bluuebunny/crossref_metadata_2025 huggingface dataset:
The architecture of multifunctional ecological networks
Authors: Hervías-Parejo Sandra , Cuevas-Blanco Mar , Lacasa Lucas , Traveset Anna , Donoso Isabel , Heleno Ruben , Nogales Manuel , Rodríguez-Echeverría Susana , Melián Carlos , Eguíluz Victor M.
Published: July 2023

Understanding how biotic interactions affect ecosystem functioning has been a research priority in natural sciences due to their critical role in bolstering ecological resilience1–3. Yet, traditional assessment of ecological complexity typically focus on species-species effective interactions that mediate a particular function (e.g. pollination4or seed dispersal5), overlooking the synergistic effect of multiple functions that further underpin species-function and function-function interactions in multifunctional ecosystems. At the same time, while ecological network theory holds a potential to quantify the relationship between biodiversity and ecosystem multifunctionality6, 7, its connection has been done mainly conceptually, due to challenges measuring different interactions and establishing their relevance across multiple niche dimensions8, 9. Such lack of quantitative studies therefore limits our ability to determine which species and interactions are important to maintain the multiple functions of ecosystems10. Here we develop a framework –derived from a resource-consumer-function tensor analysis-that bridges these gaps by framing biodiversity-ecosystem multifunctionality in terms of multilayer ecological network theory. Its application to recently collected ecological data –– reporting weighted interactions between plants, animals and fungi across multiple function types––allows to (i) unveil and quantify the existence of both (multi-functional) keystone species and a dual function keystoneness pattern, and (ii) project plants and functions into a similarity space where clear clusters emerge and the importance of weak links is manifested. This dual insight from species and functional perspectives will better guide conservation efforts to reduce biodiversity loss.
Hiding in the bush, in fear of a predator! Vegetation and predators influence shoaling among wild zebrafish
Authors: Mukherjee Ishani , Bhat Anuradha
Published: July 2023

Social responses of aquatic group-living organisms are critically dependent on predation risk and vegetation cover in their habitat. To gain insight into how these factors shape their immediate responses, we exposed wild zebrafish shoals to either vegetation, predator cues or both these factors simultaneously. Control treatments were not exposed to the above factors. By analyzing 60 unique shoals across 270 experimental trials, we found that while shoals formed significantly larger subgroups and were significantly more polarized in the presence of predator cues, both these properties decreased when shoals experienced predator cues in presence of vegetation. Furthermore, foraging was significantly lower when predator cues and/or vegetation were present. Tracking of all individuals in treatments devoid of vegetation revealed that: (i) compared to control treatments, individuals within shoals receiving predator cues had a significantly higher probability to continue being in a group and (ii) individuals occupying the front positions deviated lesser from their median position within a shoal as compared to other individuals. Anti-predator responses and foraging are critical for survival and therefore, this study provides important insights into shoal dynamics in changing environments.
Polarization and motility of one-dimensional multi-cellular trains
Authors: Ron Jonathan E. , d’Alesandro Joseph , Cellerin Victor , Voituriéz Raphael , Ladoux Benoit , Gov Nir S.
Published: July 2023

Collective cell migration, whereby cells adhere to form multi-cellular clusters that move as a single entity, play an important role in numerous biological processes, such as during development and cancer progression. Recent experimental work focused on migration of one-dimensional cellular clusters, confined to move along adhesive lanes, as a simple geometry in which to systematically study this complex system. One-dimensional migration also arises in the body when cells migrate along blood vessels, axonal projections and narrow cavities between tissues. We explore here the modes of one-dimensional migration of cellular clusters (“trains”), by implementing cell-cell interactions in a model of cell migration that contains a mechanism for spontaneous cell polarization. We go beyond simple phenomenological models of the cells as self-propelled particles, by having the internal polarization of each cell depend on its interactions with the neighboring cells, that directly affect the actin polymerization activity at the cell’s leading edges. Both Contact Inhibition of Locomotion (CIL) and Cryptic Lamellipodia (CL) interactions between neighboring cells are introduced. We find that this model predicts multiple motility modes of the cell trains, that can have several different speeds for the same polarization pattern. Comparing to experimental data we find that MDCK cells are poised along the transition region where CIL and CL roughly balance each other, where collective migration speed is most sensitive to the values of the cell-cell interaction strength.
Role of Articulatory Motor Networks in Perceptual Categorization of Speech Signals: A 7 T fMRI Study
Authors: Lankinen Kaisu , Ahveninen Jyrki , Uluç Işıl , Daneshzand Mohammad , Mareyam Azma , Kirsch John E. , Polimeni Jonathan R. , Healy Brian C. , Tian Qiyuan , Khan Sheraz , Nummenmaa Aapo , Wang Qing-mei , Green Jordan R. , Kimberley Teresa J. , Li Shasha
Published: July 2023

BACKGROUND

The association between brain regions involved in speech production and those that play a role in speech perception is not yet fully understood. We compared speech production related brain activity with activations resulting from perceptual categorization of syllables using high field 7 Tesla functional magnetic resonance imaging (fMRI) at 1-mm isotropic voxel resolution, enabling high localization accuracy compared to previous studies.

