bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-training with a rational approach for antibody sequence representation
Authors: Gao Xiangrui , Cao Changling , He Chenfeng , Lai Lipeng
Published: January 2023

Antibodies represent a specific class of proteins produced by the adaptive immune system in response to pathogens. Mining the information embedded in antibody amino acid sequences can benefit both antibody property prediction and novel therapeutic development. Protein-specific pre-training models have been used to extract latent representations from protein sequences, structural, functional, and homologous information. However, compared to other proteins, antibodies possess unique features that should be incorporated using specifically designed training methods, so there is still room for improvement in pre-training models for antibody sequences. On the one hand, existing protein pre-training models primarily utilize language models without fully considering the differences between protein sequences and language sequences. In this study, we present a Pre-trained model of Antibody sequences trained with a Rational Approach for antibodies (PARA), which employs a strategy conforming to antibody sequence patterns and an advanced natural language processing self-encoding model structure. We demonstrate PARA’s performance on several tasks by comparing it to various published pre-training models of antibodies. The results show that PARA significantly outperforms existing models on these tasks, suggesting that PARA has an advantage in capturing antibody sequence information. We believe that the antibody latent representation provided by PARA can substantially facilitate studies in relevant areas. PARA is available athttps://github.com/xtalpi-xic.
Experimental and computational analysis of REM sleep distributed cortical activity in mice
Authors: Peuvrier Mathias , Fernandez Laura , Crochet Sylvain , Destexhe Alain , Salin Paul
Published: January 2023

Although classically Rapid-Eye Movement (REM) sleep is thought to generate desynchronized activity similar to wakefulness, it was found that some brain regions can express Slow Wave activity (SWA), a pattern which is normally typical of slow-wave sleep. To investigate possible underlying mechanisms, we analyze experimental recordings and introduce a computational model of mice cerebral cortex in REM sleep. We characterized the patterns of slow-wave activity across somatosensory and motor areas, and find that the most prominent REM-related SWA is present in the primary (S1) and secondary (S2) somatosensory areas, more rarely seen in motor cortex, and absent from prefrontal cortex or hippocampus. The SWA also tends to be synchronized in S1 and S2. We next investigated possible mechanisms by using a computational model of the mouse brain consisting of adaptive Exponential (AdEx) mean-fields connected together according to the mouse connectome. To compare with experimental data, the local field potential is calculated in each mouse brain region. To reproduce the experiments, we had to assume a heterogeneous level of adaptation in different cortical regions during REM sleep. In these conditions, the model reproduces some of the experimental observations in the somato-motor areas and the other cortical areas. We then used the model to test how the presence of SWA affects cortical responsiveness. Indeed, we find that the areas expressing SWA have diminished evoked responses, which may participate to a diminished responsiveness during REM sleep.
Interaction between mutation type and gene pleiotropy drives parallel evolution in the laboratory
Authors: Ruelens Philip , Wynands Thomas , de Visser J. Arjan G.M.
Published: January 2023

What causes evolution to be repeatable is a fundamental question in evolutionary biology. Pleiotropy, i.e. the effect of an allele on multiple traits, is thought to enhance repeatability by constraining the number of available beneficial mutations. Additionally, pleiotropy may promote repeatability by allowing large fitness benefits of single mutations via adaptive combinations of phenotypic effects. Yet, this latter evolutionary potential may be reaped solely by specific types of mutations able to realize optimal combinations of phenotypic effects while avoiding the costs of pleiotropy. Here, we address the interaction of gene pleiotropy and mutation type on evolutionary repeatability in a meta-analysis of experimental evolution studies withEscherichia coli. We hypothesize that single-nucleotide polymorphisms are principally able to yield large fitness benefits by targeting highly pleiotropic genes, whereas indels and structural variants provide smaller benefits and are restricted to genes with lower pleiotropy. By using gene connectivity as proxy for pleiotropy, we show that nondisruptive single-nucleotide polymorphisms (SNPs) in highly pleiotropic genes yield the largest fitness benefits, since they contribute more to parallel evolution, especially in large populations, than inactivating SNPs, indels and structural variants. Our findings underscore the importance of considering genetic architecture together with mutation type for understanding evolutionary repeatability.
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins
Authors: Avolio Rosario , Agliarulo Ilenia , Criscuolo Daniela , Sarnataro Daniela , Auriemma Margherita , Pennacchio Sara , Calice Giovanni , Ng Martin Y. , Giorgi Carlotta , Pinton Paolo , Cooperman Barry , Landriscina Matteo , Esposito Franca , Matassa Danilo Swann
Published: January 2023

