bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraspecific chemodiversity provides plant individual- and neighbourhood-mediated associational resistance towards aphids
Authors: Ziaja Dominik , Müller Caroline
Published: December 2022

Some plant species express an extraordinarily high intraspecific diversity in phytochemicals (= chemodiversity). As discussed for biodiversity, higher chemodiversity may provide better protection against environmental stress, including herbivory. However, little is known about whether the resistance of a plant individual towards herbivores is mostly governed by its own chemodiversity or by associational resistance provided by conspecific neighbours.

To investigate the role of chemodiversity in plant-aphid interactions, we used the AsteraceaeTanacetum vulgare, whose individuals differ pronouncedly in the composition of leaf terpenoids, forming distinct chemotypes. Plants were set-up in a field consisting of 60 plots, each containing five individuals of either the same or different chemotypes. Presence of winged aphids, indicating aphid attraction, and abundance of winged and unwinged aphids, indicating fitness, were scored weekly on each plant, focusing on three commonly occurring aphid species specialised onT. vulgare. During the peak abundance of aphids, leaf samples were taken from all plants for re-analyses of the terpenoid composition and quantification of terpenoid chemodiversity, calculated on an individual plant (Shannon index, Hsind) and plot level (Hsplot).

Aphid attraction was neither influenced by chemotype nor plot-type. The real-time odour environment may be very complex in this setting, impeding clear preferences. In contrast, the abundance was affected by both chemotype and plot-type. On average, moreUroleucon tanacetiaphids were found on plants of two of the chemotypes growing in homogenous compared to heterogenous plots, supporting the associational resistance hypothesis. ForMacrosiphoniella tanacetariathe probability of presence on a plant differed between plot-types on one chemotype. Terpenoid chemodiversity expressed as a gradient revealed negative Hsploteffects onU. tanaceti, but a positive correlation of Hsindwith the abundance ofM. tanacetaria. Aphids ofM. fuscoviridewere not affected by any level of chemodiversity.

Synthesis. This study shows that not only the chemotype and chemodiversity of individual plants but also that of conspecific neighbours influence plant-herbivore interactions. These effects are highly specific with regard to the plant chemotype, the aphid species as well as its morphs (winged vs. unwinged). Furthermore, our results highlight the importance of analysing chemodiversity at different levels.
Cell surface composition and ionic strength mediate fast sedimentation in the cyanobacteriumSynechococcus elongatusPCC 7942
Authors: Zedler Julie A. Z. , Michel Marlene , Pohnert Georg , Russo David A.
Published: December 2022

Cyanobacteria are photosynthetic prokaryotes of high ecological and biotechnological relevance that have been cultivated in laboratories around the world for more than 70 years. Prolonged laboratory culturing has led to multiple microevolutionary events and the appearance of a large number of “domesticated” substrains among model cyanobacteria. Despite its widespread occurrence, strain domestication is still largely ignored. In this work we describeSynechococcus elongatusPCC 7942–KU, a novel domesticated substrain of the model cyanobacteriumSynechococcus elongatusPCC 7942, which presents a fast-sedimenting phenotype. Under higher ionic strengths the sedimentation rate increases leading to complete sedimentation in just 12 h. Through whole genome sequencing and gene deletion, we demonstrate that the Group 3 alternative sigma factor F (SigF) plays a key role in cell sedimentation. In addition, sedimentation analysis of an unpiliated mutant and differences in surface hydrophobicity suggest that mutations in SigF lead to significant changes of cell surface structures and, consequentially, to the appearance of a fast-sedimenting phenotype. This work sheds light on the determinants of the planktonic to benthic transitions and provides genetic targets to generate fast-sedimenting strains that could unlock cost-effective cyanobacterial harvesting at scale.
GelMap: Intrinsic calibration and deformation mapping for expansion microscopy
Authors: Damstra Hugo G.J. , Passmore Josiah B. , Serweta Albert K. , Koutlas Ioannis , Burute Mithila , Meye Frank J. , Akhmanova Anna , Kapitein Lukas C.
Published: December 2022

Expansion microscopy (ExM) is a powerful technique to overcome the diffraction limit of light microscopy by physically expanding biological specimen in three dimensions. Nonetheless, using ExM for quantitative or diagnostic applications requires robust quality control methods to precisely determine expansion factors and to map deformations due to anisotropic expansion. Here we present GelMap, a flexible workflow to introduce a fluorescent grid into pre-expanded hydrogels that scales with expansion and reports deformations. We demonstrate that GelMap can be used to precisely determine the local expansion factor and to correct for deformations without the use of cellular reference structures or pre-expansion ground truth images. Moreover, we show that GelMap aids sample navigation for correlative uses of expansion microscopy. Finally, we show that GelMap is compatible with expansion of tissue and can be readily implemented as a quality control step into existing ExM workflows.
NEK7 activates the NLRP1 Inflammasome
Authors: Muela-Zarzuela Inés , Gallardo-Orihuela Andrea , Pino-Ángeles Almudena , Suarez-Rivero Juan Miguel , Boy-Ruiz Daniel , de Gregorio-Procopio Marta , Oroz Javier , Mbalaviele Gabriel , Cordero Mario D.
Published: December 2022