METHODS

Blood oxygenation level dependent (BOLD) signals were obtained in 20 normal hearing subjects using a simultaneous multi-slice (SMS) 7T echo-planar imaging (EPI) acquisition with whole-head coverage and 1 mm isotropic resolution. In aspeech production localizertask, subjects were asked to produce a silent lip-round vowel /u/ in response to the visual cue “U” or purse their lips when they saw the cue “P”. In aphoneme discrimination task, subjects were presented with pairs of syllables, which were equiprobably identical or different along an 8-step continuum between the prototypic /ba/ and /da/ sounds. After the presentation of each stimulus pair, the subjects were asked to indicate whether the two syllables they heard were identical or different by pressing one of two buttons. In aphoneme classification task, the subjects heard only one syllable and asked to indicate whether it was /ba/ or /da/.

RESULTS

Univariate fMRI analyses using a parametric modulation approach suggested that left motor, premotor, and frontal cortex BOLD activations correlate with phoneme category variability in the /ba/–/da/ discrimination task. In contrast, the variability related to acoustic features of the phonemes were the highest in the right primary auditory cortex. Our multivariate pattern analysis (MVPA) suggested that left precentral/inferior frontal cortex areas, which were associated with speech production according to the localizer task, play a role also in perceptual categorization of the syllables.

CONCLUSIONS

The results support the hypothesis that articulatory motor networks in the left hemisphere that are activated during speech production could also have a role in perceptual categorization of syllables. Importantly, high voxel-resolution combined with advanced coil technology allowed us to pinpoint the exact brain regions involved in both perception and production tasks.
Distinct groups of RNA viruses associated with thermoacidophilic bacteria
Authors: Urayama Syun-ichi , Fukudome Akihito , Hirai Miho , Okumura Tomoyo , Nishimura Yosuke , Takaki Yoshihiro , Kurosawa Norio , Koonin Eugene V. , Krupovic Mart , Nunoura Takuro
Published: July 2023

Recent massive metatranscriptome mining substantially expanded the diversity of the bacterial RNA virome, suggesting that additional groups of riboviruses infecting bacterial hosts remain to be discovered. We employed full length double-stranded (ds) RNA sequencing for identification of riboviruses associated with microbial consortia dominated by bacteria and archaea in acidic hot springs in Japan. Whole sequences of two groups of multisegmented riboviruses genomes were obtained. One group, which we denoted hot spring riboviruses (HsRV), consists of unusual viruses with distinct RNA-dependent RNA polymerases (RdRPs) that seem to be intermediates between typical ribovirus RdRPs and viral reverse transcriptases. We also identified viruses encoding HsRV-like RdRPs in moderate aquatic environments, including marine water, river sediments and salt marsh, indicating that this previously overlooked ribovirus group is not restricted to the extreme ecosystem. The HsRV-like viruses are candidates for a distinct phylum or even kingdom within the viral realmRiboviria. The second group, denoted hot spring partiti-like viruses (HsPV), is a distinct branch within the familyPartitiviridae. All genome segments in both these groups of viruses display the organization typical of bacterial riboviruses, where multiple open reading frames encoding individual proteins are preceded by ribosome-binding sites. Together with the identification in bacteria-dominated habitats, this genome architecture indicates that riboviruses of these distinct groups infect thermoacidophilic bacterial hosts.
Impact of PET reconstruction on Aβ-amyloid quantitation in cross-sectional and longitudinal analyses
Authors: Ruwanpathirana Gihan P. , Williams Robert C. , Masters Colin L. , Rowe Christopher C. , Johnston Leigh A. , Davey Catherine E.
Published: July 2023

Amyloid beta (Aβ) accumulation in Alzheimer’s disease (AD) is typically measured using standardized uptake value ratio (SUVR) and the Centiloid scale (CL). The low spatial resolution of PET images is known to degrade quantitative metrics due to the partial volume effect (PVE). This paper examines the impact of spatial resolution, as determined by the reconstruction configuration, on the Aβ-PET quantitation in both cross-sectional and longitudinal data.