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.
A Generative Model of Memory Construction and Consolidation
Authors: Spens Eleanor , Burgess Neil
Published: January 2023

Episodic memories are (re)constructed, combining unique features with familiar schemas, share neural substrates with imagination, and show schema-based distortions that increase with consolidation. Here we present a computational model in which hippocampal replay (from an autoassociative network) trains generative models (variational autoencoders) in neo-cortex to (re)create sensory experiences via latent variable representations in entorhinal, medial prefrontal, and anterolateral temporal cortices. Simulations show effects of memory age and hippocampal lesions in agreement with previous models, but also provide mechanisms for se-mantic memory, imagination, episodic future thinking, relational inference, and schema-based distortions including boundary extension. The model explains how unique sensory and predict-able conceptual or schematic elements of memories are stored and reconstructed by efficiently combining both hippocampal and neocortical systems, optimising the use of limited hippocam-pal storage for new and unusual information. Overall, we believe hippocampal replay training neocortical generative models provides a comprehensive account of memory construction, ima-gination and consolidation.
A systematic mapping of the genomic and proteomic variation associated with monogenic diabetes
Authors: Kuznetsova Ksenia , Vašíček Jakub , Skiadopoulou Dafni , Molnes Janne , Udler Miriam , Johansson Stefan , Njølstad Pål Rasmus , Manning Alisa , Vaudel Marc
Published: January 2023

Aims

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Multiple genes have been described to be responsible for monogenic diabetes, but the information on the variants is not unified among different resources. In this work, we aimed to develop an automated pipeline that collects all the genetic variants associated with monogenic diabetes from different resources, unify the data and translate the genetic sequences to the proteins.

Methods

The pipeline developed in this work is written in Python with the use of Jupyter notebook. It consists of 6 modules that can be implemented separately. The translation step is performed using the ProVar tool also written in Python. All the code along with the intermediate and final results is available for public access and reuse.

Results

The resulting database had 2701 genomic variants in total and was divided into two levels: the variants reported to have an association with monogenic diabetes and the variants that have evidence of pathogenicity. Of them, 2565 variants were found in the ClinVar database and the rest 136 were found in the literature showing that the overlap between resources is not absolute.

Conclusions

We have developed an automated pipeline for collecting and harmonizing data on genetic variants associated with monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins associated with monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

Research in context

Monogenic diabetes is a group of Mendelian diseases with an autosomal-dominant pattern of inheritance.

Monogenic diabetes is mainly caused by rare genetic variants that are usually evaluated manually.

The data on the variants are stored in several resources and are not unified in terms of the genomic coordinates, alleles, and variant annotation.

What can be done for the systematic evaluation of the variants and their protein consequences?

In this work, we have created an automated Jupyter notebook-based pipeline for the collection and unification of the variants associated with monogenic diabetes.

The database of the genetic variants was created and translated to all possible variant protein sequences.

These results will be used for the analysis of proteomics data and protein structure modeling.
Minimal impact of proprioceptive loss on implicit sensorimotor adaptation and perceived movement outcome
Authors: Tsay Jonathan S. , Chandy Anisha M. , Chua Romeo , Miall R. Chris , Cole Jonathan , Farnè Alessandro , Ivry Richard B. , Sarlegna Fabrice R.
Published: January 2023

Implicit sensorimotor adaptation keeps our movements well-calibrated amid changes in the body and environment. We have recently postulated that implicit adaptation is driven by a perceptual error: the difference between the desired and perceived movement outcome. According to this perceptual re-alignment model, implicit adaptation ceases when the perceived movement outcome – a multimodal percept determined by a prior belief conveying the intended action, the motor command, and feedback from proprioception and vision – is aligned with the desired movement outcome. Here, we examined the role of proprioception in implicit motor adaptation and perceived movement outcome by examining individuals who lack proprioception. We used a modified visuomotor rotation task designed to isolate implicit adaptation and probe perceived outcome throughout the experiment. Surprisingly, implicit adaptation and perceived outcome were minimally impacted by deafferentation, posing a challenge to the perceptual re-alignment model of implicit adaptation.
Selection, recombination and population history effects on runs of homozygosity (ROH) in wild red deer (Cervus elaphus)
Authors: Hewett Anna M. , Stoffel Martin A. , Peters Lucy , Johnston Susan E. , Pemberton Josephine M.
Published: January 2023