Inflammasomes including those assembled by NLRP1 and NLRP3 regulate the innate immune system by inducing interleukin (IL)-1β and IL-18 maturation. Inflammasomes are functionally regulated by post-translational modifications such as phosphorylation. The current paradigm posits that NEK7 is the essential and seletive activator of NLRP3; whether this kinase interacts with NLRP3 structurally-related member, NLRP1, has never been explored. Here, we find that NEK7 binds to NLRP1 and promotes its activation independently of NLRP3. IL-1β maturation induced by NLRP1 or NLRP3 inflammasome activators, but not those of the NLRC4 or AIM2 inflammasome is impared in Nek7 deficient cells. This discovery expands the spectrum of NEK7 actions in the regulation of inflammasome pathways.
Laminar Neural Dynamics of Auditory Evoked Responses: Computational Modeling of Local Field Potentials in Auditory Cortex of Non-Human Primates
Authors: Chien Vincent S.C. , Wang Peng , Maess Burkhard , Fishman Yonatan , Knösche Thomas R.
Published: December 2022

Evoked neural responses to sensory stimuli have been extensively investigated in humans and animal models both to enhance our understanding of brain function and to aid in clinical diagnosis of neurological and neuropsychiatric conditions. Recording and imaging techniques such as electroencephalography (EEG), magnetoencephalography (MEG), local field potentials (LFPs), and calcium imaging provide complementary information about different aspects of brain activity at different spatial and temporal scales. Modeling and simulations provide a way to integrate these different types of information to clarify underlying neural mechanisms.

In this study, we aimed to shed light on the neural dynamics underlying auditory evoked responses by fitting a rate-based model to LFPs recorded via multi-contact electrodes which simultaneously sampled neural activity across cortical laminae. Recordings included neural population responses to best-frequency (BF) and non-BF tones at four representative sites in primary auditory cortex (A1) of awake monkeys. The model considered major neural populations of excitatory, parvalbumin-expressing (PV), and somatostatin-expressing (SOM) neurons across layers 2/3, 4, and 5/6. Unknown parameters, including the connection strength between the populations, were fitted to the data. Our results revealed similar population dynamics, fitted model parameters, predicted equivalent current dipoles (ECD), tuning curves, and lateral inhibition profiles across recording sites and animals, in spite of quite different extracellular current distributions. We found that PV firing rates were higher in BF than in non-BF responses, mainly due to different strengths of tonotopic thalamic input, whereas SOM firing rates were higher in non-BF than in BF responses due to lateral inhibition.

In conclusion, we demonstrate the feasibility of the model-fitting approach in identifying the contributions of cell-type specific population activity to stimulus-evoked LFPs across cortical laminae, providing a foundation for further investigations into the dynamics of neural circuits underlying cortical sensory processing.
FERMO: a Dashboard for Streamlined Rationalized Prioritization of Molecular Features from Mass Spectrometry Data
Authors: Zdouc Mitja M. , Bayona Maldonado Lina M. , Augustijn Hannah E. , Soldatou Sylvia , de Jonge Niek , Jaspars Marcel , van Wezel Gilles P. , Medema Marnix H. , van der Hooft Justin J. J.
Published: December 2022

Small molecules can selectively modulate biological processes and thus generate phenotypic variation. Biological samples are complex matrices, and liquid chromatography tandem mass spectrometry often detects hundreds of molecules, of which only a fraction may be associated with this variation. The challenge therefore lies in the prioritization of the most relevant molecules for further investigation. Tools are needed to effectively contextualize mass spectrometric data with phenotypical and environmental (meta)data. To accelerate this task, we developed FERMO, a dashboard application combining mass spectrometry data with qualitative and quantitative biological observations. FERMO’s centralized interface enables users to rapidly inspect data, formulate hypotheses, and prioritize molecules of interest. We demonstrate the applicability of FERMO in a case study on antibiotic activity of bacterial extracts, where we successfully prioritized the bioactive molecule siomycin out of 143 molecular features. We expect that besides natural product discovery, FERMO will find application in a wide range of omics-driven fields.
LRRC37B is a species-specific regulator of voltage-gated channels and excitability in human cortical neurons
Authors: Libé-Philippot Baptiste , Lejeune Amélie , Wierda Keimpe , Vlaeminck Ine , Beckers Sofie , Gaspariunaite Vaiva , Bilheu Angéline , Nyitrai Hajnalka , Vennekens Kristel M. , Bird Thomas W. , Soto Daniela , Dennis Megan Y , Comoletti Davide , Theys Tom , de Wit Joris , Vanderhaeghen Pierre
Published: December 2022

