bluuebunny/crossref_metadata_2025 huggingface dataset:
Collagen content and cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of collagen cross-linking inhibitor beta-aminopropionitrile
Authors: Brashear Sarah E. , Wohlgemuth Ross P. , Hu Lin-Ya , Jbeily Elias H. , Christiansen Blaine A. , Smith Lucas R.
Published: July 2022

In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture during fibrosis that relate more closely to functional muscle stiffness. One of these architectural changes in dystrophic muscle is collagen cross-linking, which has been shown to increase the passive muscle stiffness in models of fibrosis including themdxmouse, a model of DMD. We tested whether the intraperitoneal injections of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking enzyme lysyl oxidase, would reduce collagen cross- linking and passive stiffness in young and adultmdxmice compared to saline-injected controls. We found no significant differences between BAPN treated and saline treated mice in collagen cross-linking and stiffness parameters. However, we observed that while collagen cross-linking and passive stiffness scaled positively in dystrophic muscles, collagen fiber alignment scaled with passive stiffness distinctly between muscles. We also observed that the dystrophic diaphragm showed the most dramatic fibrosis in terms of collagen content, cross-linking, and stiffness. Overall, we show that while BAPN was not effective at reducing collagen cross- linking, the positive association between collagen cross-linking and stiffness in dystrophic muscles still show cross-linking as a viable target for reducing passive muscle stiffness in DMD or other fibrotic muscle conditions.

Key Points

BAPN did not reduce collagen cross-linking or passive stiffness in any muscle

Collagen cross-links scaled with passive stiffness in dystrophic muscles

Themdxdiaphragm showed the most dramatic fibrosis related to collagen content, cross- linking, and passive stiffness

Collagen fiber alignment scales with passive stiffness differently between muscles
Pathway-specific inputs to the superior colliculus support flexible triggering of innate behaviors
Authors: Li Chen , Kühn Norma K. , Alkislar Ilayda , Dublanc Arnau Sans , Zemmouri Firdaouss , Paesmans Soraya , Reinhard Katja , Farrow Karl
Published: July 2022

Behavioral flexibility requires the ability to modify the feedforward transmission of sensory information. The superior colliculus mediates visually guided innate defensive behaviors via cell-type specific projections. However, how brain-wide inputs to the superior colliculus are organized to modulate visual processing and enable flexible behavior remains unknown. To determine these rules, we focused on inhibitory projection (Gad2) neurons. Trans-synaptic tracing and neuronal recordings revealed that Gad2 neurons projecting to the dorsal lateral geniculate nucleus (LGd) and the parabigeminal nucleus (PBG) form two separate anatomical and functional populations, where each circuit received a different set of non-retinal inputs. Inhibiting LGd or PBG projecting Gad2 neurons resulted in opposing effects on behavior; increasing freezing or escape probability to visual looming stimuli, respectively. These data suggest that projection-specific sampling of brain-wide inputs provide a circuit design principle that enables feed-forward transfer of visual threat to be independently adjusted to produce context specific behavior.
Molecular annotation of AOPs guides the development of the next generation mechanistic chemical safety assessment and new approach methods
Authors: Saarimäki Laura Aliisa , Morikka Jack , Pavel Alisa , Korpilähde Seela , del Giudice Giusy , Federico Antonio , Fratello Michele , Serra Angela , Greco Dario
Published: July 2022

Mechanistic toxicology has emerged as a powerful framework to inform on the safety of chemicals and guide the development of new safe-by-design compounds. Although toxicogenomics provides support towards mechanistic evaluation of chemical exposures, the implementation of toxicogenomics-based evidence in the regulatory setting is still hindered by uncertainties related to the analysis and interpretation of such data. Adverse Outcome Pathways (AOPs) are multi-scale models that link chemical exposures to adverse outcomes through causal cascades of key events (KEs). The use of mechanistic evidence through the AOP framework is actively promoted for the development of new approach methods (NAMs) and to reduce animal experimentation. However, in order to unleash the full potential of AOPs and build confidence into toxicogenomics, robust and unified associations between KEs and patterns of molecular alteration need to be established.

Here, we hypothesised that systematic curation of molecular events associated with KEs would enable the modelling of AOPs through gene-level data, creating the much-needed link between toxicogenomics and the systemic mechanisms depicted by the AOPs. This, in turn, introduces novel ways of benefitting from the AOP concept, including predictive models, read-across, and targeted assays, while also reducing the need for multiple testing strategies. Hence, we developed a multi-step strategy to annotate the AOPs relevant to human health risk assessment. We show that our framework successfully highlights relevant adverse outcomes for chemical exposures with strongin vitroandin vivoconvergence, supporting chemical grouping and other data-driven approaches. Finally, we defined and experimentally validated a panel of robust AOP-derivedin vitrobiomarkers for pulmonary fibrosis.
Extensive hybridisation throughout clownfishes evolutionary history
Authors: Schmid Sarah , Micheli Baptiste , Cortesi Fabio , Donati Giulia , Salamin Nicolas
Published: July 2022