The distribution of runs of homozygosity (ROH) may be shaped by a number of interacting processes such as selection, recombination and population history, but little is known about the importance of these mechanisms in shaping ROH in wild populations. We combined an empirical dataset of >3,000 red deer genotyped at >35,000 genome-wide autosomal SNPs and evolutionary simulations to investigate the influence of each of these factors on ROH. We assessed ROH number and location in two populations of red deer (a focal and comparison) to investigate the effect of population history. We investigated the role of recombination using both a physical map and a genetic linkage map to search for ROH. We found differences in ROH distribution between both populations and both map types indicating that population history and local recombination rate have a substantial effect on ROH. Finally, we ran forward genetic simulations with varying population histories, recombination rates and levels of selection, allowing us to further interpret our empirical data. These simulations showed that population history has a greater effect on ROH distribution than either recombination or selection. We further show that selection can cause genomic regions where ROH are common, so called ROH hotspots, only when the effective population size (Ne) is large or selection is particularly strong. In populations having undergone a population bottleneck, genetic drift can outweigh the effect of selection. We show that most ROH hotspots in the Rum population are in line with expectations from neutral simulations, however two ROH hotspots show possible signatures of selection. Overall, we conclude that in this population, genetic drift resulting from a historical population bottleneck is most likely to have resulted in the observed ROH distribution, with selection possibly playing a minor role.
Transcriptional and Histone acetylation changes associated with CRE elements expose key factors governing the regulatory circuit in early stage of Huntington’s disease models
Authors: Arancibia-Opazo Sandra , Contreras-Riquelme J. Sebastián , Sánchez Mario , Cisternas-Olmedo Marisol , Vidal René L. , Martin Alberto J. M. , Sáez Mauricio A.
Published: January 2023

Huntington’s disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP which in turn induces altered histone acetylation patterns and transcriptional deregulation.

Here, we have studied differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. Analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade.

Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD.

Here we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD, a starting point for early onset indicators of the progression of this disease.
The more, the merrier: multivariate phase synchronization methods excel pairwise ones in estimating functional brain connectivity from reconstructed neural sources
Authors: Bruña Ricardo , Cuesta Pablo , Ramírez-Toraño Federico , Suárez-Méndez Isabel , Pereda Ernesto
Published: January 2023

The estimation of functional connectivity (FC) from electro-(EEG) or magnetoencephalographic (MEG) recordings suffers from low spatial resolution, being one of the reasons for the reduced number of sensors compared to the number of reconstructed sources of activity. This problem can be avoided by estimating FC between larger regions instead of individual sources. However, combining all the sources in each area to produce a single time series per region is far from trivial.

We have used simultaneous EEG/MEG data from 11 participants and compared the FC estimates from both techniques by using different multivariate approaches. Since the underlying generators are identical for EEG and MEG, the more similar the FC estimation from both techniques is, the more accurate it is likely to be. The results show that using either the average or the root-mean-square of the bivariate source-to-source FC estimates consistently outperforms the use of a representative time series from each area.

We concluded that the reconstructed activity in each brain region is too complex to be reduced to a single representative time series and that full multivariate approaches must be used to describe between-area FC from electrophysiological recordings accurately. Moreover, the high correlation between the FC values estimated from EEG and MEG suggests that the results found in the high-sensitivity, low-noise MEG can be transferable to the more affordable EEG, at least when high-quality source reconstruction is used.
Single-cell sequencing for the molecular identity involved in zinc therapy for spinal cord injury
Authors: Shi Zuqiang , Lin Jiaquan , Ge Minghao , Hu Hengshuo , Mao Liang , Tian Miaomiao , Tian He , Mei Xifan
Published: January 2023