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits, but the underlying molecular mechanisms remain largely unknown. Here we report that the hominid-specific geneLRRC37Bencodes a novel receptor expressed in a subset of human cortical pyramidal neurons (CPNs). LRRC37B protein localizes at the axon initial segment (AIS), the specialized domain triggering action potentials.LRRC37Bectopic expression in mouse CPNsin vivoleads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. At the molecular level, LRRC37B acts as a receptor for the secreted ligand FGF13A and interacts with the voltage gated sodium channel (VGSC) beta subunit SCN1B, thereby inhibiting the channel function of VGSC, specifically at the AIS. Electrophysiological recordings in adult human cortical slices reveals that endogenous expression of LRRC37B in human CPNs reduces neuronal excitability.LRRC37Bthus acts as a species-specific modifier of human cortical neuron function, with important implications for human brain evolution and diseases.
TrAGEDy: Trajectory Alignment of Gene Expression Dynamics
Authors: Laidlaw Ross F. , Briggs Emma M. , Matthews Keith R. , McCulloch Richard , Otto Thomas D.
Published: December 2022

1

Motivation

Single-cell transcriptomics sequencing is used to compare different biological processes. However, often, those processes are asymmetric which are difficult to integrate. Current approaches often rely on integrating samples from each condition before either cluster-based comparisons or analysis of an inferred shared trajectory.

Results

We present Trajectory Alignment of Gene Expression Dynamics (TrAGEDy), which allows the alignment of independent trajectories to avoid the need for error-prone integration steps. Across simulated datasets, TrAGEDy returns the correct underlying alignment of the datasets, outperforming current tools which fail to capture the complexity of asymmetric alignments. When applied to real datasets, TrAGEDy captures more biologically relevant genes and processes, which other differential expression methods fail to detect when looking at the developments of T cells and the bloodstream forms ofTrypanosoma bruceiwhen affected by genetic knockouts.

Availability and Implementation

TrAGEDy is freely available athttps://github.com/No2Ross/TrAGEDy, and implemented in R.

Contact

thomasdan.otto@glasgow.ac.uk
Comprehensive profiling of polyclonal sera targeting a non-enveloped viral capsid
Authors: Álvarez-Rodríguez Beatriz , Buceta Javier , Geller Ron
Published: December 2022

Despite their fundamental role in resolving viral infections, our understanding of how polyclonal neutralizing antibody responses target non-enveloped viruses remains limited. To define these responses, we obtained the full antigenic profile of multiple human and mouse polyclonal sera targeting the capsid of a prototypical picornavirus. Our results uncover significant variation in the breadth and strength of neutralization sites targeted by individual human polyclonal responses, which contrasted with homogenous responses observed in experimentally infected mice. We further use these comprehensive antigenic profiles to define key structural and evolutionary parameters that are predictive of escape, assess epitope dominance at the population level, and reveal a need for at least two mutations to achieve significant escape from multiple sera. Overall, our data provide the first comprehensive analysis of how polyclonal sera target a non-enveloped viral capsid and help define both immune dominance and escape at the population level.
Ecological assembly of natural soundscapes in the Garajonay National Park (Spain)
Authors: Ortiz-Álvarez Rüdiger , García-Puig Marta , Garate Leire
Published: December 2022

Natural sound contains data about the ecology of animal populations, communities, and the full ecosystem, resulting from a complex evolution and varying according to the environment. Amongst the processes that are hypothesized to explain sound assemblages, or soundscapes, one is the acoustic niche hypothesis: sounds produced by species calling at the same time seek avoid overlapping, leading to an acoustic differentiation of signals. Soundscapes are more complex in the most pristine environments and show responses to habitat degradation and physical perturbations; hence here, we focus on La Gomera, in the Canary Islands (Spain). This island is the only location in Europe where primary cloud forests are well preserved and thrive on an island with varied orography, microclimates, disturbances, and vegetation types. In this article, we adapted a method to quantify the importance of acoustic niche partitioning and also the opposite process: acoustic aggregation. To do so, we explored soundscapes at different temporal scales in forests with variable degrees of perturbation and maturity. A secondary goal of this report is to compare how soundscapes could differ in an area affected by a wildfire, and undisturbed equivalents, in summer in winter, seasons with contrasting temperatures and wind regimes. We conclude that tracking faunal activity and behavior through soundscape monitoring could be a piece of useful complementary information to guide conservation decisions and future restoration efforts in the Garajonay National Park (La Gomera).

Highlights

○ The mature forest and the transitional forest are similar in terms of sound levels, frequencies, and dynamics, although the transitional forest had higher sound levels of the lower frequencies (higher NDSI).

○ The mature forest has stronger and more active assembly mechanisms (i.e., acoustic aggregation and acoustic niche partitioning) and a higher acoustic diversity index (ADI) than the transitional forest. Assembly organizes differently in both locations.