The contribution of hybridisation in the generation of global species diversity has long been controversial among evolutionary biologists. However, it is now increasingly accepted that hybridisation has many impacts on the process of speciation. Notably, it is an important mechanism fostering adaptive radiation since it can generate new phenotypic combinations enabling the occupancy of new niches. Here, we focused on clownfish (Pomacentridae), a clade of 28 coral reef fishes displaying a mutualistic interaction with sea anemones. This behaviour is the key innovation that triggered adaptive radiation of clownfishes, as each species is able to occupy a different combination of host anemone species and habitat. Previous work suggested that hybridisation might be responsible for the extant diversity of clownfish species. To test this hypothesis, we analysed whole-genome datasets for each clownfish species. First, we reconstructed the phylogeny of the clade based on topology weighting methods, which enables the visualisation of the relationships between taxa across the genome. Then, we highlighted possible ancient hybridisation events based on a comparative genomic framework for detecting introgression in genomes. The resulting phylogeny is consistent with previous works based on a few mitochondrial and nuclear genes, and shallow nodes are now well supported in contrast to past studies. Furthermore, we detected multiple past hybridisation events throughout the evolutionary history of clownfishes, corroborating the potential role of hybridisation in the clownfish adaptive radiation. This study adds to the growing number of studies investigating the genomic mechanisms behind species diversification, drawing us closer to understanding how Earth biodiversity is generated.
GePI: Retrieval of fully automated recognition and extraction of gene and protein interaction mentions from unstructured literature
Authors: Faessler Erik , Hahn Udo , Schäuble Sascha
Published: July 2022

Motivation

Knowledge about interactions between genes and proteins is vital for bio-molecular research. A large part of this knowledge is published in written text and not accessible in a structured way. To remedy this situation, several repositories of automatically extracted interaction facts were proposed over the years. However, existing solutions lack key features such as permanently updated data resources, easy accessibility and structured result generation ready to be used for downstream analyses.

Results

We propose GePI, a database portal for fully automated extraction and presentation of molecular interaction facts from scientific literature. GePI offers batch queries, immediate inspection of textual evidence and full text filters. To this end, GePI leverages two gene recognition and normalization approaches as well as optimized runtime for molecular event extraction. The resulting natural language processing pipeline is applied to the full set of publicly available documents from PubMed and the PubMed Central open access subset accounting for more than 33M abstracts and 4.2M complete articles as of 2022. To accommodate the rapid growth of the scientific literature, the fact database is automatically updated several times per week. In summary, our web application GePI allows for the first time a free and easy-to-use investigation of gene and protein interaction information as soon as they are published with unique query possibilities.

Availability and Implementation

The GePI web interface is available at http://gepi.coling.uni-jena.de.

Contact

erik.faessler@uni-jena.de
Fotomics: Fourier transform-based omics imagification for deep learning-based cell-identity mapping using single-cell omics profiles
Authors: Zandavi Seid Miad , Liu Derong , Chung Vera , Anaissi Ali , Vafaee Fatemeh
Published: July 2022

Different omics profiles, depending on the underlying technology, encompass measurements of several hundred to several thousand molecules in a biological sample or a cell. This study develops upon the concept of “omics imagification” as a process of transforming a vector representing these numerical measurements into an image with a one-to-one relationship with the corresponding sample. The proposed imagification process transforms a high-dimensional vector of molecular measurements into a two-dimensional RGB image to enable holistic molecular representation of a biological sample and to improve the classification of different biological phenotypes using automated image recognition methods in computer vision. A transformed image represents 2D coordinates of molecules in a neighbour-embedded space representing molecular abundance and gene intensity. The proposed method was applied to a single-cell RNA sequencing (scRNA-seq) data to “imagify” gene expression profiles of individual cells. Our results show that a simple convolutional neural network trained on single-cell transcriptomics images accurately classifies diverse cell types outperforming the best-performing scRNA-seq classifiers such as support vector machine and random forest.
CXCR7 promotes foetal myoblast fusion at muscle fiber tips independently of Myomaker via a ß1integrin-EGFR-dependent mechanism
Authors: Nassari Sonya , Blavet Cédrine , Duprez Delphine , Fournier-Thibault Claire
Published: July 2022

Muscle growth must be tightly regulated during development in order to obtain the final muscle shape. Myoblast fusion is a critical step of muscle growth, driving the formation of syncytial myofibers attaching at both ends to tendons. We investigated the role of the CXCR7 chemokine receptor in foetal muscle growth during chicken limb development. We show that CXCR7 displays a regionalized expression at the tips of myofibers close to tendons in foetal limb muscles, which is exclusive to the central location of the fusion gene MYOMAKER (TMEM8C in chicken) in foetal muscles. CXCR7 promotes myoblast fusion independently of TMEM8C in chicken limb muscles and in foetal myoblast cultures and requires EGF receptor signalling. The CXCR7 ligand, CXCL12, expressed in connective tissue, increases ß1integrin activation at the myotendinous junction and CXCR7 expression at muscle tips, resulting in a fusion promoting effect independent from a direct binding of CXCL12 to CXCR7 receptor. Our results evidence a CXCR7-dependent/TMEM8C-independent fusion mechanism at the myofiber tips that regulates muscle growth at the tendon/muscle interface during foetal myogenesis.
Back to the Meadow Brown: eyespot variation and field temperature in a classic butterfly polymorphism
Authors: Mowbray Sophie , Bennie Jonathan , Rhodes Marcus W. , Smith David A.S. , ffrench-Constant Richard H.
Published: July 2022

