Sima , Di-Silvio Lucy , Grigoriadis Agamemnon E. , Coward Trevor , Veschini Lorenzo
Published: August 2022

Creating vascularised cellular environments in vitro is a current challenge in tissue engineering and a bottleneck towards developing functional stem cell-derived microtissues for regenerative medicine and basic investigations. Here we have developed a new workflow to manufacture Vasculature on Chip (VoC) systems efficiently, quickly, and inexpensively. We have employed 3D printing for fast-prototyping of bespoke VoC and coupled them with a refined organotypic culture system (OVAA) to grow patent capillaries in vitro using tissue-specific endothelial and stromal cells. Furthermore, we have designed and implemented a pocket-size flow driver to establish physiologic perfusive flow throughout our VoC-OVAA with minimal medium use and waste. Using our platform, we have created vascularised microtissues and perfused them at physiologic flow rates for extended times and observed flow-dependent vascular remodelling. Overall, we present for the first time a scalable and customisable system to grow vascularised and perfusable microtissues, a key initial step to grow mature and functional tissues in vitro. We envision that this technology will empower fast prototyping and validation of increasingly biomimetic in vitro systems, including interconnected multi-tissue systems.
In vivo Quantification of Neural Criticality and Complexity in Mouse Cortex and Striatum in a Model of Cocaine Abstinence
Authors: Smith Wesley C.
Published: August 2022

Self-organized criticality is a hallmark of complex dynamic systems at phase transitions. Systems that operate at or near criticality have large-scale fluctuations or “avalanches”, the frequency and duration power of which are best fit with a power law revealing them to be scale-free and fractal, and such power laws are ubiquitous. It is an attractive concept in neuroscience since spiking avalanches are exhibited by neural tissue, and may underpin how minuscule events could scale up to circuits and provide adaptive psychobiological function. Much is yet to be understood about criticalityin vivoin the healthy brain and in disorders such as addiction, as drugs may alter the critical state’s “tuning” to generate drug seeking and dysphoria. Thus, here a novel toolset was developed to use neural avalanches and their self-similarity, rather than power law fit slope exponents as is canonically done, to quantify criticality in a previously collected high-density electrophysiologicalin vivocorticostriatal dataset from a mouse model of early cocaine abstinence. During behavioral quiescence, in the prefrontal cortex but not ventral striatum of cocaine-dosed mice, it was found that critical tuning is enhanced compared to drug-free controls. Additionally, an empirical biological demonstration of complexity’s theoretical correlation to criticality was shown in drug-free mice, was exponentially enhanced in drug-treated cortex, but was absent in the drug-treated striatum. As shown, quantifying criticality grants experimental support for the “critical brain hypothesis” and allows for statistical interpretation of inter-subject variability and development of further testable hypotheses in systems neuroscience.

Significance Statement

The “critical brain hypothesis” asserts neural networks are comparable to material in phase transitions at a critical point, their “avalanches” of system-wide spike bursts best seen in log-log plots of probability vs. avalanche size or duration, with slope following a scale-free or fractal power law. In discussing criticality, “critical tuning” is mentioned but quantification thereof left for later experimentation, despite being necessary for a scientific hypothesis. Presented are methods to quantify critical tuning through assessing similarity or fractalness among corticostriatal avalanches collected using high-density electrophysiology in cocaine-conditioned mice, along with an empiricalin vivoconfirmation of the mathematical concept that data complexity correlates with criticality. Interestingly, cocaine enhances critical tuning in cortex and aberrantly modifies complexity in a region-specific manner.
Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues
Authors: Pearson Gemma L. , Walker Emily M. , Lawlor Nathan , Lietzke Anne , Sidarala Vaibhav , Zhu Jie , Stromer Tracy , Reck Emma C. , Stendahl Ava M. , Li Jin , Levi-D’Ancona Elena , Pasmooij Mabelle B. , Hubers Dre L. , Renberg Aaron , Mohamed Kawthar , Parekh Vishal S. , Zhang Irina X. , Thompson Benjamin , Zhang Deqiang , Ware Sarah A. , Haataja Leena , Parker Stephen C.J. , Arvan Peter , Yin Lei , Kaufman Brett A. , Satin Leslie S. , Sussel Lori , Stitzel Michael L. , Soleimanpour Scott A.
Published: August 2022