Methods

Cross-sectional Study-89 subjects with [18F]-florbetapir scans (44 Aβ-, 45 Aβ+) were reconstructed using 69 reconstruction configurations. For each reconstruction, Aβ SUVR was calculated and the spatial resolution was calculated as full-width-at-half-maximum (FWHM) using the barrel phantom method (Lodgeet al, 2018). The change of SUVR and the effect size of the difference in SUVR between Aβ- and Aβ+ groups with FWHM were examined.

Longitudinal study-79 subjects (46 Aβ-, 33 Aβ+) with three [18F]-flutemetamol scans were analysed. All scans were reconstructed using low-, medium- and high-resolution reconstruction configurations and Aβ CLs were calculated. Since linear Aβ accumulation was assumed over a 10-year interval, for each reconstruction configuration, Aβ accumulation rate differences (ARD) between the second and first periods were calculated for all the subjects and compared. Zero ARD was used as a consistency metric. The number of Aβ-accumulators was also used to compare reconstruction configurations.

Results

Cross-sectional-SUVRs in both Aβ- and Aβ+ groups were impacted by the FWHM of the reconstruction method; Aβ- SUVRs increased for FWHM ≥ 4.5 mm, while Aβ+ SUVRs decreased across the FWHM range. High-resolution reconstructions provided the best statistical separation between groups.

Longitudinal study-In the Aβ-group, the median ARD of low-resolution reconstructed data was greater than zero whereas the ARDs of higher-resolution reconstructions were not significantly different to zero, indicating less consistent rates in the low-than the higher-resolution data. Higher-resolution reconstructions identified 10 additional Aβ-accumulators in the Aβ-group, resulting in a 22% increased group size compared to the low-resolution reconstructions. Higher-resolution reconstructions reduced the average CL values of the negative group by 12 points.

Conclusions

High-resolution PET reconstructions, inherently less impacted by PVE, may improve Aβ-PET quantitation in both cross-sectional and longitudinal data. In the cross-sectional analysis, separation of Aβ groups’ SUVRs increased with spatial resolution. Longitudinal analysis showed better Aβ accumulation consistency in higher-resolution compared to low-resolution reconstructions. The identification of more Aβ-accumulators from the higher-resolution reconstruction may be helpful in early-stage AD therapies.
Modelling population genetic screening in rare neurodegenerative diseases
Authors: Spargo Thomas P , Iacoangeli Alfredo , Ryten Mina , Forzano Francesca , Pearce Neil , Al-Chalabi Ammar
Published: July 2023

Importance

Genomic sequencing enables rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but less well understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation.

Observations

We explore the probability of subsequent disease following genetic screening of several of variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), comparing with screening for phenylketonuria which is well established. The risk following a positive screening test was 0.5% forC9orf72in ALS and 0.4% forHTTin HD, when testing repeat expansions for which the test had sub-optimal performance (sensitivity=99% and specificit =90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1, when testing pathogenic SNVs (sensitivity=99.96% and specificity=99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%).

Conclusions and Relevance

We show that risk following a positive screening test result can be strikingly low for rare neurological diseases. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols of very high sensitivity and specificity, careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.
Stimulus-dependent functional network topology in mouse visual cortex
Authors: Tang Disheng , Zylberberg Joel , Jia Xiaoxuan , Choi Hannah
Published: July 2023

Information is processed by networks of neurons in the brain. On the timescale of sensory processing, those neuronal networks have relatively fixed anatomical connectivity, while functional connectivity, which defines the interactions between neurons, can vary depending on the ongoing activity of the neurons within the network. We thus hypothesized that different types of stimuli, which drive different neuronal activities in the network, could lead those networks to display stimulus-dependent functional connectivity patterns. To test this hypothesis, we analyzed electrophysiological data from the Allen Brain Observatory, which utilized Neuropixels probes to simultaneously record stimulus-evoked activity from hundreds of neurons across 6 different regions of mouse visual cortex. The recordings had single-cell resolution and high temporal fidelity, enabling us to determine fine-scale functional connectivity. Comparing the functional connectivity patterns observed when different stimuli were presented to the mice, we made several nontrivial observations. First, while the frequencies of different connectivity motifs (i.e., the patterns of connectivity between triplets of neurons) were preserved across stimuli, the identities of the neurons within those motifs changed. This means that functional connectivity dynamically changes along with the input stimulus, but does so in a way that preserves the motif frequencies. Secondly, we found that the degree to which functional modules are contained within a single brain region (as opposed to being distributed between regions) increases with increasing stimulus complexity. This suggests a mechanism for how the brain could dynamically alter its computations based on its inputs. Altogether, our work reveals unexpected stimulus-dependence to the way groups of neurons interact to process incoming sensory information.
ReTrace: Topological evaluation of white matter tractography algorithms using Reeb graphs
Authors: Shailja S. , Chen Jefferson W. , Grafton Scott T. , Manjunath B.S.
Published: July 2023