Since the classic work of E.B. Ford, alternate hypotheses have focused on explaining eyespot variation in the Meadow Brown butterfly strictly as a genetic polymorphism and the role of temperature in this classic example of natural selection has therefore been overlooked. Here we use large and continuous field collections from three sites in the UK to examine the effect of field temperature on total eyespot variation using the same presence/absence scoring as Ford. We show that higher developmental temperatures in the field lead to the disappearance of the spots visible while the butterfly is at rest, explaining Ford’s original observation that hindwing spotting declines across the season as temperatures increase. Analysis of wing damage supports the historical hypothesis that hindwing spots confuse aerial predators. However, as hindwing spotting declines over the season, a ‘trade-off’ is suggested between their role in deflecting predators early in the season and their later developmental cost. In contrast, the large forewing eyespot is always present, scales with forewing length and its variation is best explained by day of the year rather than developmental temperature. As this large forewing spot is thought to be involved in ‘startling’ predators, its constant presence is therefore likely required for defence. We model annual total spot variation with phenological data from the UK and derive predictions as to how spot patterns will continue to change under increasing summer temperatures, predicting that spotting will continue to decrease both across a single season and year or year as our climate warms.

Summary statement

We show that a long-held example of ‘genetic’ polymorphism, eyespot variation is the Meadow Brown butterfly, is correlated with field temperature during butterfly development.
Asymmetric trichotomous data partitioning enables development of predictive machine learning models using limited siRNA efficacy datasets
Authors: Monopoli Kathryn R. , Korkin Dmitry , Khvorova Anastasia
Published: July 2022

Chemically modified small interfering RNAs (siRNAs) are promising therapeutics guiding sequence-specific silencing of disease genes. However, identifying chemically modified siRNA sequences that effectively silence target genes is a challenge. Such determinations necessitate computational algorithms. Machine Learning (ML) is a powerful predictive approach for tackling biological problems, but typically requires datasets significantly larger than most available siRNA datasets. Here, we describe a framework for applying ML to a small dataset (356 modified sequences) for siRNA efficacy prediction. To overcome noise and biological limitations in siRNA datasets, we apply a trichotomous (using two thresholds) partitioning approach, producing several combinations of classification threshold pairs. We then test the effects of different thresholds on random forest (RF) ML model performance using a novel evaluation metric accounting for class imbalances. We identify thresholds yielding a model with high predictive power outperforming a simple linear classification model generated from the same data. Using a novel method to extract model features, we observe target site base preferences consistent with current understanding of the siRNA-mediated silencing mechanism, with RF providing higher resolution than the linear model. This framework applies to any classification challenge involving small biological datasets, providing an opportunity to develop high-performing design algorithms for oligonucleotide therapies.
Adult neural stem cells and neurogenesis are resilient to intermittent fasting
Authors: Gabarró-Solanas Rut , Davaatseren Amarbayasgalan , Kepčija Tatjana , Crespo-Enríquez Iván , Urbán Noelia
Published: July 2022

Intermittent fasting (IF) is a promising non-pharmacological strategy to counteract ageing which has been shown to increase the number of adult-born neurons in the dentate gyrus of mice. However, it is still unclear which steps of the adult neurogenesis process are regulated by IF. The number of adult neural stem cells (NSCs) decreases with age in an activation-dependent manner. To counteract the loss of the stem cell pool, adult NSCs are mostly found in an inactive, quiescent state which ensures their long-term maintenance. We aimed to determine if and how IF impacts the activity and maintenance of adult NSCs in the hippocampus. We chose an every-other-day fasting protocol with food re-administration at night, which we found effectively induces fasting features and preserves the circadian activity pattern of mice. To determine the effects of IF on NSCs and all following steps in the neurogenic lineage, we combined fasting with lineage tracing and label retention assays. We found that IF does not affect NSC activation or maintenance. Contrary to previous reports, we also found that IF does not increase hippocampal neurogenesis. We obtained the same results regardless of strain, sex, diet length, tamoxifen administration or new-born neuron identification method. Our data suggest that NSCs maintain homeostasis upon IF and that this intervention is not a reliable strategy to increase adult neurogenesis.
Single particle profiler for measuring content and properties of nano-sized bioparticles
Authors: Sych Taras , Schlegel Jan , Barriga Hanna M.G. , Ojansivu Miina , Hanke Leo , Weber Florian , Bostancioglu R. Beklem , Ezzat Kariem , Stangl Herbert , Plochberger Birgit , Laurencikiene Jurga , El Andaloussi Samir , Fürth Daniel , Stevens Molly M. , Sezgin Erdinc
Published: July 2022