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes and metabolic dysfunction-associated steatotic liver disease, yet the consequences of impaired mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across multiple metabolic tissues. Surprisingly, we demonstrate that defects in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with type 2 diabetes, cause reductions of β cell mass due to dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted deficiency anywhere in the mitochondrial quality control pathway (e.g., genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in β cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signalingin vivorestores β cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues and may be a promising target to treat or prevent metabolic disorders.
Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST
Authors: Long Yahui , Ang Kok Siong , Li Mengwei , Chong Kian Long Kelvin , Sethi Raman , Zhong Chengwei , Xu Hang , Ong Zhiwei , Sachaphibulkij Karishma , Chen Ao , Li Zeng , Fu Huazhu , Wu Min , Lim Hsiu Kim Lina , Liu Longqi , Chen Jinmiao
Published: August 2022

Advances in spatial transcriptomics technologies have enabled the gene expression profiling of tissues while retaining its spatial context. Effective exploitation of this data combination requires spatially informed analysis tools to perform three key tasks, spatial clustering, multi-sample integration, and cell type deconvolution. Here, we present GraphST, a novel graph self-supervised contrastive learning method that incorporates spatial location information and gene expression profiles to accomplish all three tasks in a streamlined process while outperforming existing methods in each task. GraphST combines graph neural networks with self-supervised contrastive learning to learn informative and discriminative spot representations by minimizing the embedding distance between spatially adjacent spots and vice versa. With GraphST, we achieved 10% higher clustering accuracy on multiple datasets than competing methods, and better delineated the fine-grained structures in tissues such as the brain and embryo. Moreover, GraphST is the only method that can jointly analyze multiple tissue slices in both vertical and horizontal integration while correcting for batch effects. Lastly, compared to other methods, GraphST’s cell type deconvolution achieved higher accuracy on simulated data and better captured spatial niches such as the germinal centers of the lymph node in experimentally acquired data. We further showed that GraphST can recover the immune cell distribution in different regions of breast tumor tissue and reveal spatial niches with exhausted tumor infiltrating T cells. Through our examples, we demonstrated that GraphST is widely applicable to a broad range of tissue types and technology platforms. In summary, GraphST is a streamlined, user friendly and computationally efficient tool for characterizing tissue complexity and gaining biological insights into the spatial organization within tissues.
UVC-based air disinfection system for rapid inactivation of SARS-CoV-2 present in the air
Authors: Garg Harry , Ringe Rajesh P. , Das Supankar , Parkash Suraj , Thakur Bhuwaneshwar , Delipan Rathina , Kumar Ajay , Kulkarni Kishor , Bansal Kanika , Patil Prabhu B. , Alam Tabish , Balam Nagesh Babu , Meena Chandan Swaroop , Thakur Krishan Gopal , Kumar Ashok , Kumar Ashwani
Published: August 2022

The novel coronavirus disease 2019 (COVID-19) infections have rapidly spread throughout the world, and the virus has acquired an ability to spread via aerosols even at long distances. Hand washing, face-masking, and social distancing are the primary preventive measures against infections. With mounting scientific evidence, World Health Organisation (WHO) declared COVID-19 an air-borne disease. This ensued the need to disinfect air to reduce the transmission. Ultraviolet C (UVC) comprising the light radiation of 200-280 nm range is a commonly used method for inactivation of pathogens. The heating, ventilation, and air conditioning (HVAC) systems are not beneficial in closed spaces due to poor or no ability to damage circulating viruses. Therefore, standard infection-prevention practices coupled with a strategy to reduce infectious viral load in air substantially might be helpful in reducing virus transmissibility. In this study, we implemented UV light-based strategies to combat COVID-19 and future pandemics. We tested various disinfection protocols by using UVC-based air purification systems and currently installed such a system in workspaces, rushed out places, hospitals and healthcare facilities for surface, air, and water disinfection. In this study, we designed a prototype device to test the dose of UVC required to inactivate SARS-CoV-2 in aerosols and demonstrate that the radiation rapidly destroys the virus in aerosols. The UVC treatment renders the virus non-infectious due to chemical modification of nucleic acid. We also demonstrate that UVC treatment alters the Spike protein conformation that may further affect the infectivity of the virus. We show by using a mathematical model based on the experimental data that UVC-based air disinfection strategy can substantially reduce the risk of virus transmission. The systematic treatment by UVC of air in the closed spaces via ventilation systems could be helpful in reducing the active viral load in the air.
Tudor domain containing protein 5-like(Tdrd5l) identifies a novel germline body and regulates maternal RNAs during oogenesis
Authors: Pozmanter Caitlin , Benner Leif , Kelly Sydney E , Curnutte Harrison , Van Doren Mark
Published: August 2022