We present ReTrace, a novel graph matching-based topological evaluation and validation method for tractography algorithms. ReTrace uses a Reeb graph whose nodes and edges capture the topology of white matter fiber bundles. We evaluate the performance of 96 algorithms from the ISMRM Tractography Challenge and the the standard algorithms implemented in DSI Studio for the population-averaged Human Connectome Project (HCP) dataset. The existing evaluation metrics such as the f-score, bundle overlap, and bundle overreach fail to account for fiber continuity resulting in high scores even for broken fibers, branching artifacts, and mis-tracked fiber crossing. In contrast, we show that ReTrace effectively penalizes the incorrect tracking of fibers within bundles while concurrently pinpointing positions with significant deviation from the ground truth. Based on our analysis of ISMRM challenge data, we find that no single algorithm consistently outperforms others across all known white matter fiber bundles, highlighting the limitations of the current tractography methods. We also observe that deterministic tractography algorithms perform better in tracking the fundamental properties of fiber bundles, specifically merging and splitting, compared to probabilistic tractography. We compare different algorithmic approaches for a given bundle to highlight the specific characteristics that contribute to successful tracking, thus providing topological insights into the development of advanced tractography algorithms.
Time-, tissue- and treatment-associated heterogeneity in tumour-residing migratory DCs
Authors: Lee Colin YC , Kennedy Bethany C , Richoz Nathan , Dean Isaac , Tuong Zewen K , Gaspal Fabrina , Li Zhi , Willis Claire , Hasegawa Tetsuo , Whiteside Sarah K , Posner David A , Carlesso Gianluca , Hammond Scott A , Dovedi Simon J , Roychoudhuri Rahul , Withers David R , Clatworthy Menna R
Published: July 2023

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to a maturation programme enriched in regulatory molecule expression, including PD-L1, termed mRegDC. However, the spatio- temporal dynamics and role of mRegDCs in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs were the dominant DC population arriving in the dLN, but a subset remained tumour-resident despite CCR7 expression. These tumour-retained mRegDCs were phenotypically and transcriptionally distinct from their dLN counterparts and were heterogeneous. Specifically, they demonstrated a progressive reduction in the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour mRegDCs spatially co-localised with PD-1+CD8+T cells in human and murine solid tumours. Following anti-PD-L1 treatment, tumour-residing mRegDCs adopted a state enriched in lymphocyte stimulatory molecules, including OX40L, which was capable of augmenting anti- tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in mRegDCs that may underpin a variable capacity to support intratumoural cytotoxic T cells, and provide insights into their role in cancer immunotherapy.
Single-cell analysis of signalling and transcriptional responses to type I interferons
Authors: Rigby Rachel E. , Rue-Albrecht Kevin , Sims David , Rehwinkel Jan
Published: July 2023

Type I interferons (IFNs) play crucial roles in antiviral defence, autoinflammation and cancer immunity. The human genome encodes 17 different type I IFNs that all signal through the same receptor. Non-redundant functions have been reported for some type I IFNs. However, whether different type I IFNs induce different responses remains largely unknown. We stimulated human peripheral blood mononuclear cells (PBMCs) with recombinant type I IFNs to address this question in multiple types of primary cells. We analysed signalling responses by mass cytometry and changes in gene expression by bulk and single-cell RNA sequencing. We found cell-type specific changes in the phosphorylation of STAT transcription factors and in the gene sets induced and repressed upon type I IFN exposure. We further report that the magnitude of these responses varied between different type I IFNs, whilst qualitatively different responses to type I IFN subtypes were not apparent. Taken together, we provide a rich resource mapping signalling responses and IFN-regulated genes in immune cells.

Highlights

Mass cytometry and scRNAseq analysis of human PBMCs stimulated with type I IFNs

Cell type-specific phosphorylation of STAT proteins and induction of ISGs

Different type I IFNs induce qualitatively similar responses that vary in magnitude

Identification of ten core ISGs, up-regulated by all cell types in response to all type I IFNs

In brief

Rigbyet al.provide a single-cell map of signalling and transcriptomic responses to type I IFNs inex vivostimulated human PBMCs. Different cell types responded in unique ways but differences between different type I IFNs were only quantitative. These rich datasets are available via an easy-to-use interactive interface (https://rehwinkellab.shinyapps.io/ifnresource/).