It is technically challenging to study the content and properties of nanoscale bioparticles in a high-throughput and single-molecule manner. We developed a high-throughput analysis method, called single particle profiler (SPP) that provides single-particle information on content and biophysical properties of thousands of particles. We applied SPP to measure the mRNA encapsulation efficiency of lipid nanoparticles, viral binding efficiency of different nanobodies and biophysical heterogeneity of liposomes, lipoproteins, exosomes and viruses.
High-resolution characterisation of short-term temporal variability in the taxonomic and resistome composition of wastewater influent
Authors: Chau KK , Goodall T , Bowes M , Easterbrook K , Brett H , Hughes J , Crook DW , Read DS , Walker AS , Stoesser N
Published: July 2022

Wastewater-based epidemiology (WBE) for population-level surveillance of antimicrobial resistance (AMR) is gaining significant traction, but the impact of wastewater sampling methods on results is unclear. In this study we characterised taxonomic and resistome differences between single-timepoint-grab and 24H-composites of wastewater influent from a large UK-based wastewater treatment work (WWTW [population equivalent:223,435]).

We autosampled hourly influent grab samples (n=72) over three consecutive weekdays, and prepared additional 24H-composites (n=3) from respective grabs. For taxonomic profiling, metagenomic DNA was extracted from all samples and 16S-rRNA gene sequenced. One composite and six grabs from day one underwent metagenomic sequencing for metagenomic dissimilarity estimation and resistome profiling.

Taxonomic abundances of phyla varied significantly across hourly grab samples but followed a repeating diurnal pattern for all three days. Hierarchical clustering grouped grab samples into four time periods dissimilar in both 16S rRNA gene-based profiles and metagenomic distances. 24H-composites resembled mean daily phyla abundances and showed low variability of taxonomic profiles. Of the 122 AMR gene families (AGFs) identified across all day one samples, single grab samples identified a median of 6 (IQR:5-8) AGFs not seen in the composite. However, 36/36 of these hits were at lateral coverage <0.5 (median:0.19; IQR:0.16-0.22) and potential false positives. Conversely, the 24H-composite identified three AGFs not seen in any grab with higher lateral coverage (0.82; 0.55-0.84). Additionally, several clinically significant human AGFs (blaVIM, blaIMP, blaKPC) were intermittently or completely missed by grab sampling but captured by the 24H-composite.

Wastewater influent undergoes significant taxonomic and resistome changes on short timescales potentially affecting interpretation of results based on sampling strategy. Grab samples are more convenient and potentially capture low-prevalence/transient targets but are less comprehensive and temporally variable. Therefore, we recommend 24H-composite sampling where feasible. Further validation and optimisation of WBE methods is vital for its development into a robust AMR surveillance approach.

Highlights

Influent undergoes significant taxonomic/resistome changes over short timescales.

Taxonomic abundances fluctuate diurnally but repeat for the 3 weekdays sampled.

Detection of less prevalent AMR determinants is time-dependent for grab sampling.

Single timepoint grab samples may produce temporally variable metagenomic profiles.

24H-composites reflect mean daily taxa and more reliably captured AMR determinants.
Control of PHYTOCHROME KINASE SUBSTRATE subcellular localization and biological activity by protein S-acylation
Authors: Vazquez Ana Lopez , Petrolati Laure Allenbach , Dessimoz Christophe , Lampugnani Edwin R. , Glover Natasha , Fankhauser Christian
Published: July 2022

PHYTOCHROME KINASE SUBSTRATE (PKS) proteins are involved in light-regulated growth orientation responses. They act downstream of phytochromes to control hypocotyl gravitropism in the light and act early in phototropin signaling. Despite their importance for plant development, little is known about their molecular mode of action except that they belong to a protein complex comprising the phototropins at the plasma membrane. Identifying evolutionarily conservation is one approach to reveal biologically important protein motifs. Here, we show that PKS sequences are restricted to seed plants and that these proteins share 6 motifs (A to F from the N- to the C-terminus). While motif D is also found in BIG GRAIN proteins the remining domains are PKS specific. We provide evidence that motif C is S-acylated on highly conserved cysteines, which mediates PKS protein association with the plasma membrane. This motif is also required for PKS4-mediated phototropism and control of hypocotyl gravitropism in the light. Finally, our data suggests that the mode of PKS4 plasma membrane association is important for its biological activity. Our work identifies the mode of plasma membrane association of PKS proteins and strongly suggests that this is their site of action to modulate environmentally regulated organ positioning.
How Turkey vultures tune their airspeed to environmental and behavioral factors
Authors: Rader Jonathan , Hedrick Tyson L.
Published: July 2022