Spinal cord injury (SCI) is a severe traumatic neurological condition often caused by car accidents, violent impacts, or unintentional falls and can have devastating consequences for the patient. SCI include primary and secondary injuries. Followed by primary injury, and secondary injuries including inflammatory responses and oxidative stress, which exacerbate the disease process of SCI. Therefore, the treatment of SCI, especially the suppression of secondary injuries, is a major focus of attention in the field of neuroscience. In previous studies, we have demonstrated that zinc therapy can exert neuroprotective effects in mice after acute SCI, including reducing the inflammatory response in the central nervous system, decreasing the neuronal apoptosis and downregulating oxidative stress at the region of injury. However, little is known about how zinc therapy systematically alleviates SCI. Here, we have systematically analysed and mapped the single-cell atlas of the spinal cord in mice with SCI treated by zinc therapy, which provides a systematic analysis of the transcriptome of individual cells in the spinal cord. Among the results, we found that zinc therapy-induced alterations in the IL-17 inflammatory pathway and produced immune heterogeneity in microglia which are the inherent immune cells in the central nervous system. By cell subpopulations clustering analysis, we defined seven microglia subpopulations in zinc-therapy spinal cord tissue and identified the presence of novel VEGFA+ microglia. This finding presents that the microglia subpopulations affected by zinc therapy may have the potential to promote angiogenesis, which is a potential mechanism for the treatment of SCI. In conclusion, this study maps/reveals the transcriptomic of zinc therapy for the treatment of acute SCI with unprecedented resolution and provides a molecular basis for the clinical application.
Multiomic interpretation of fungus-infected ant metabolomes during manipulated summit disease
Authors: Will I. , Attardo G. M. , de Bekker C.
Published: January 2023

Camponotus floridanusants show altered behaviors followed by a fatal summiting phenotype when infected with manipulatingOphiocordyceps camponoti-floridanifungi. Host summiting as a strategy to increase transmission is also observed with parasite taxa beyond fungi, including aquatic and terrestrial helminths and baculoviruses. The drastic phenotypic changes can sometimes reflect significant physiological changes within host cells that span molecular levels from metabolites to nucleic acids. Nevertheless, the underlying mechanisms still need to be fully characterized. To investigate the small molecules producing summiting behavior, we infectedC. floridanusants withO. camponoti-floridaniand sampled their heads for LC-MS/MS when we observed the characteristic summiting phenotype. We link this metabolomic data with our previous genomic and transcriptomic data to propose mechanisms that underlie manipulated summiting behavior in “zombie ants.” This “multiomic” evidence points toward the dysregulation of neurotransmitter levels and neuronal signaling. We propose that these processes are altered during infection and manipulation based on 1) differential expression of neurotransmitter synthesis and receptor genes, 2) altered abundance of metabolites and neurotransmitters (or their precursors) with known behavioral effects in ants and other insects, and 3) possible suppression of a connected immunity pathway. We additionally report signals for metabolic activity during manipulation related to primary metabolism, detoxification, and anti-stress protectants.
Rapid turnover and evolution of sex-determining regions amongSebastesrockfishes
Authors: Sykes Nathan T.B. , Raj Kolora Sree Rohit , Sudmant Peter H. , Owens Gregory L.
Published: January 2023

Nature has evolved a wealth of sex determination (SD) mechanisms, driven by both genetic and environmental factors. Recent studies of SD in fishes have shown that not all taxa fit the classic paradigm of sex chromosome evolution and diverse SD methods can be found even among closely related species. Here, we apply a suite of genomic approaches to investigate sex-biased genomic variation in eight species ofSebastesrockfish found in the northeast Pacific Ocean. Using recently assembled chromosome-level rockfish genomes, we leverage published sequence data to identify disparate sex chromosomes and sex-biased loci in five species. We identify two putative male sex chromosomes inS. diaconus, a single putative sex chromosome in the sibling speciesS. carnatusandS. chrysomelas, and an unplaced sex determining contig in the sibling speciesS. miniatusandS. crocotulus. Our study provides evidence for disparate means of sex determination within a recently diverged set of species, and sheds light on the diverse origins of sex determination mechanisms present in the animal kingdom.
Defining the contribution of microRNA-specific slicing Argonautes in animals
Authors: Pal Anisha , Vasudevan Vaishnav , Houle François , Lantin Michael , Maniates Katherine A. , Huberdeau Miguel Quévillon , Abbott Allison L. , Simard Martin J.
Published: January 2023