Tudor domain-containing proteins are conserved across the animal kingdom for their function in germline development and fertility. Previously, we demonstrated thatTudor domain-containing protein 5-like (Tdrd5l)plays an important role in the germline where it promotes male identity. However, Tdrd5l is also expressed in both the ovary and testis during later stages of germline development, suggesting that it plays a role in germline differentiation in both sexes. We found that Tdrd5l localizes to a potentially novel germline body and plays a role in post-transcriptional gene regulation. RNA sequencing ofTdrd5l-mutant ovaries compared to wild-type showed that differentially expressed genes were enriched for maternally deposited RNAs. Additionally, embryos laid byTdrd5l-mutant females exhibited reduced viability and displayed dorsal appendage defects suggesting a failure of proper dorsal-ventral (D/V) patterning. As D/V patterning is dependent ongurken (grk), we examined Grk expression during oogenesis. We observed premature accumulation of Grk protein in nurse cells indicating that translation is no longer properly repressed during mRNA transport to the oocyte. We also observed increased nurse cell accumulation of the cytoplasmic polyadenylation element binding protein Oo18 RNA-Binding Protein (Orb or CPEB), a translational activator of Grk. Decreasingorbfunction was able to partially rescue theTdrd5l-mutant phenotype, and so defects in Orb are likely a primary cause of the defects inTdrd5lmutants. Our data indicate thatTdrd5lis important for translational repression of maternal mRNAs such asorb, and possibly others, following their synthesis in the nurse cells and during their transport to the oocyte.
Prediction of the 3D cancer genome from genomic rearrangements using InfoHiC
Authors: Lee Yeonghun , Park Sung-Hye , Lee Hyunju
Published: August 2022

Although cancer genomes often contain complex genomic rearrangements, its impact on tumorigenesis is still unclear, especially when they are involved in non-coding regions. Understanding 3D genome architecture is crucial for uncovering the impacts of genomic rearrangements. Here, we present InfoHiC, a method for predicting 3D genome folding and cancer Hi-C from complex genomic rearrangements. InfoHiC provides distinct interaction views of multiple contigs from the cancer Hi-C matrix. We then validated cancer Hi-C prediction using breast cancer cell line data and found contig-specific interaction changes. Moreover, we applied InfoHiC to patients with breast cancer and identified neo topologically associating domains and super-enhancer hijacking events associated with oncogenic overexpression and poor survival outcomes. Finally, we applied InfoHiC to pediatric patients with medulloblastoma, and found genomic rearrangements in non-coding regions that caused super-enhancer hijacking events of medulloblastoma driver genes (GFI1, GFI1B, and PRDM6). In summary, InfoHiC can predict genome folding changes in cancer genomes and may reveal therapeutic targets by uncovering the functional impacts of non-coding genomic rearrangements.
A four-point molecular handover during Okazaki maturation
Authors: Botto Margherita M. , Borsellini Alessandro , Lamers Meindert H.
Published: August 2022

DNA replication introduces thousands of RNA primers into the lagging strand that need to be removed for replication to be completed. In Escherichia coli when the replicative DNA polymerase Pol IIIα terminates at a previously synthesized RNA primer, DNA Pol I takes over and continues DNA synthesis while displacing the downstream RNA primer. The displaced primer is subsequently excised by an endonuclease, followed by the sealing of the nick by a DNA ligase. Yet how the sequential actions of Pol IIIα, Pol I, endonuclease and ligase are coordinated is poorly defined. Here we show that each enzymatic activity prepares the DNA substrate for the next activity, creating an efficient four-point molecular handover. The cryo-EM structure of Pol I bound to a DNA substrate with both an upstream and downstream primer reveals how it displaces the primer in a manner analogous to the monomeric helicases. Moreover, we find that in addition to its flap-directed nuclease activity, the endonuclease domain of Pol I also specifically cuts at the RNA/DNA junction, thus marking the end of the RNA primer and creating an 5’ end that is a suitable substrate for the ligase activity of LigA once all RNA has been removed.
Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution
Authors: Martin Reese A. , Tate Ann T.
Published: August 2022