Animals must tune their physical performance to changing environmental conditions, and the breadth of environmental tolerance may contribute to delineating the species’ geographic range. A common environmental challenge that flying animals face is the reduction of air density at high elevation and a reduction in the effectiveness of lift production that accompanies it. Turkey vultures (Cathartes aura) inhabit a >3000 m elevation range, and fly considerably higher, necessitating that they compensate for air density differences through behavior, physiology, or biomechanics. We predicted that birds flying at high elevation would demonstrate higher median flight speeds while maintaining similar glide angles. We used 3-dimensional videography to track Turkey vultures flying at three elevations and found a negative relationship between median airspeed and air density that matched our prediction. Additionally, neither the ratio of horizontal speed to sinking speed nor flapping behavior varied with air density. These results were robust to varying flight behavior (climbing vs. level flight). Finally, we derived a glide polar from the free-flying vultures and showed that they are proficient at tuning their flight speed to minimize their cost of transport during straight-line flight, but transition to a minimum power strategy during gliding turns.
Deep attention based variational autoencoder for antimicrobial peptide discovery
Authors: Ghorbani Mahdi , Prasad Samarjeet , Brooks Bernard R. , Klauda Jeffery B.
Published: July 2022

Antimicrobial peptides (AMPs) have been proposed as a potential solution against multiresistant pathogens. Designing novel AMPs requires exploration of a vast chemical space which makes it a challenging problem. Recently natural language processing and generative deep learning have shown great promise in exploring the vast chemical space and generating new chemicals with desired properties. In this study we leverage a variational attention mechanism in the generative variational autoencoder where attention vector is also modeled as a latent vector. Variational attention helps with the diversity and quality of the generated AMPs. The generated AMPs from this model are novel, have high statistical fidelity and have similar physicochemical properties such as charge, hydrophobicity and hydrophobic moment to the real to the real antimicrobial peptides.
Development of a quantitative metagenomic approach to establish quantitative limits and its application to viruses
Authors: Langenfeld Kathryn , Hegarty Bridget , Vidaurri Santiago , Crossette Emily , Duhaime Melissa , Wigginton Krista
Published: July 2022

Quantitative metagenomic methods are maturing but continue to lack clearly-defined analytical limits. Here, we developed a computational tool, QuantMeta, to determine the absolute abundance of targets in metagenomes spiked with synthetic DNA standards. The tool establishes (1) entropy-based detection thresholds to confidently determine the presence of targets, and (2) an approach to identify and correct read mapping or assembly errors and thus improve the quantification accuracy. Together this allows for an approach to confidently quantify absolute abundance of targets, be they microbial populations, genes, contigs, or metagenome assembled genomes (MAGs). We applied the approach to quantify single- and double-stranded DNA viruses in wastewater viral metagenomes, including pathogens and bacteriophages. Concentrations of total DNA viruses in wastewater influent and effluent were greater than 108copies/mL using QuantMeta. Human-associated DNA viruses were detected and quantifiable with QuantMeta thresholds, including polyomavirus, papillomavirus, and crAss-like phages, at concentrations similar to previous reports that utilized quantitative PCR-based assays. Our results highlight the higher detection thresholds of quantitative metagenomics (∼500 copies/μL) as compared to PCR-based quantification (∼10 copies/μL) despite a sequencing depth of 200 million reads per sample. The QuantMeta approach, applicable to both viral and cellular metagenomes, advances quantitative metagenomics by improving the accuracy of measured target absolute abundances.
A manually curated annotation characterises genomic features of P. falciparum lncRNAs
Authors: Hoshizaki Johanna , Adjalley Sophie H. , Thathy Vandana , Judge Kim , Berriman Matthew , Reid Adam James , Lee Marcus C. S.
Published: July 2022

Background

Important regulation occurs at the level of transcription in Plasmodium falciparum and growing evidence suggests that these apicomplexan parasites have complex regulatory networks. Recent studies implicate long noncoding RNAs (lncRNAs) as transcriptional regulators in P. falciparum. However, due to limited research and the lack of necessary experimental tools, our understanding of their role in the malaria-causing parasite remains largely unelucidated. In this work, we address one of these limitations, the lack of an updated and improved lncRNA annotation in P. falciparum.

Results

We generated long-read RNA sequencing data and integrated information extracted and curated from multiple sources to manually annotate lncRNAs. We identified 1522 novel lncRNAs and validated and refined 847 existing annotations. Utilising the collated datasets, we generated evidence-based ranking scores for each annotation and characterised the distinct genomic contexts and features of P. falciparum lncRNAs. Certain features indicated subsets with potential biological significance such as 25 lncRNAs containing multiple introns, 335 lncRNAs lacking mutations in piggyBac mutagenic studies and lncRNAs associated with specific biologic processes including two new types of lncRNAs found proximal to var genes.

Conclusions

The insights and the annotation presented in this study will serve as valuable tools for researchers seeking to understand the role of lncRNAs in parasite biology through both bioinformatics and experimental approaches.
‘Sniff Olfactometer (SO) Protocols
Authors: Ni Jiayue , Tang Qi , Huang Jianbo Dave , Solla Leto , Kelson Hannah , Weeks Marcus , Alcott Zoe , Ong Justin , Gomez Andrea , Ding Kaifeng , Acree A. Terry E.
Published: July 2022