Graphical abstract
The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and adapt to glucose depletion
Authors: Niphadkar Shreyas , Karinje Lavanya , Laxman Sunil
Published: July 2023

To sustain growth in changing nutrient conditions, cells reorganize outputs of metabolic networks and appropriately reallocate resources. Signaling by reversible protein phosphorylation can control such metabolic adaptations. In contrast to kinases, the functions of phosphatases that enable metabolic adaptation as glucose depletes are poorly studied. Using aSaccharomyces cerevisiaedeletion screen, we identified the requirement of PP2A-like phosphatase Ppg1 for appropriate carbon allocations towards gluconeogenic outputs – trehalose, glycogen, UDP-glucose, UDP-GlcNAc – specifically after glucose depletion. This homeostatic Ppg1 function is mediated via regulation of the assembly of the Far complex - a multi-subunit complex that tethers to the ER and mitochondrial outer membranes as localized signaling hubs. We show that the Far complex assembly is Ppg1 catalytic activity-dependent. The assembled Far complex is required to maintain gluconeogenic outputs after glucose depletion. Glucose in turn regulates Far complex abundance. This Ppg1-mediated Far complex assembly, and dependent control of gluconeogenic outputs enhances adaptive growth under glucose depletion. Our study illustrates how protein dephosphorylation is required for the assembly of a multi-protein scaffold present in localized cytosolic pools, to thereby enable cells metabolically adapt to nutrient fluctuations.
LRP1 mediates leptin transport by coupling with the short-form leptin receptor in the choroid plexus
Authors: Uner Aaron Aykut , Yang Won-Mo , Kang Min-Cheol , Rodrigues Kellen Cristina da Cruz , Aydogan Ahmet , Seo Ji A , Mendes Natalia F. , Kim Min-Seon , Timzoura Fatima Ezzahra , Holtzman Michael J. , Lehtinen Maria , Prevot Vincent , Kim Young-Bum
Published: July 2023

Adipocyte-derived leptin enters the brain to exert its anorexigenic action, yet its transport mechanism is poorly understood. Here we report that LRP1 (low-density lipoprotein receptor-related protein-1) mediates the transport of leptin across the blood-CSF barrier inFoxj1expressing cells highly enriched at the choroid plexus (ChP), coupled with the short-form leptin receptor, and LRP1 deletion from ependymocytes and ChP cells leads to leptin resistance and hyperphagia, causing obesity. Thus, LRP1 in epithelial cells is a principal regulator of leptin transport in the brain.
Putting cognitive tasks on trial: A measure of reliability convergence
Authors: Kadlec Jan , Walsh Catherine , Sadé Uri , Amir Ariel , Rissman Jesse , Ramot Michal
Published: July 2023

The surge in interest in individual differences has coincided with the latest replication crisis centered around brain-wide association studies of brain-behavior correlations. Yet the reliability of the measures we use in cognitive neuroscience, a crucial component of this brain-behavior relationship, is often assumed but not directly tested. Here, we evaluate the reliability of different cognitive tasks on a large dataset of over 250 participants, who each completed a multi-day task battery. We show how reliability improves as a function of number of trials, and describe the convergence of the reliability curves for the different tasks, allowing us to score tasks according to their suitability for studies of individual differences. To improve the accessibility of these findings, we designed a simple web-based tool that implements this function to calculate the convergence factor and predict the expected reliability for any given number of trials and participants, even based on limited pilot data.
Competition for light can drive adverse species-composition shifts in the Amazon Forest under elevated CO2
Authors: Joshi Jaideep , Hofhansl Florian , Singh Shipra , Stocker Benjamin D. , Brännström Åke , Franklin Oskar , Blanco Carolina C. , Aleixo Izabela F. , Lapola David , Prentice Iain Colin , Dieckmann Ulf
Published: July 2023