Components of immune systems face significant selective pressure to efficiently use organismal resources, mitigate infection, and resist parasitic manipulation. A theoretically optimal immune defense balances investment in constitutive and inducible immune components depending on the kinds of parasites encountered, but genetic and dynamic constraints can force deviation away from theoretical optima. One such potential constraint is pleiotropy, the phenomenon where a single gene affects multiple phenotypes. Although pleiotropy can prevent or dramatically slow adaptive evolution, it is prevalent in the signaling networks that compose metazoan immune systems. We hypothesized that pleiotropy is maintained in immune signaling networks despite slowed adaptive evolution because it provides some other advantage, such as forcing network evolution to compensate in ways that increase host fitness during infection. To study the effects of pleiotropy on the evolution of immune signaling networks, we used an agent-based modeling approach to evolve a population of host immune systems infected by simultaneously co-evolving parasites. Four kinds of pleiotropic restrictions on evolvability were incorporated into the networks, and their evolutionary outcomes were compared to, and competed against, non-pleiotropic networks. As the networks evolved, we tracked several metrics of immune network complexity, relative investment in inducible and constitutive defenses, and features associated with the winners and losers of competitive simulations. Our results suggest non-pleiotropic networks evolve to deploy highly constitutive immune responses regardless of parasite prevalence, but some implementations of pleiotropy favor the evolution of highly inducible immunity. These inducible pleiotropic networks are no less fit than non-pleiotropic networks and can out-compete non-pleiotropic networks in competitive simulations. These provide a theoretical explanation for the prevalence of pleiotropic genes in immune systems and highlight a mechanism that could facilitate the evolution of inducible immune responses.

Author Summary

Genes involved in immune defense are hotspots of adaptive evolution as they resist rapidly evolving parasites and pathogens. Pleiotropic genes, which affect multiple discrete traits, have been shown to evolve at a much slower rate than non-pleiotropic genes but are highly represented in the immune system. The evolutionary effects of pleiotropic signaling genes on immune evolution are poorly understood, so we developed a model of pleiotropic signaling network evolution to address this gap in knowledge. Our results show that pleiotropy may be an important genomic feature in the development of inducible immunity.
Coupling of protein condensates to ordered lipid domains determines functional membrane organization
Authors: Wang Hong-Yin , Chan Sze Ham , Dey Simli , Castello-Serrano Ivan , Ditlev Jonathon A. , Rosen Michael K. , Levental Kandice R , Levental Ilya
Published: August 2022

During T-cell activation, the transmembrane adaptor Linker of Activation of T-cells (LAT) forms biomolecular condensates with Grb2 and Sos1, facilitating signaling. LAT has also been associated with cholesterol-rich condensed lipid domains. However, the potential coupling between protein condensation and lipid phase separation and its role in organizing T-cell signaling were unknown. Here, we report that LAT/Grb2/Sos1 condensates reconstituted on model membranes can induce and template lipid domains, indicating strong coupling between lipid- and protein-based phase separation. Correspondingly, activation of T-cells induces protein condensates that associate with and stabilize raft-like membrane domains. Inversely, lipid domains nucleate and stabilize LAT protein condensates in both reconstituted and living systems. This coupling of lipid and protein assembly is functionally important, since uncoupling of lipid domains from cytoplasmic protein condensates abrogates T-cell activation. Thus, thermodynamic coupling between protein condensates and ordered lipid domains regulates the functional organization of living membranes.

Membrane-associated protein condensates couple to ordered membrane domains to determine the functional organization of T-cell plasma membranes
How Subjective Idea Valuation Energizes and Guides Creative Idea Generation
Authors: Lopez-Persem Alizée , Rodriguez Sarah Moreno , Ovando-Tellez Marcela , Bieth Théophile , Guiet Stella , Brochard Jules , Volle Emmanuelle
Published: August 2022

What drives us to search for creative ideas, and why does it feel good to find one? While previous studies demonstrated the positive influence of motivation on creative abilities, how reward and subjective values play a role in creativity remains unknown. This study proposes to characterize the role of individual preferences (how people value ideas) in creative ideation via behavioral experiments and computational modeling. Using the Free Generation of Associates Task coupled with rating tasks, we demonstrate the involvement of valuation processes during idea generation: preferred ideas are provided faster. We found that valuation depends on the adequacy and originality of ideas and guides response selection and creativity. Finally, our computational model correctly predicts the speed and quality of human creative responses, as well as interindividual differences in creative abilities. Altogether, this model introduces the mechanistic role of valuation in creativity. It paves the way for a neurocomputational account of creativity mechanisms.