Most olfactometers used to study human olfaction have stimulus durations of more than 1 second and often lasting minutes(Dravnieks 1975; Leland et al. 2001; Schmidt and Cain 2010). During long stimulations, olfactory receptor responses and their resulting behaviors are modulated by adaptation and habituation to the stimulus(Pellegrino et al. 2017; Rankin 2009; Wilson and Linster 2008). For example, EOG results from the first deorphanized olfactory receptor tissue reached a maximum in ∼1 s, dropping to 1/2 maximum in the next second, and showing little signal reduction until the stimulation stopped after 6 seconds(Zhao et al. 1998). Longer stimulations can result in complete habituation; receptors still respond even though the behavior shows complete habituation (Barwich 2014). To minimize the effects of adaption and habituation on stimulus responses, the sniff olfactometer (SO) combined the precision of a blast olfactometer with the gentleness of a stream olfactometer by blasting a brief odorant puff (70ms duration) into a subject’s self-imposed inhalation air stream(Rochelle 2017; Rochelle et al. 2017b; Wyckoff and Acree 2017). Here we describe SO protocols for threshold determinations of odorants in aqueous headspaces using odorant recognition probabilities associated with Log(odorant-concentrations(Rochelle et al. 2017a)). During a single trial a subject, preconditioned to associate a veridical name with a given odor (e.g., a pyrazine with “nuts” when the odor was detected and “not nuts” if it wasn’t) was cued to “inhale” and 750ms later, a 15ml-70ms puff of odorant headspace was delivered into their inhalation airstream. A session consisted of 12 randomized double-blind trials of 3 different odorant concentrations. Additional sessions with different concentrations were conducted until the response probability to the samples ranged from below 0.2 to above 0.8. The robustness of the fitted function and the size of their confidence intervals depended on the difference between the concentrations of the odorants during a single session: small differences in sample concentration resulted in the data failing to fit a logistic function; larger concentration differences resulted in a better fit to the model. However, if one of the stimuli had no odorant at all i.e., a blank, the response to the blank was random.
Reducing Merkel cell activity in the whisker follicle disrupts cortical encoding of whisker movement amplitude and velocity
Authors: Lemercier Clément E. , Krieger Patrik
Published: July 2022

Merkel cells (MCs) and associated primary sensory afferents of the whisker follicle-sinus complex robustly code whisker self-movement, angle, and whisk phase during whisking. However, direct evidence of their roles in encoding whisker movement at cortical level is currently missing. To this end, spiking activity of primary somatosensory barrel cortex (wS1) neurons was measured in response to varying whisker deflection amplitude and velocity in transgenic mice with previously established reduced mechanoelectrical coupling at MC-associated afferents. Under reduced MC activity, wS1 neurons exhibited increased sensitivity to whisker deflection. This appeared to arise from a lack of variation in response magnitude to varying whisker deflection amplitude and velocity. This latter effect was further indicated by weaker variation in the temporal profile of the evoked spiking activity when whisker deflection amplitude and velocity varied. Nevertheless, under reduced MC activity, wS1 neurons retained the ability to discriminate stimulus features based on the timing of the first post-stimulus spike. Collectively, results from this study suggest that MCs contribute to both cortical encoding of whisker amplitude and velocity predominantly by tuning cortical response magnitude and by patterning evoked spiking activity, rather than in tuning cortical response latency.
A translational swine model for Crohn’s disease
Authors: Winogrodzki T , Metwaly A , Grodziecki A , Liang W , Klinger B , Flisikowski K , Flisikowska T , Fischer K , Steiger K , Haller D , Schnieke A
Published: July 2022

Crohn’s Disease (CD) is incurable, and represents a lifelong burden for patients and its incidence is increasing worldwide. A key contributing factor is a dysregulated immune response. Here we report the generation of genome edited pigs with a deletion of the transcript-destabilizing AU-rich element (ARE) and a constitutive decay element (CDE) in the TNF gene which recapitulate major characteristics of human CD, including ulcerative transmural ileocolitis, increased abundance of proinflammatory cytokines, evidence for impaired integrity of the intestinal epithelial cell barrier, immune cell infiltration, and dysbiotic microbial communities. This physiologically relevant CD model enables human-scale and long-term studies to assess diagnostic, nutritional or microbial interventions, filling the gap for translating findings into the clinic.
The SSU Processome Component Utp25p is a Pseudohelicase
Authors: Helwer Rafe , Charette J. Michael
Published: July 2022

RNA helicases are involved in nearly all aspects of RNA metabolism and factor prominently in ribosome assembly. The SSU processome includes 10 helicases and many helicase-cofactors. Together, they mediate the structural rearrangements that occur during ribosomal SSU assembly. During the identification of the SSU processome component Utp25, it was noticed that the protein displays some sequence similarity to DEAD-box RNA helicases and is essential for growth. Interestingly, mutational ablation showed that Utp25’s DEAD-box motifs are dispensable. Here, we use AlphaFold to show that Utp25 retains considerable structural similarity to DEAD-box helicases and is the first fully validated pseudohelicase.
Brain Network Architecture Constrains Age-related Cortical Thinning
Authors: Petersen Marvin , Nägele Felix L. , Mayer Carola , Schell Maximilian , Rimmele D. Leander , Petersen Elina , Kühn Simone , Gallinat Jürgen , Hanning Uta , Fiehler Jens , Twerenbold Raphael , Gerloff Christian , Thomalla Götz , Cheng Bastian
Published: July 2022