○ In both the mature and the transitional forests, we found an inverse relationship between the ADI and acoustic niche partitioning. At the highest diversities (more frequency bands occupied), the weakest is the temporal avoidance of calls with similar frequencies.

○ The vulnerability of the burned location is highest during the harsh summer, but in winter, it hosts a community very similar to the intact vegetation in terms of ADI and sound levels.
Community Detection in Brain Connectome using Quantum Annealer Devices
Authors: Wierzbiński Marcin , Falcó-Roget Joan , Crimi Alessandro
Published: December 2022

Recent advancements in network neuroscience are pointing in the direction of considering the brain as a small-world system with segregated regions integrated to facilitate different cognitive tasks and functions. In this context, community detection is a pivotal issue in computational neuroscience. In this paper we explore community detection within brain connectomes using the power of quantum annealers, and in particular the Leap’s Hybrid Solver. Our results shows that quantum annealers can achieve higher modularity index compared to classical annealer while computing communities of brain connectomes. Those promising preliminary results points out that quantum annealers might be the better choice compared to classical computing optimization process.
A map of signaling responses in the human airway epithelium
Authors: Mccauley Katherine B , Kukreja Kalki , Jaffe Aron B , Klein Allon M
Published: December 2022

Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling–response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of all epithelial cell types. This map recapitulates the gamut of known airway epithelial signaling responses to these pathways. It defines convergent states induced by multiple ligands and diverse, ligand-specific responses in basal-cell and secretory-cell metaplasia. We show that loss of canonical differentiation induced by multiple pathways is associated with cell cycle arrest, but that arrest is not sufficient to block differentiation. Using the signaling-response map, we show that a TGFB1-mediated response underlies specific aberrant cells found in multiple lung diseases and identify interferon responses in COVID-19 patient samples. Thus, we offer a framework enabling systematic evaluation of tissue signaling responses.
A chromosome level genome assembly of longnose gar,Lepisosteus osseus
Authors: Mallik Rittika , Carlson Kara B. , Wcisel Dustin J. , Fisk Michael , Yoder Jeffrey A. , Dornburg Alex
Published: December 2022

Holosteans (gars and bowfins) represent the sister lineage to teleost fishes, the latter being a clade that comprises over half of all living vertebrates and includes important models for comparative genomics and human health. A major distinction between the evolutionary history of teleosts and holosteans is that all teleosts experienced a genome duplication event in their early evolutionary history. As holostean genomes did not undergo a round of genome duplication, they have been heralded as a means to bridge teleost models to other vertebrate genomes. However, only three species of holosteans have been genome sequenced to date and sequencing of more species is needed to fill sequence sampling gaps and provide a broader comparative basis for understanding holostean genome evolution. Here we report the first high quality reference genome assembly and annotation of the longnose gar (Lepisosteus osseus). Our final assembly consists of 22,709 scaffolds with a total length of 945 bp with contig N50of 116.6 kb. Using BRAKER2, we annotated a total of 30,068 genes. Analysis of the repetitive regions of the genome reveals the genome to contain 29.1% transposable elements, and the longnose gar to be the only other known vertebrate outside of the spotted gar to contain CR1, L2, Rex1, and Babar. These results highlight the potential utility of holostean genomes for understanding the evolution of vertebrate repetitive elements and provide a critical reference for comparative genomic studies utilizing ray-finned fish models.

Significance

Over half of all living vertebrates are teleost fishes, including numerous experimental models such as zebrafish (Danio rerio) and medaka (Oryzias latipes). However, translating research in teleost models to other organisms such as humans is often challenged by the fact that teleosts experienced a genome duplication event in their early evolutionary history. Recent genome sequencing of three holosteans, the sister lineage to teleosts that did not experience a genome duplication event, has revealed these taxa to be critical for linking homologs between teleosts and other vertebrates. Sequencing of holostean genomes remains limited, thereby impeding further comparative genomic studies. Here we fill this sampling gap through the genomic sequencing of the longnose gar (Lepisosteus osseus). This annotated reference genome will provide a useful resource for a range of comparative genomic applications that span fields as diverse as immunogenetics, developmental biology, and the understanding of regulatory sequence evolution.
7-Tesla evidence for columnar and rostral–caudal organization of the human periaqueductal gray response in the absence of threat: a working memory study
Authors: Fischbach Alexandra K. , Satpute Ajay B. , Quigley Karen S. , Kragel Philip A. , Chen Danlei , Bianciardi Marta , Wald Lawrence L. , Wager Tor D. , Choi Ji-Kyung , Zhang Jiahe , Barrett Lisa Feldman , Theriault Jordan E.
Published: December 2022