The resilience of biodiverse forests to climate change depends on an interplay of adaptive processes operating at multiple temporal and organizational scales. These include short-term acclimation of physiological processes like photosynthesis and respiration, mid-term changes in forest structure due to competition, and long-term changes in community composition arising from competitive exclusion and genetic trait evolution. To investigate the roles of diversity and adaptation for forest resilience, we present Plant-FATE, a parsimonious eco-evolutionary vegetation model. Tested with data from a hyperdiverse Amazonian terra-firme forest, our model accurately predicts multiple emergent ecosystem properties characterizing forest structure and function. Under elevated CO2conditions, we predict an increase in productivity, leaf area, and aboveground biomass, with the magnitude of this increase declining in nutrient-deprived soils if trees allocate more carbon to the rhizosphere to overcome nutrient limitation. Furthermore, increased aboveground productivity leads to greater competition for light and drives a shift in community composition towards fast-growing but short-lived species characterized by lower wood densities. Such a transition reduces the carbon residence time of woody biomass, dampening carbon-sink strength and potentially rendering the Amazon Forest more vulnerable to future climatic extreme events.
Covalent macrocyclic proteasome inhibitors mitigate resistance inPlasmodium falciparum
Authors: Bennett John M. , Ward Kurt E. , Muir Ryan , Kabeche Stephanie , Yoo Euna , Yeo Tomas , Lam Grace , Zhang Hao , Almaliti Jehad , Berger Gabriel , Faucher Franco F. , Lin Gang , Gerwick William H. , Yeh Ellen , Fidock David A. , Bogyo Matthew
Published: July 2023

ThePlasmodiumproteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinins. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible macrocyclic inhibitors of theP. falciparumproteasome. We identified compounds with excellent potency and low cytotoxicity, however, the first generation suffered from poor microsomal stability. Further optimization of an existing macrocyclic scaffold resulted in an irreversible covalent inhibitor carrying a vinyl sulfone electrophile that retained high potency, low cytotoxicity, and had acceptable metabolic stability. Importantly, unlike the parent reversible inhibitor that selected for multiple mutations in the proteasome, with one resulting in a 5,000-fold loss of potency, the irreversible analog only showed a 5-fold loss in potency for any single point mutation. Furthermore, an epoxyketone analog of the same scaffold retained potency against a panel of known proteasome mutants. These results confirm that macrocycles are optimal scaffolds to target the malarial proteasome and that the use of a covalent electrophile can greatly reduce the ability of the parasite to generate drug resistance mutations.
Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies
Authors: Lehman Sarah J. , Meller Artur , Solieva Shahlo O. , Lotthammer Jeffrey M. , Greenberg Lina , Langer Stephen J. , Greenberg Michael J. , Tardiff Jil C. , Bowman Gregory R. , Leinwand Leslie
Published: July 2023

In genetic cardiomyopathies, a frequently described phenomenon is how similar mutations in one protein can lead to discrete clinical phenotypes. One example is illustrated by two mutations in beta myosin heavy chain (β-MHC) that are linked to hypertrophic cardiomyopathy (HCM) (Ile467Val, I467V) and left ventricular non-compaction (LVNC) (Ile467Thr, I467T). To investigate how these missense mutations lead to independent diseases, we studied the molecular effects of each mutation using recombinant human β-MHC Subfragment 1 (S1) inin vitroassays. Both HCM-I467V and LVNC-I467T S1 mutations exhibited similar mechanochemical function, including unchanged ATPase and enhanced actin velocity but had opposing effects on the super-relaxed (SRX) state of myosin. HCM-I467V S1 showed a small reduction in the SRX state, shifting myosin to a more actin-available state that may lead to the “gain-of-function” phenotype commonly described in HCM. In contrast, LVNC-I467T significantly increased the population of myosin in the ultra-slow SRX state. Interestingly, molecular dynamics simulations reveal that I467T allosterically disrupts interactions between ADP and the nucleotide-binding pocket, which may result in an increased ADP release rate. This predicted change in ADP release rate may define the enhanced actin velocity measured in LVNC-I467T, but also describe the uncoupled mechanochemical function for this mutation where the enhanced ADP release rate may be sufficient to offset the increased SRX population of myosin. These contrasting molecular effects may lead to contractile dysregulation that initiates LVNC-associated signaling pathways that progress the phenotype. Together, analysis of these mutations provides evidence that phenotypic complexity originates at the molecular level and is critical to understanding disease progression and developing therapies.
InterpretingCis-Regulatory Interactions from Large-Scale Deep Neural Networks for Genomics
Authors: Toneyan Shushan , Koo Peter K
Published: July 2023

The rise of large-scale, sequence-based deep neural networks (DNNs) for predicting gene expression has introduced challenges in their evaluation and interpretation. Current evaluations align DNN predictions with experimental perturbation assays, which provides insights into the generalization capabilities within the studied loci but offers a limited perspective of what drives their predictions. Moreover, existing model explainability tools focus mainly on motif analysis, which becomes complex when interpreting longer sequences. Here we introduce CREME, anin silicoperturbation toolkit that interrogates large-scale DNNs to uncover rules of gene regulation that it learns. Using CREME, we investigate Enformer, a prominent DNN in gene expression prediction, revealingcis-regulatory elements (CREs) that directly enhance or silence target genes. We explore the intricate complexity of higher-order CRE interactions, the relationship between CRE distance from transcription start sites on gene expression, as well as the biochemical features of enhancers and silencers learned by Enformer. Moreover, we demonstrate the flexibility of CREME to efficiently uncover a higher-resolution view of functional sequence elements within CREs. This work demonstrates how CREME can be employed to translate the powerful predictions of large-scale DNNs to study open questions in gene regulation.
Correlated evolution of conspicuous coloration and burrowing in crayfish
Authors: Graham Zackary A. , Padilla Perez Dylan J.
Published: July 2023