microRNAs regulate gene expression through interaction with an Argonaute protein family member. While some members of this protein family retain an enzymatic activity capable of cleaving RNA molecules complementary to Argonaute-bound small RNAs, the role of the slicing activity in the canonical microRNA pathway is still unclear in animals. To address the importance of slicing Argonautes in animals, we createdCaenorhabditis elegansstrains, carrying catalytically dead endogenous ALG-1 and ALG-2, the only two slicing Argonautes essential for the miRNA pathway in this animal model. We observe that the loss of ALG-1 and ALG-2 slicing activity affects overall animal fitness and causes phenotypes, reminiscent of miRNA defects, only when grown and maintained at restrictive temperature. Furthermore, the analysis of global miRNA expression shows that the catalytic activity of ALG-1 and ALG-2 differentially regulate the level of specific subsets of miRNAs in young adults. We also demonstrate that altering the slicing activity of those miRNA-specific Argonautes does not result in any defect in the production of canonical miRNAs. Together, these data support that the slicing activity of miRNA- specific Argonautes function to maintain the levels of a set of miRNAs for optimal viability and fitness in animals particularly exposed to specific growing conditions.
The catalytic activity of microRNA Argonautes plays a modest role in microRNA star strand destabilization inC. elegans
Authors: Kotagama Kasuen , Grimme Acadia L. , Braviner Leah , Yang Bing , Sakhawala Rima M. , Yu Guoyun , Benner Lars Kristian , Joshua-Tor Leemor , McJunkin Katherine
Published: January 2023

Many Argonaute proteins can cleave RNA (“slicing”) as part of the microRNA-induced silencing complex (miRISC), even though miRNA-mediated target repression is generally independent of target cleavage. Here we use genome editing inC. elegansto examine the role of miRNA-guided slicing in organismal development. In contrast to previous work, slicing-inactivating mutations did not interfere with normal development when introduced by CRISPR. We find that unwinding and decay of miRNA star strands is weakly defective in the absence of slicing, with the largest effect observed in embryos. Argonaute-Like Gene 2 (ALG-2) is more dependent on slicing for unwinding than ALG-1. The miRNAs that displayed the greatest (albeit minor) dependence on slicing for unwinding tend to form stable duplexes with their star strand, and in some cases, lowering duplex stability alleviates dependence on slicing. Gene expression changes were consistent with negligible to moderate loss of function for miRNA guides whose star strand was upregulated, suggesting a reduced proportion of mature miRISC in slicing mutants. While a few miRNA guide strands are reduced in the mutant background, the basis of this is unclear since changes were not dependent on EBAX-1, a factor in the Target-Directed miRNA Degradation (TDMD) pathway. Overall, this work defines a role for miRNA Argonaute slicing in star strand decay; future work should examine whether this role could have contributed to the selection pressure to conserve catalytic activity of miRNA Argonautes across the metazoan phylogeny.
Wirelessin vivoRecording of Cortical Activity by an Ion-Sensitive Field Effect Transistor
Authors: Bhatt Suyash , Masterson Emily , Zhu Tianxiang , Eizadi Jenna , George Judy , Graupe Nesya , Vareberg Adam , Phillips Jack , Bok Ilhan , Dwyer Matthew , Ashtiani Alireza , Hai Aviad
Published: January 2023

Wireless brain technologies are empowering basic neuroscience and clinical neurology by offering new platforms that minimize invasiveness and refine possibilities during electrophysiological recording and stimulation. Despite their advantages, most systems require on-board power supply and sizeable transmission circuitry, enforcing a lower bound for miniaturization. Designing new minimalistic architectures that can efficiently sense neurophysiological events will open the door to standalone microscale sensors and minimally invasive delivery of multiple sensors. Here we present a circuit for sensing ionic fluctuations in the brain by an ion-sensitive field effect transistor that detunes a single radiofrequency resonator in parallel. We establish sensitivity of the sensor by electromagnetic analysis and quantify response to ionic fluctuationsin vitro. We validate this new architecturein vivoduring hindpaw stimulation in rodents and verify correlation with local field potential recordings. This new approach can be implemented as an integrated circuit for wirelessin siturecording of brain electrophysiology.
Cortex-wide topography of 1/f-exponent in Parkinson’s disease
Authors: Helson Pascal , Lundqvist Daniel , Svenningsson Per , Vinding Mikkel C. , Kumar Arvind
Published: January 2023