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain–body communication, and is often studied for its role in “fight-or-flight” and “freezing” responses to threat. We used ultra-high field 7-Tesla fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining itsin vivofunction in humans during a working memory task (N = 87). Relative to baseline fixation, both mild and moderate task-elicited cognitive demands elicited bilateral BOLD increases in ventrolateral PAG (vlPAG), a region previously observed to show increased activity during anticipated painful threat in both non-human and human animals. The present task posed only the most minimal (if any) “threat”. The mild-demand condition involved a task easier than remembering a phone number, elicited a heart rate decrease relative to baseline, yet nonetheless elicited a bilateral vlPAG response. Across PAG voxels, BOLD signal intensity correlated with changes in physiological reactivity (relative to baseline) and showed some evidence of spatial organization along the rostral–caudal axis. These findings suggest that the PAG may have a broader role in coordinating brain—body communication during a minimally to moderately demanding task, even in the absence of threat.
Replication in the presence of dengue convalescent serum impacts Zika virus neutralization sensitivity and fitness
Authors: Marano Jeffrey M. , Weger-Lucarelli James
Published: December 2022

Flaviviruses like dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne viruses that cause febrile, hemorrhagic, and neurological diseases in humans, resulting in 400 million infections annually. Due to their co-circulation in many parts of the world, flaviviruses must replicate in the presence of pre-existing adaptive immune responses targeted at serologically closely related pathogens, which can provide protection or enhance disease. However, the impact of pre-existing cross-reactive immunity as a driver of flavivirus evolution, and subsequently the implications on the emergence of immune escape variants, is poorly understood. Therefore, we investigated how replication in the presence of convalescent dengue serum drives ZIKV evolution. We used anin vitrodirected evolution system, passaging ZIKV in the presence of serum from humans previously infected with DENV (anti-DENV) or serum from DENV-naïve patients (control serum). Following five passages in the presence of serum, we performed next-generation sequencing to identify mutations that arose during passaging. We studied two non-synonymous mutations found in the anti-DENV passaged population (E-V355I and NS1-T139A) by generating individual ZIKV mutants and assessing fitness in mammalian cells and live mosquitoes, as well as their sensitivity to antibody neutralization. Both viruses had increased fitness in Vero cells with and without the addition of anti-DENV serum and in human lung epithelial and monocyte cells. In Aedes aegypti mosquitoes—using blood meals with and without anti-DENV serum—the mutant viruses had significantly reduced fitness compared to wild-type ZIKV. These results align with the trade-off hypothesis of constrained mosquito-borne virus evolution. Notably, only the NS1-T139A mutation escaped neutralization, while E-V335I demonstrated enhanced neutralization sensitivity to neutralization by anti-DENV serum, indicating that neutralization escape is not necessary for viruses passaged under cross-reactive immune pressures. Future studies are needed to assess cross-reactive immune selection in humans and relevant animal models or with different flaviviruses.
Neural circuit mechanisms for transforming learned olfactory valences into wind-oriented movement
Authors: Aso Yoshinori , Yamada Daichi , Bushey Daniel , Hibbard Karen , Sammons Megan , Otsuna Hideo , Shuai Yichun , Hige Toshihide
Published: December 2022

How memories are used by the brain to guide future action is poorly understood. In olfactory associative learning in Drosophila, multiple compartments of the mushroom body act in parallel to assign valence to a stimulus. Here, we show that appetitive memories stored in different compartments induce different levels of upwind locomotion. Using a photoactivation screen of a new collection of split-GAL4 drivers and EM connectomics, we identified a cluster of neurons postsynaptic to the mushroom body output neurons (MBONs) that can trigger robust upwind steering. These UpWind Neurons (UpWiNs) integrate inhibitory and excitatory synaptic inputs from MBONs of appetitive and aversive memory compartments, respectively. After training, disinhibition from the appetitive-memory MBONs enhances the response of UpWiNs to reward-predicting odors. Blocking UpWiNs impaired appetitive memory and reduced upwind locomotion during retrieval. Photoactivation of UpWiNs also increased the chance of returning to a location where activation was initiated, suggesting an additional role in olfactory navigation. Thus, our results provide insight into how learned abstract valences are gradually transformed into concrete memory-driven actions through divergent and convergent networks, a neuronal architecture that is commonly found in the vertebrate and invertebrate brains.
Development of nuclear microsatellite markers in Yerba mate (Ilex paraguariensisSt. Hil., Aquifoliaceae Bartl.) from whole-genome sequence data
Authors: Tassano Carolina , Olano Rodrigo A. , Gaiero Paola , Vaio Magdalena , Speranza Pablo R.
Published: December 2022