Conspicuous colors have fascinated biologists for centuries, leading to much research on the evolution and functional significance of color traits. However, some authors have critiqued the adaptationist dogma amongst color researchers. When investigating a color trait, researchers often exclusively consider the alternative hypotheses—they assume color is adaptive. The null hypothesis of animal color—that coloration is non-adaptive or evolutionary neutral, is rarely considered. Here, we use phylogenetic comparative methods to investigate color evolution throughout freshwater crayfishes. Within the taxa we analyzed, conspicuous colors have evolved independently over 50 times. The intuitive, but not evolutionary-justified assumption when presented these results is to assume that these colors are an adaptation. But contrary to this intuition, our work might support the hypothesis that coloration in crayfish is neutral; because we show that conspicuous colors are evolutionary correlated to a semi-terrestrial burrowing lifestyle. Conspicuous coloration being common in semi-terrestrial burrowers is paradoxical, because these species are nocturnal, and rarely leave their burrows. Overall, our work brings into question to traditional view of animal coloration as a perfectly adapted phenotype.
Modeling the Neurocognitive Dynamics of Language across the Lifespan
Authors: Guichet C. , Banjac S. , Achard S. , Mermillod M. , Baciu M.
Published: July 2023

Healthy aging is associated with a heterogeneous decline across cognitive functions, typically observed between language comprehension and language production (LP). Examining resting-state fMRI and neuropsychological data from 628 healthy adults (age 18-88) from the CamCAN cohort, we performed state-of-the-art graph theoretical analysis to uncover the neural mechanisms underlying this variability. At the cognitive level, our findings suggest that LP is not an isolated function but is modulated throughout the lifespan by the extent of inter-cognitive synergy between semantic and domain-general processes. At the cerebral level, we show that DMN (Default Mode Network) suppression coupled with FPN (Fronto-Parietal Network) integration is the way for the brain to compensate for the effects of dedifferentiation at a minimal cost, efficiently mitigating the age-related decline in LP. Relatedly, reduced DMN suppression in midlife could compromise the ability to manage the cost of FPN integration. This may prompt older adults to adopt a more cost-efficient compensatory strategy that maintains global homeostasis at the expense of LP performances. Taken together, we propose that midlife represents a critical neurocognitive juncture that signifies the onset of LP decline, as older adults gradually lose control over semantic representations. We summarize our findings in a novel SENECA model (Synergistic, Economical, Nonlinear, Emergent, Cognitive Aging), integrating connectomic and cognitive dimensions within a complex system perspective.

Highlights

Lexical production (LP) relies on the interplay between domain-general and semantic processes throughout life.

DMN (Default Mode Network) suppression cooperates with FPN (Fronto-Parietal Network) integration to maintain LP performance at a minimal cost.

Midlife marks a neurocognitive shift, with reduced DMN suppression prompting a more cost-efficient compensatory strategy that prioritizes homeostasis over LP performance.
A short-lived peptide signal regulates cell-to-cell communication inListeria monocytogenes
Authors: Bejder Benjamin S. , Monda Fabrizio , Gless Bengt H. , Bojer Martin S. , Ingmer Hanne , Olsen Christian A.
Published: July 2023

Quorum sensing (QS) is a mechanism that regulates group behavior in bacteria, and in Gram-positive bacteria, the communication molecules are often cyclic peptides, called autoinducing peptides (AIPs). We recently showed that pentameric thiolactone-containing AIPs fromListeria monocytogenes, and from other species, spontaneously undergo rapid rearrangement to homodetic cyclopeptides, which hampers our ability to study the activity of these short-lived compounds. Here, we developed chemically modified analogues that closely mimic the native AIPs while remaining structurally intact, by introducing N-methylation or thioester-to-thioether substitutions. The stablilized AIP analogues exhibit strong QS agonism inL. monocytogenesand allow structure–activity relationships to be studied. Our data provide evidence that loudly suggest that the most potent AIP is in fact the very short-lived thiolactone-containing pentamer. Further, we find that the QS system inL. monocytogenesis more promiscuous with respect to the structural diversity allowed for agonistic AIPs than reported for the more extensively studied QS systems inStaphylococcus aureusandStaphylococcus epidermidis. The developed compounds will be important for uncovering the biology ofL. monocytogenes, and the design principles should be broadly applicable to the study of AIPs in other species.
Structure-based engineering of Tor complexes uncovers different roles of two types of yeast TORC1s
Authors: Kamada Yoshiaki , Umeda Chiharu , Mukai Yukio , Ohtsuka Hokuto , Otsubo Yoko , Yamashita Akira , Kosugi Takahiro
Published: July 2023