Parkinson’s Disease causes progressive and debilitating changes to the brain as well as to the mind. While the diagnostic hallmark features are the characteristic movement-related symptoms, the disease also causes decline in sensory processing, cognitive, emotional performance and most patients develop dementia over time. The extent of symptoms and the brain-wide projections of neuromodulators such as dopamine suggest that many brain regions are simultaneously affected in Parkinson’s disease. To characterise such disease-related and brain-wide changes in neuronal function, we performed a source level analysis of resting state magnetoencephalogram (MEG) from two groups: Parkinson’s disease patients and healthy controls. Besides standard spectral analysis, we quantified the aperiodic component of the neural activity by fitting a power law (κ/fλ) to the MEG spectrum and then studied its relationship with age and UPDRS. Consistent with previous results, the most significant spectral changes were observed in the high theta/low alpha band (7-10 Hz) in all brain regions. Furthermore, analysis of the aperiodic part of the spectrum showed that, in all but frontal regions, λ was significantly larger in Parkinson’s disease patients than in control subjects. Our results indicate for the first time that Parkinson’s disease is associated with significant changes in population activity across the whole neocortex. Surprisingly, even early sensory areas showed a significantly larger λ in patients than in healthy controls. Moreover, λ was not affected by the L-dopa medication. Finally, λ was positively correlated with patient age but not with UPDRS-III (summary measure of motor symptoms’ clinical rating). Because λ is closely associated excitationinhibition balance, our results propose new hypotheses about manifestation of Parkinson’s disease in cortical networks.
Absolute quantification of photoreceptor outer segment proteins
Authors: Skiba Nikolai P. , Lewis Tylor R. , Spencer William J. , Castillo Carson M. , Shevchenko Andrej , Arshavsky Vadim Y.
Published: January 2023

Photoreceptor cells generate neuronal signals in response to capturing light. This process, called phototransduction, takes place in a highly specialized outer segment organelle. There are significant discrepancies in the reported amounts of many proteins supporting this process, particularly those of low abundance, which limits our understanding of their molecular organization and function. In this study, we used quantitative mass spectrometry to simultaneously determine the abundances of twenty key structural and functional proteins residing in mouse rod outer segments. We computed the absolute number of molecules of each protein residing within an individual outer segment and the molar ratio amongst all twenty proteins. The molar ratios of proteins comprising three well-characterized constitutive complexes in outer segments differed from the established subunit stoichiometries of these complexes by less than 7%, highlighting the exceptional precision of our quantification. Overall, this study resolves multiple existing discrepancies regarding the outer segment abundances of these proteins, thereby advancing our understanding of how the phototransduction pathway functions as a single, well-coordinated molecular ensemble.
Gene expression of macaques infected with malaria species of zoonotic concern
Authors: Trujillo Amber E. , Bergey Christina M.
Published: January 2023

A multitude of malaria species (genusPlasmodium) infects primates. Due to their public health importance, the human-infective species have garnered the most focus, but increased knowledge of non-human primate malaria species is warranted to improve our evolutionary understanding of host-parasite interactions. Additionally, the broad host tropism of some primate malaria parasites and their realized or theorized zoonotic potential add urgency to understanding of primate-parasite interactions. Here, we use comparative transcriptomics to understand the rhesus macaque (Macaca mulatta) response to two malaria parasites used as analogues to human-infective species of differing severity and which may represent emerging zoonotic threats:P. coatneyi, comparable to human-infectiveP. falciparum, andP. cynomolgi, comparable to human-infectiveP. vivax. We first validate our transcriptomics-based proxy of parasite load through comparison to gold-standard microscopy-based measures. We then find that malaria-associated host genes have functional links to immune system regulation and blood cells. Host genes with differing expression by malaria species were more likely to be involved in brain-linked functions, perhaps due to the differential central nervous system involvement of the two parasite species. Such comparative work on primate malaria species may help elucidate the essential and species-specific molecular mechanisms that underlie differing clinical presentations and zoonotic risk.
An invariant relationship between NonREM and REM sleep and the wave model of their dynamics
Authors: Kharchenko Vasili , Zhdanova Irina V.
Published: January 2023