Ilex paragariensisSt. Hil. (yerba mate) (Aquifoliaceae Bartl.) is a plant species with great economic and cultural importance because its leaves are processed and ground to make infusions like mate or tereré. The species is distributed in a continuous area that includes southern Brazil, and part of Paraguay and Argentina. Uruguay represents the southern distribution limit of the species, where small populations can be found as part of riparian forests. Although there are previous reports of molecular markers for this and other species in the genus, the available markers were not informative enough to represent the intra and interpopulation genetic diversity in these marginal populations. In this study, we developed highly informative nuclear polymorphic microsatellite markers to optimize genetic studies inI. paraguariensis. Markers were identified in contigs from the genome sequence of two individuals and then tested for amplification and polymorphism in a diverse panel and at population level. Markers which passed these tests detected levels of heterozygosity similar to those reported for Brazilian populations and great diversity within populations from Uruguay. This set of markers were successfully multiplexed, substantially reducing the costs of the analysis. In combination with previously reported nuclear and plastid markers, they can be used to evaluate the genetic diversity of rear edge populations, identify genotypes for paternity studies and provide relevant information for the conservation and management of germplasm.
Physiologic and nanoscale distinctions define glutamatergic synapses in tonic vs phasic neurons
Authors: He Kaikai , Han Yifu , Li Xiling , Hernandez Roberto X. , Riboul Danielle V. , Feghhi Touhid , Justs Karlis A. , Mahneva Olena , Perry Sarah , Macleod Gregory T. , Dickman Dion
Published: December 2022

Neurons exhibit a striking degree of functional diversity, each one tuned to the needs of the circuitry in which it is embedded. A fundamental functional dichotomy occurs in activity patterns, with some neurons firing at a relatively constant “tonic” rate, while others fire in bursts - a “phasic” pattern. Synapses formed by tonic vs phasic neurons are also functionally differentiated, yet the bases of their distinctive properties remain enigmatic. A major challenge towards illuminating the synaptic differences between tonic and phasic neurons is the difficulty in isolating their physiological properties. At theDrosophilaneuromuscular junction (NMJ), most muscle fibers are co-innervated by two motor neurons, the tonic “MN-Ib” and phasic “MN-Is”. Here, we employed selective expression of a newly developed botulinum neurotoxin (BoNT-C) transgene to silence tonic or phasic motor neurons. This approach revealed major differences in their neurotransmitter release properties, including probability, short-term plasticity, and vesicle pools. Furthermore, Ca2+imaging demonstrated ~two-fold greater Ca2+influx at phasic neuron release sites relative to tonic, along with enhanced synaptic vesicle coupling. Finally, confocal and super resolution imaging revealed that phasic neuron release sites are organized in a more compact arrangement, with enhanced stoichiometry of voltage-gated Ca2+channels relative to other active zone scaffolds. These data suggest that distinctions in active zone nano-architecture and Ca2+influx collaborate to differentially tune glutamate release at synapses of tonic vs phasic neuronal subtypes.
Mutation divergence over space in tumour expansion
Authors: Li Haiyang , Tu Fengyu , Deng Lijuan , Yang Zixuan , Han Yuqing , Fu Xing , Wang Long , Gu Di , Werner Benjamin , Huang Weini
Published: December 2022

Mutation accumulation in tumour evolution is one major cause of intra-tumour heterogeneity (ITH), which often leads to drug resistance during treatment. Previous studies with multi-region sequencing have shown that mutation divergence among samples within the patient is common, and the importance of spatial sampling to obtain a complete picture in tumour measurements. However, quantitative comparisons of the relationship between mutation heterogeneity and tumour expansion modes, sampling distances as well as the sampling methods are still few. Here, we investigate how mutations diverge over space by varying the sampling distance and tumour expansion modes using individual based simulations. We measure ITH by the Jaccard index between samples and quantify how ITH increases with sampling distance, the pattern of which holds in various sampling methods and sizes. We also compare the inferred mutation rates based on the distributions of Variant Allele Frequencies (VAF) under different tumour expansion modes and sampling sizes. In exponentially fast expanding tumours, a mutation rate can always be inferred in any sampling size. However, the accuracy compared to the true value decreases when the sampling size decreases, where small sampling sizes result in a high estimate of the mutation rate. In addition, such an inference becomes unreliable when the tumour expansion is slower such as in surface growth.
How Does Perceptual Discriminability Relate to Neuronal Receptive Fields?
Authors: Zhou Jingyang , Chun Chanwoo
Published: December 2022