Public Significance Statement

This study addresses the role of individual preferences in creativity. It demonstrates that preferences for ideas energize creative idea production: the more participants like their ideas, the faster they provide them. Moreover, preferences rely on an equilibrium between the adequacy and originality of ideas and vary across individuals. This study introduces a computational model which incorporates individual preferences and that correctly predicts the speed and quality of responses in a creative idea generation task, as well as inter-individual differences in creative abilities. Comparison of several versions of this model demonstrated that preferences guide the selection of creative responses.
A high-speed, modular display system for diverse neuroscience applications
Authors: Isaacson Matthew , Ferguson Lisa , Loesche Frank , Ganguly Ishani , Chen Jim , Chiu Andy , Liu Jinyang , Dickson William , Reiser Michael
Published: August 2022

Visual stimulation of animals in the laboratory is a powerful technique for studying sensory control of complex behaviors. Since commercial displays are optimized for human vision, we established a novel display system based on custom-built modular LED panels that provides millisecond refresh, precise synchronization, customizable color combinations, and varied display configurations. This system simplifies challenging experiments. With variants of this display, we probed the speed limits of motion vision and examined the role of color vision in behavioral experiments with tethered flying Drosophila. Using 2-photon calcium imaging, we comprehensively mapped the tuning of visual projection neurons across the fly’s field of view. Finally, using real-time behavior analysis, we developed low-latency interactive virtual environments and found that flying flies can independently control their navigation along two dimensions. This display system uniquely addresses most technical challenges of small animal vision experiments and is thoroughly documented for replicability.
Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
Authors: Casalino Lorenzo , Seitz Christian , Lederhofer Julia , Tsybovsky Yaroslav , Wilson Ian A. , Kanekiyo Masaru , Amaro Rommie E.
Published: August 2022

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.

One-Sentence Summary

In situ dynamics of influenza glycoproteins expose antigenically relevant states and a new site of vulnerability in neuraminidase.
Multiple T6SSs, mobile auxiliary modules, and effectors revealed in a systematic analysis of theVibrio parahaemolyticuspan-genome
Authors: Jana Biswanath , Keppel Kinga , Fridman Chaya Mushka , Bosis Eran , Salomon Dor
Published: August 2022

Type VI secretion systems (T6SSs) play a major role in interbacterial competition and in bacterial interactions with eukaryotic cells. The distribution of T6SSs and the effectors they secrete vary between strains of the same bacterial species. Therefore, a pan-genome investigation is required to better understand the T6SS potential of a bacterial species of interest. Here, we performed a comprehensive, systematic analysis of T6SS gene clusters and auxiliary modules found in the pan-genome ofVibrio parahaemolyticus, an emerging pathogen widespread in marine environments. We identified four different T6SS gene clusters within genomes of this species; two systems appear to be ancient and widespread, whereas the other two systems are rare and appear to have been more recently acquired via horizontal gene transfer. In addition, we identified diverse T6SS auxiliary modules containing putative effectors with either known or predicted toxin domains. Many auxiliary modules are possibly horizontally shared betweenV. parahaemolyticusgenomes, since they are flanked by DNA mobility genes. We further investigated a DUF4225-containing protein encoded on an Hcp auxiliary module, and we showed that it is an antibacterial T6SS effector that exerts its toxicity in the bacterial periplasm, leading to cell lysis. Computational analyses of DUF4225 revealed a widespread toxin domain associated with various toxin delivery systems. Taken together, our findings reveal a diverse repertoire of T6SSs and auxiliary modules in theV. parahaemolyticuspan-genome, as well as novel T6SS effectors and toxin domains that can play a major role in the interactions of this species with other cells.

Importance

Gram-negative bacteria employ toxin delivery systems to mediate their interactions with neighboring cells.Vibrio parahaemolyticus, an emerging pathogen of humans and marine animals, was shown to deploy antibacterial toxins into competing bacteria via the type VI secretion system (T6SS). Here, we analyzed 1,727V. parahaemolyticusgenomes and revealed the pan-genome T6SS repertoire of this species, including the T6SS gene clusters, horizontally shared auxiliary modules, and toxins. We also identified a role for a previously uncharacterized domain, DUF4225, as a widespread antibacterial toxin associated with diverse toxin delivery systems.
Immune response against SARS-CoV-2 of primary healthcare personnel in a commune of Santiago, Chile: follow-up at 6 months
Authors: Olea A. , Matute I. , Hirmas M. , González C. , Iruretagoyena M. , Munita J. , Pedroni E. , Gómez MI. , Cortés L. , Hormazábal J.
Published: August 2022

Background

The COVID-19 pandemic that emerged in Wuhan, China at the end of 2019, spread rapidly around the world with almost 600 million cases and 6.3 million deaths today. The most affected were health workers with at least three times the risk of contracting the disease than the general community. Most studies on seroprevalence in health workers focus on hospital care establishments and what happens in Primary Health Care (PHC) has not been investigated with the same intensity.