Age-related cortical atrophy, approximated by cortical thickness measurements from magnetic resonance imaging, follows a characteristic pattern over the lifespan. Although its determinants remain unknown, mounting evidence demonstrates correspondence between the connectivity profiles of structural and functional brain networks and cortical atrophy in health and neurological disease. Here, we performed a cross-sectional multimodal neuroimaging analysis of 2633 individuals from a large population-based cohort to characterize the association between age-related differences in cortical thickness and functional as well as structural brain network topology. We identified a widespread pattern of age-related cortical thickness differences including “hotspots” of strong age effects located in brain areas with high centrality (structural network hubs). Regional age-related differences were furthermore strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences as well as its change throughout the later lifespan was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients. Lastly, the identified difference pattern covaried significantly with cognitive and motor performance. Our findings indicate that connectivity profiles of functional and structural brain networks might act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.
Swapped genetic code blocks viral infections and gene transfer
Authors: Nyerges Akos , Vinke Svenja , Flynn Regan , Owen Siân V. , Rand Eleanor A. , Budnik Bogdan , Keen Eric , Narasimhan Kamesh , Marchand Jorge A. , Baas-Thomas Maximilien , Liu Min , Chen Kangming , Chiappino-Pepe Anush , Hu Fangxiang , Baym Michael , Church George M.
Published: July 2022

Removing cellular transfer RNAs (tRNAs), making their cognate codons unreadable, creates a genetic firewall that prevents viral replication and horizontal gene transfer. However, numerous viruses and mobile genetic elements encode parts of the translational apparatus, including tRNAs, potentially rendering a genetic-code-based firewall ineffective. In this paper, we show that such horizontally transferred tRNA genes can enable viral replication in Escherichia coli cells despite the genome-wide lack of three codons and the previously essential cognate tRNAs and release factor 1. By repurposing viral tRNAs, we then develop recoded cells bearing an amino-acid-swapped genetic code that reassigns two of the six serine codons to leucine during translation. This amino-acid-swapped genetic code renders cells completely resistant to viral infections by mistranslating viral proteomes and prevents the escape of synthetic genetic information by engineered reliance on serine codons to produce leucine-requiring proteins. Finally, we also repurpose the third free codon to biocontain this virus-resistant host via dependence on an amino acid not found in nature.
Directed Shortest Walk on Temporal Graphs
Authors: Khodaverdian Alex , Yosef Nir
Published: July 2022

Background

The use of graphs as a way of abstracting and representing biological systems has provided a powerful analysis paradigm. Specifically, graph optimization algorithms are routinely used to address various connectivity queries, such as finding paths between proteins in a protein-protein interaction network, while maximizing objectives such as parsimony. While present studies in this field mostly concern static graphs, new types of data now motivate the need to account for changes that might occur to the elements (nodes) that are represented by the graph on the relationships (edges) between them.

Results and Discussion

We define the notion of Directed Temporal Graphs as a series of directed subgraphs of an underlying graph, ordered by time, where only a subset of vertices and edges are present. We then build up towards the Time Conditioned Shortest Walk problem on Directed Temporal Graphs: given a series of time ordered directed graphs, find the shortest walk from any given source node at time point 1 to a target node at time T ≥ 1, such that the walk is consistent (monotonically increasing) with the timing of nodes and edges. We show, contrary to the Directed Shortest Walk problem which can be solved in polynomial time, that the Time Conditioned Shortest Walk (TCSW) problem is NP-Hard, and is hard to approximate to factor for T ≥ 3 and ε > 0. Lastly, we develop an integer linear program to solve a generalized version of TCSW, and demonstrate its ability to reach optimality with instances of the human protein interaction network.

Conclusion

We demonstrate that when extending the shortest walk problem in computational biology to account for multiple ordered conditions, the problem not only becomes hard to solve, but hard to approximate, a limitation which we address via a new solver. From this narrow definition of TCSW, we relax the constraint of time consistency within the shortest walk, deriving a direct relationship between hardness of approximation and the allowable step size in our walk between time conditioned networks. Lastly we briefly explore a variety of alternative formulations for this problem, providing insight into both tractable and intractable variants.

Availability

Our solver for the general k-Time Condition Shortest Walk problem is available at https://github.com/YosefLab/temporal_condition_shortest_walk
Integration of microprism and microelectrode arrays enables simultaneous electrophysiology and two-photon imaging across all cortical layers
Authors: Yang Qianru , Wu Bingchen , Castagnola Elisa , Pwint May Yoon , Williams Nathaniel , Vazquez Alberto L. , Cui X. Tracy
Published: July 2022