Abstract

Perception is an outcome of neuronal computations. Our perception changes only when the underlying neuronal responses change. Because visual neurons preferentially respond to adjustments in some pixel values of an image more than others, our perception has greater sensitivity in detecting change to some pixel combinations more than others. Here, we examined how perceptual discriminability varies to arbitrary image perturbations assuming different models of neuronal responses. In particular, we investigated that under the assumption of different neuronal computations, how perceptual discriminability relates to neuronal receptive fields – the change in pixel combinations that invokes the largest increase in neuronal responses. We assumed that perceptual discriminability reflects the magnitude of change (the L2 norm) in neuronal responses, and the L2 norm assumption gained empirical support. We examined how perceptual discriminability relates to deterministic and stochastic neuronal computations. In the case of deterministic neuronal computations, perceptual discriminability is completely determined by neuronal receptive fields. For multiple layers of canonical linear-nonlinear (LN) computations in particular (which is a feed-forward neural network), neuronal receptive fields are linear transforms of the first-layer neurons’ image filters. When one image is presented to the neural network, the first-layer neurons’ filters and the linear transform completely determine neuronal receptive fields across all layers, and perceptual discriminability to arbitrary distortions to the image. We expanded our analysis to examine stochastic neuronal computations, in which case perceptual discriminability can be summarized as the magnitude of change in stochastic neuronal responses, with the L2 norm being replaced by a Fisher-information computation. Using a practical lower bound on Fisher information, we showed that for stochastic neuronal computations, perceptual discriminability is completely determined by neuronal receptive fields, together with how responses co-variate across neurons.
A high-level programming language for generative protein design
Authors: Hie Brian , Candido Salvatore , Lin Zeming , Kabeli Ori , Rao Roshan , Smetanin Nikita , Sercu Tom , Rives Alexander
Published: December 2022

Combining a basic set of building blocks into more complex forms is a universal design principle. Most protein designs have proceeded from a manual bottom-up approach using parts created by nature, but top-down design of proteins is fundamentally hard due to biological complexity. We demonstrate how the modularity and programmability long sought for protein design can be realized through generative artificial intelligence. Advanced protein language models demonstrate emergent learning of atomic resolution structure and protein design principles. We leverage these developments to enable the programmable design of de novo protein sequences and structures of high complexity. First, we describe a high-level programming language based on modular building blocks that allows a designer to easily compose a set of desired properties. We then develop an energy-based generative model, built on atomic resolution structure prediction with a language model, that realizes all-atom structure designs that have the programmed properties. Designing a diverse set of specifications, including constraints on atomic coordinates, secondary structure, symmetry, and multimerization, demonstrates the generality and controllability of the approach. Enumerating constraints at increasing levels of hierarchical complexity shows that the approach can access a combinatorially large design space.
Combining Aperiodic 1/f Slopes and Brain Simulation: An EEG/MEG Proxy Marker of Excitation/Inhibition Imbalance in Alzheimer’s Disease
Authors: Martínez-Cañada Pablo , Perez-Valero Eduardo , Minguillon Jesus , Pelayo Francisco , López-Gordo Miguel A. , Morillas Christian
Published: December 2022

Accumulation and interaction of amyloid-beta (Aβ) and tau proteins during progression of Alzheimer’s disease (AD) are shown to tilt neuronal circuits away from balanced excitation/inhibition (E/I). Current available techniques for noninvasive interrogation of E/I in the intact human brain, e.g., magnetic resonance spectroscopy (MRS), are highly restrictive (i.e., limited spatial extent), have low temporal and spatial resolution and suffer from the limited ability to distinguish accurately between different neurotransmitters complicating its interpretation. As such, these methods alone offer an incomplete explanation of E/I. Recently, the aperiodic component of neural power spectrum, often referred to in the literature as the ‘ 1/f slope’, has been described as a promising and scalable biomarker that can track disruptions in E/I potentially underlying a spectrum of clinical conditions, such as autism, schizophrenia, or epilepsy, as well as developmental E/I changes as seen in aging. Using 1/f slopes from resting-state spectral data and computational modelling we developed a new method for inferring E/I alterations in AD. We tested our method on recent freely and publicly available electroencephalography (EEG) and magnetoencephalography (MEG) datasets of patients with AD or prodromal disease and demonstrated the method’s potential for uncovering regional patterns of abnormal excitatory and inhibitory parameters. Our results provide a general framework for investigating circuit-level disorders in AD and developing therapeutic interventions that aim to restore the balance between excitation and inhibition.
Evolutionary effects of individual variation and dimensionality of higher-order interactions on robustness of species coexistence
Authors: Baruah Gaurav , Barabás György , John Robert
Published: December 2022