Explaining the complex structure and dynamics of sleep, which consist of alternating and physiologically distinct NonREM and REM sleep episodes, has posed a significant challenge. In this study, we demonstrate that a single wave model concept captures the distinctly different overnight dynamics of the four primary sleep measures - the duration and intensity of NonREM and REM sleep episodes - with high quantitative precision. Additionally, the model accurately predicts how these measures respond to sleep deprivation or abundance. Furthermore, the model passes the ultimate test, as its prediction leads to a novel experimental finding—an invariant relationship between the duration of NonREM episodes and the intensity of REM episodes, the product of which remains constant over consecutive sleep cycles. These results suggest a functional unity between NonREM and REM sleep, establishing a comprehensive and quantitative framework for understanding normal sleep and sleep disorders.
Interactions between terminal ribosomal RNA helices stabilize theEscherichia colilarge ribosomal subunit
Authors: Nissley Amos J. , Kamal Tammam S. , Cate Jamie H. D.
Published: January 2023

The ribosome is a large ribonucleoprotein assembly that uses diverse and complex molecular interactions to maintain proper folding.In vivoassembled ribosomes have been isolated using MS2-tags installed in either the 16S or 23S ribosomal RNAs (rRNAs), to enable studies of ribosome structure and functionin vitro. RNA tags in theEscherichia coli50S subunit have commonly been inserted into an extended helix H98 in 23S rRNA, as this addition does not affect cellular growth orin vitroribosome activity. Here, we find thatE. coli50S subunits with MS2 tags inserted in H98 are destabilized compared to wild type (WT) 50S subunits. We identify the loss of RNA-RNA tertiary contacts that bridge helices H1, H94, and H98 as the cause of destabilization. Using cryogenic electron microscopy (cryo-EM), we show that this interaction is disrupted by the addition of the MS2 tag and can be restored through the insertion of a single adenosine in the extended H98 helix. This work establishes ways to improve MS2 tags in the 50S subunit that maintain ribosome stability and investigates a complex RNA tertiary structure that may be important for stability in various bacterial ribosomes.
Immune sensing of food allergens promotes aversive behaviour
Authors: Florsheim Esther B. , Bachtel Nathaniel D. , Cullen Jaime , Lima Bruna G. C. , Godazgar Mahdieh , Zhang Cuiling , Carvalho Fernando , Gautier Gregory , Launay Pierre , Wang Andrew , Dietrich Marcelo O. , Medzhitov Ruslan
Published: January 2023

In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations1–3. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.
Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
Authors: Garcia Gustavo , Irudayam Joseph Ignatius , Jeyachandran Arjit Vijay , Dubey Swati , Chang Christina , Cario Sebastian Castillo , Price Nate , Arumugam Sathya , Marquez Angelica L. , Shah Aayushi , Fanaei Amir , Chakravarty Nikhil , Joshi Shantanu , Sinha Sanjeev , French Samuel W. , Parcells Mark , Ramaiah Arunachalam , Arumugaswami Vaithilingaraja
Published: January 2023

RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2’,3’-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.
High tissue-specificity of lncRNAs maximises the prediction of tissue of origin of circulating DNA
Authors: Mouhou Elyas , Genty Fabien , M’selmi Walid El , Chouali Hanae , Zagury Jean-François , Clerc Sigrid Le , Proudhon Charlotte , Noirel Josselin
Published: January 2023

Several studies have made it possible to envision a translational application of plasma DNA sequencing in cancer diagnosis and monitoring. However, the extremely low concentration of circulating tumour DNA (ctDNA) fragments among the total cell-free DNA (cfDNA) remains a formidable challenge to overcome and statistical models have yet to be improved enough to become of practical use. In this study, we set about appraising the predictive value of a variety of binary classification models based on cfDNA sequencing using fragmentation features extracted around transcription start sites (TSSs). We investigated (1) features summarising mapped fragment density around each TSS, (2) long non-coding RNA (lncRNA) genes versus coding genes and (3) selection criteria to generate gene classes to be assigned by the model. Given that, in healthy samples, most of the cfDNA comes from lymphomyeloid lineages, we could identify the model parametrisation with the best accuracy in those lineages using publicly available datasets of healthy patients’ cfDNA. Our results show that (1) the way tissue-specific gene classes are defined matters more than what fragmentation features are included, and (2) in particular, lncRNAs are more tissue specific than coding genes and stand out in terms of both sensitivity and specificity in our results.