Objectives

to determine the prevalence and know the variation of antibody titers for SARS-CoV-2 in serial samples of primary healthcare personnel from the commune of La Pintana.

Method

an analytical observational study with a cross-sectional and a longitudinal component, carried out from November 2020 to June 2021. The first component consisted of an IgG antibody seroprevalence study performed at baseline (time 0) in volunteer of a universe of 900 workers. The longitudinal component considered the monitoring of IgG antibodies in those who presented a positive result at baseline and the analysis of neutralizing antibodies in a random sub-sample of 50% of them. Additionally, sociodemographic and clinical information was collected via a questionnaire. Univariate, bivariate, and longitudinal analyses were performed to evaluate differences in antibodies. The study was approved by the Universidad del Desarrollo’s Scientific Ethics Committee.

Results

463 primary healthcare workers participated, mostly women and with a median of 38 years; doctors and nurses represented 9.5% each and 14.7% had a history of COVID-19. The seroprevalence at baseline was 22.3% and was associated with younger age, being a doctor and having been in close contact of a case. IgG titers increased with the vaccine, but decreased over time. At the 6-month follow-up, 76% had neutralizing antibodies. Those belonging to indigenous peoples had higher IgG levels and higher rates of neutralizing antibodies.

Conclusion

Healthcare workers were highly affected by COVID-19, and the medical profession and younger age were factors associated with increased risk. Antibodies decrease over time, highlighting the importance of follow-up studies, as well as the importance of vaccination boosters in healthcare workers, especially those in PHC.

Financing

This project was funded by the Universidad del Desarrollo, COVID19-UDD 2020-21 Funds.
Temperature dependence in Bragg edge neutron transmission measurements
Authors: Al-Falahat Ala'a M. , Kardjilov Nikolay , Woracek Robin , Boin Mirko , Markötter Henning , Kuhn Luise Theil , Makowska Malgorzata , Strobl Markus , Pfretzschner Beate , Banhart John , Manke Ingo
Published: July 2022

A systematic study has been carried out to investigate the neutron transmission signal as a function of sample temperature. In particular, the experimentally determined wavelength-dependent neutron attenuation spectra for a martensitic steel at temperatures ranging from 21 to 700°C are compared with simulated data. A theoretical description that includes the Debye–Waller factor in order to describe the temperature influence on the neutron cross sections was implemented in the nxsPlotter software and used for the simulations. The analysis of the attenuation coefficients at varying temperatures shows that the missing contributions due to elastic and inelastic scattering can be clearly distinguished: while the elastically scattered intensities decrease with higher temperatures, the inelastically scattered intensities increase, and the two can be separated from each other by analysing unique sharp features in the form of Bragg edges. This study presents the first systematic approach to quantify this effect and can serve as a basis , for example, to correct measurements taken during in situ heat treatments, in many cases being a prerequisite for obtaining quantifiable results.
In situ study of the preoxidation of polyacrylonitrile fibers
Authors: Chen Rongchao , Li Zhihong , Shi Ying , Liu Li-Zhi , Li Dongfeng , Zhao Yixin , Lv Baoliang
Published: July 2022

In the production of polyacrylonitrile-based carbon fibers (PAN-CFs), preoxidation is a key step to improving the thermal stability of the fibers and forming their structural prototype. However, structural evaluation of PAN fibers during preoxidation remains ambiguous, partly due to a lack of in situ studies. This contribution reports an in situ study of the preoxidation of PAN fibers using wide-angle X-ray scattering and small-angle X-ray scattering techniques on a synchrotron radiation beamline. The structural changes of the skeleton and pores in the fibers are revealed and correspond to five kinds of diffraction spots (peaks) and two kinds of scattering streaks, respectively. The preoxidation shows obvious stages, and the corresponding possible mechanism is analyzed.