Although the eco-evolutionary effects of individual variation for species coexistence are still widely debated, theoretical evidence appears to support a negative impact on coexistence. Mechanistic models of eco-evolutionary effects of individual variation focus largely on pairwise interactions, while the dynamics of communities where both pairwise and higher-order interactions (HOIs) are pervasive are not known. In addition, most studies have focused on effects of high dimensional HOIs on species coexistence when in reality such HOIs could be highly structured and low-dimensional, as species interactions could primarily be mediated through phenotypic traits. Here, combining quantitative genetics and Lotka-Volterra equations, we explored the eco-evolutionary effects of individual variation on the patterns of species coexistence in a competitive community dictated by pairwise interactions and HOIs. Specifically, we compare six different models in which HOIs were modelled to be trait-mediated (low-dimensional) or random (high-dimensional) and evaluated its impact on robustness of species coexistence in the presence of different levels of individual variation. Across the six different models, we found that individual variation did not promote species coexistence, irrespective of whether interactions were pairwise or were of higher-order. However, individual trait variation could stabilize communities to external perturbation more so when interactions were of higher order. When compared across models, species coexistence is promoted when HOIs strengthen pairwise intraspecific competition more so than interspecific competition, and when HOIs act in a hierarchical manner. Additionally, across the models, we found that species’ traits tend to cluster together when individual variation in the community was low. We argue that, while individual variation can influence community patterns in many different ways, they more often lead to fewer species coexisting together.
HAPNEST: efficient, large-scale generation and evaluation of synthetic datasets for genotypes and phenotypes
Authors: Wharrie Sophie , Yang Zhiyu , Raj Vishnu , Monti Remo , Gupta Rahul , Wang Ying , Martin Alicia , O’Connor Luke J , Kaski Samuel , Marttinen Pekka , Palamara Pier Francesco , Lippert Christoph , Ganna Andrea ,   Intervene Consortium
Published: December 2022

Existing methods for simulating synthetic genotype and phenotype datasets have limited scalability, constraining their usability for large-scale analyses. Moreover, a systematic approach for evaluating synthetic data quality and a benchmark synthetic dataset for developing and evaluating methods for polygenic risk scores are lacking. We present HAPNEST, a novel approach for efficiently generating diverse individual-level genotypic and phenotypic data. In comparison to alternative methods, HAPNEST shows faster computational speed and a lower degree of relatedness with reference panels, while generating datasets that preserve key statistical properties of real data. These desirable synthetic data properties enabled us to generate 6.8 million common variants and nine phenotypes with varying degrees of heritability and polygenicity across 1 million individuals. We demonstrate how HAPNEST can facilitate biobank-scale analyses through the comparison of seven methods to generate polygenic risk scoring across multiple ancestry groups and different genetic architectures.
Is short sleep bad for the brain? Brain structure and cognitive function in short sleepers
Authors: Fjell Anders M. , Sørensen Øystein , Wang Yunpeng , Amlien Inge K. , Baaré William F.C. , Bartrés-Faz David , Boraxbekk Carl-Johan , Brandmaier Andreas M. , Demuth Ilja , Drevon Christian A. , Ebmeier Klaus P. , Ghisletta Paolo , Kievit Rogier , Kühn Simone , Madsen Kathrine Skak , Nyberg Lars , Solé-Padullés Cristina , Vidal-Piñeiro Didac , Wagner Gerd , Watne Leiv Otto , Walhovd Kristine B.
Published: December 2022

Many sleep less than recommended without experiencing daytime tiredness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this question using a combined cross-sectional and longitudinal sample of 47,029 participants (age 20-89 years) with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. 701 participants who reported to sleep < 6 hours did not experience daytime tiredness or sleep problems. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime tiredness and sleep problems (n = 1619) and participants sleeping the recommended 7-8 hours (n = 3754). However, both groups of short sleepers showed slightly lower general cognitive function, 0.16 and 0.19 standard deviations, respectively. Analyses using acelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income and education. The results suggest that some people can cope with less sleep without obvious negative consequences for brain morphometry, in line with a view on sleep need as individualized. Tiredness and sleep problems seem to be more relevant for brain structural differences than sleep duration per se. However, the slightly lower performance on tests of general cognitive function warrants closer examination by experimental designs in natural settings.

Significance statement

Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here we show that daytime tiredness and sleep problems are more important variables for regional brain volumes than sleep duration. However, participants sleeping < 6 hours had slightly lower scores on tests of general cognitive function. This indicates that sleep need is individual, and that sleep duration per se may be a less relevant variable for brain health than daytime tiredness and sleep problems. The association between habitual short sleep and lower scores on tests of general cogntitive function must be further scrutinized in natural settings.
Nucleus accumbens acetylcholine receptors modulate the balance of flexible and inflexible cue-directed motivation
Authors: Townsend Erica S. , Amaya Kenneth A. , Smedley Elizabeth B. , Smith Kyle S.
Published: December 2022

Sign-tracking is a conditioned response where animals interact with reward-predictive cues and can be used as a means to approximate a cue’s motivational value. The nucleus accumbens core (NAc) has been highly implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum broadly has been attributed to both incentive motivation and behavioral flexibility. Here, we show that sign-tracking responses are indeed flexible in the face of a contingency change in the form of an omission schedule, and that this flexibility is mediated by NAc ACh. Using behavioral and pharmacological methods, we show that blockade of NAc nicotinic receptors (nAChRs) augmented sign-tracking persistence, while blockade of muscarinic receptors (mAChRs) enhanced response flexibility following introduction of the omission schedule. Further, we detail how mAChR or nAChR antagonism impacted the microstructure of sign-tracking responses. These results indicate that NAc ACh receptors have opposing roles in the regulation of sign-tracking response flexibility without altering the motivational value of the cue.