Electrophysiology is a vital tool in neuroscience research with increasing translational value. It is used to record or modulate neuronal activity with high temporal but lower spatial resolution. Optical technologies, such as two-photon microscopy (TPM) can complement electrophysiological recordings with large-scale imaging at cellular resolution. Combining these two provides a powerful platform to elucidate and coordinate multimodal functions. Prior attempts have been limited to the superficial brain from a top-down optical view. Here, we describe a novel combination of transparent microelectrode arrays (MEAs) with glass microprisms for simultaneous electrophysiology and optical imaging of all cortical layers in a vertical plane. We tested our device in Thy1-GCaMP6 mice for over 4 months and demonstrated its capability for multisite single-unit recording, microstimulation, and simultaneous TPM calcium imaging. Using this setup, we reveal how amplitude, frequency, and depth of microstimulation impact neural activation patterns across the cortical column. This work presents a multimodal tool that extends integrated electrophysiology and optical imaging from the superficial brain to the whole cortical column, opening new avenues of neuroscience research and neurotechnology development.
Innate Immune Stimulation using 3D Wireframe DNA Origami
Authors: Du Rebecca R. , Cedrone Edward , Dobrovolskaia Marina A. , Bathe Mark
Published: July 2022

3D wireframe DNA origami have programmable structural and sequence features that render them potentially suitable for prophylactic and therapeutic applications. However, their innate immunological properties, which stem from parameters including geometric shape and CpG content, remain largely unknown. Here, we investigate the immunostimulatory properties of 3D wireframe DNA origami on the TLR9 pathway using both reporter cell lines and primary immune cells. Our results suggest that bare 3D polyhedral wireframe DNA origami induce minimal TLR9 activation despite the presence of numerous internal CpG dinucleotides. However, when displaying multivalent CpG-containing ssDNA oligos, wireframe DNA origami induce robust TLR9 pathway activation, along with enhancement of downstream immune response as evidenced by increases in Type I and Type III IFN production in peripheral blood mononuclear cells. Further, we find that CpG copy number and spatial organization each contribute to the magnitude of TLR9 signaling, and that NANP-attached CpGs do not require phosphorothioate stabilization to elicit signaling. These results suggest key design parameters for wireframe DNA origami that can be programmed to modulate immune pathway activation controllably for prophylactic and therapeutic applications.
BayesTME: A unified statistical framework for spatial transcriptomics
Authors: Zhang Haoran , Hunter Miranda V. , Chou Jacqueline , Quinn Jeffrey F. , Zhou Mingyuan , White Richard , Tansey Wesley
Published: July 2022

Spatial variation in cellular phenotypes underlies heterogeneity in immune recognition and response to therapy in cancer and many other diseases. Spatial transcriptomics (ST) holds the potential to quantify such variation, but existing analysis methods address only a small part of the analysis challenge, such as spot deconvolution or spatial differential expression. We present BayesTME, an end-to-end Bayesian method for analyzing spatial transcriptomics data. BayesTME unifies several previously distinct analysis goals under a single, holistic generative model. This unified approach enables BayesTME to (i) be entirely reference-free without any need for paired scRNA-seq, (ii) outperform a large suite of methods in quantitative benchmarks, and (iii) uncover a new type of ST signal: spatial differential expression within individual cell types. To achieve the latter, BayesTME models each phenotype as spatially adaptive and discovers statistically significant spatial patterns amongst coordinated subsets of genes within phenotypes, which we term spatial transcriptional programs. On human and zebrafish melanoma tissues, BayesTME identifies spatial transcriptional programs that capture fundamental biological phenomena like bilateral symmetry, differential expression between interior and surface tumor cells, and tumor-associated fibroblast and macrophage reprogramming. Our results demonstrate BayesTME’s power in unlocking a new level of insight from spatial transcriptomics data and fostering a deeper understanding of the spatial architecture of the tumor microenvironment. BayesTME is open source and publicly available (https://github.com/tansey-lab/bayestme).
Unifying the Identification of Biomedical Entities with the Bioregistry
Authors: Hoyt Charles Tapley , Balk Meghan , Callahan Tiffany J. , Domingo-Fernández Daniel , Haendel Melissa A. , Hegde Harshad B. , Himmelstein Daniel S. , Karis Klas , Kunze John , Lubiana Tiago , Matentzoglu Nicolas , McMurry Julie , Moxon Sierra , Mungall Christopher J. , Rutz Adriano , Unni Deepak R. , Willighagen Egon , Winston Donald , Gyori Benjamin M.
Published: July 2022

The standardized identification of biomedical entities is a cornerstone of interoperability, reuse, and data integration in the life sciences. Several registries have been developed to catalog resources maintaining identifiers for biomedical entities such as small molecules, proteins, cell lines, and clinical trials. However, existing registries have struggled to provide sufficient coverage and metadata standards that meet the evolving needs of modern life sciences researchers. Here, we introduce the Bioregistry, an integrative, open, community-driven metaregistry that synthesizes and substantially expands upon 23 existing registries. The Bioregistry addresses the need for a sustainable registry by leveraging public infrastructure and automation, and employing a progressive governance model centered around open code and open data to foster community contribution. The Bioregistry can be used to support the standardized annotation of data, models, ontologies, and scientific literature, thereby promoting their interoperability and reuse. The Bioregistry can be accessed throughhttps://bioregistry.ioand its source code and data are available under the MIT and CC0 Licenses athttps://github.com/biopragmatics/bioregistry.