Author summary

Dying cells, even in healthy individuals, release a fraction of the digested fragments of their genetic material into the bloodstream. Interestingly, these circulating cell-free DNA (cfDNA) fragments bear the footprint left by nucleosomes ; the position of which depends on the transcriptional state specific to each tissue. This footprint, given away by the sizes and genomic positions of cfDNA fragments, can be revealed by deep sequencing and statistical models can be trained to recognise the tissue from where those fragments originate. This information, if made sensitive enough, could be a useful medical technique to carry out so-called “liquid biopsies”, allowing clinicians to diagnose at an early stage or to precisely monitor a number of diseases, including cancer.

In this work, we comprehensively evaluated the features of circulating DNA fragments in the vicinity of transcriptional start sites to increase the ability of statistical models to recognise the tissue of origin of cfDNA of healthy individuals. Broadly speaking, nucleosome patterns allow a statistical model distinguish active versus inactive genes or tissue-specific versus housekeeping genes. The purpose of this study was to find the classes of genes with the strongest ability to recognise the true tissue of origin. From this work, we conclude that long non-coding RNA genes allow for a more sensitive and specific detection of the tissue of origin.
Subtractive adaptation is a more effective and general mechanism in binocular rivalry than divisive adaptation
Authors: Inês Cravo Maria , Bernardes Rui , Castelo-Branco Miguel
Published: January 2023

The activity of neurons is influenced by random fluctuations and can be strongly modulated by firing rate adaptation, especially in sensory systems. Still, there is an ongoing debate about the characteristics of neuronal noise and the mechanisms of adaptation, and even less is known about how exactly they affect perception. Noise and adaptation play central roles in binocular rivalry, a visual phenomenon where two images compete for perceptual dominance. Here, we investigated the effects of different noise processes and adaptation mechanisms on visual perception by simulating a model of binocular rivalry with Gaussian white noise, Ornstein-Uhlenbeck noise, and pink noise, in variants with divisive adaptation, subtractive adaptation, and without adaptation. By simulating the nine versions of the model for a wide range of parameter values, we find that white noise only produces rivalry when paired with subtractive adaptation and that subtractive adaptation reduces the influence of noise intensity on rivalry strength and introduces convergence of the mean percept duration, an important metric of binocular rivalry, across all noise processes. In sum, our results show that white noise is an insufficient description of background activity in the brain and that subtractive adaptation is a stronger and more general switching mechanism in binocular rivalry than divisive adaptation, with important noise-filtering properties.

Author Summary

Visual neurons adapt to the environment by reducing the number of spikes evoked by a constant stimulus. They are also susceptible to random spikes produced by nearby neurons. These two phenomena, adaptation and noise, are essential features of brain activity and affect how we perceive the world. Although we know a great deal about the visual system, our understanding of the properties and mechanisms of neuronal noise and adaptation is still piecemeal, and even less is known about how these microscopic processes affect macroscopic behaviors. We shed light on this question by studying a bistable visual phenomenon called binocular rivalry, where two images compete for perception and where noise and adaptation play important roles. We simulated the activity of neurons involved in binocular rivalry to test different hypotheses about the statistics of neuronal noise and the mechanisms of adaptation. Our results reveal important differences between subtractive and divisive adaptation, suggesting that subtractive adaptation is a stronger switching mechanism in binocular rivalry and an effective noise filter. Our simulations also show the fundamental distinction between noise with and without temporal correlation, supporting the correlated noise hypothesis.
Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial metabolic reprogramming
Authors: Wang Yongxing , Kulkarni Vikram V. , García Jezreel Pantaleón , Leiva-Juárez Miguel M. , Goldblatt David L. , Gulraiz Fahad , Chen Jichao , Donepudi Sri Ramya , Lorenzi Philip L. , Wang Hao , Wong Lee-Jun , Tuvim Michael J. , Evans Scott E.
Published: January 2023

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs’ intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (ΔΨm), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics.

Author Summary

Pneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.