Certain proteins assemble into diverse complex states, each having a distinctive and unique function in the cell. The target of rapamycin complex 1 (TORC1) plays a central role in signaling pathways for cells to respond to their environment, such as nutritional status. TORC1 is widely recognised for its association with various diseases. The budding yeastSaccharomyces cerevisiaehas two types of TORC1s comprising different constituent proteins, Tor1- and Tor2-containing TORC1s but are considered to have the same function. Here, we rationally redesigned the complex states by structure-based engineering and constructed a Tor2 mutant to form TORC2 but not TORC1. Functional analysis of the mutant revealed that the two types of TORC1s induced different phenotypes-rapamycin, caffeine and pH dependences of cell growth and replicative and chronological lifespans. These findings are expected to provide further insights into various fields such as molecular evolution and lifespan.
Charting the brain networks of impulsivity: Meta-analytic synthesis, functional connectivity modelling and neurotransmitter associations
Authors: Gell Martin , Langner Robert , Küppers Vincent , Cieslik Edna C. , Satterthwaite Theodore D. , Eickhoff Simon B. , Müller Veronika I.
Published: July 2023

Impulsivity is a multidimensional construct that plays a crucial role in human behaviour and is believed to be a transdiagnostic marker of several psychiatric disorders. However, given its multifaceted nature, comprehensive investigations of its neural correlates are challenging. In this study, we used a multi-modal approach to investigate the functional network organisation of two domains in which impulsivity manifests: decision-making and action control. Within domain ALE meta-analyses identified two distinct functional systems: one located in the default-mode network, associated with value-based judgments and goal-directed decision-making, and the other distributed across higher-order networks associated with cognitive control. These systems were organised into four specialised communities of default-mode, cingulo-insular, frontoparietal, and temporal regions. Integration within those communities was associated with serotonin receptor density. These findings reinforce insights from previous behavioural research and provide substantial evidence for the multidimensional nature of impulsivity on the neural level.
AMPK activation induces RALDHhightolerogenic dendritic cells through rewiring of glucose and lipid metabolism
Authors: Brombacher E. C. , Patente T. A. , van der Ham A. J. , Moll T. J. A. , Otto F. , Verheijen F. W. M. , Zaal E. A. , de Ru A.H. , Tjokrodirijo R. T. N. , Berkers C. R. , van Veelen P. A. , Guigas B. , Everts B.
Published: July 2023

It is well known that dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. The AMP-activated kinase (AMPK) is a central nutrient and energy sensor whose activation promotes catabolism while inhibiting ATP-consuming anabolic pathways. Yet the contribution of AMPK activation to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a number of distinct metabolic changes, in particular increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest that AMPK may serve as new target to direct DC-driven immune responses in therapeutic settings.
Molecular Dynamics Simulations on Quercetin-3-(6-Malonylglucoside) FromMorus AlbaShows Optimal Inhibition of Bcl-2 with Favorable Anti-Tumor Activities
Authors: Omirin Emmanuel Sunday , Omotuyi Olaposi Idowu , Afokhume Oluwaseun Grace , Okoh Ehisdiame Favour , Boboye Samuel Oluwaseun , Ibitoye Babatunde Oluwaseun , Adelegan Olabode Oluwagbemiga , Olugbogi Ezekiel Abiola , Aderiye Michael Aladejare , Agosile Oluwafemi Ojo
Published: July 2023

The target of most cancer chemotherapeutic agents is to drive cancer cells toward death. A fine balance between anti-apoptotic and pro-apoptotic proteins is needed to maintain cellular homeostasis. Any shift favoring the pro-apoptotic ones is needed to drive cellular death in cancer chemotherapy. However, anti-apoptotic proteins such as Bcl-2 and Bcl-xL bind with pro-apoptotic proteins to hinder apoptosis mechanisms. Overexpression of these anti-apoptotic proteins lead to several cancers by preventing apoptosis. In this study, molecular docking, ADMET predictions, and molecular dynamics simulations were performed for the identification of potent inhibitors of anti-apoptotic Bcl-2 with compounds ofMorus alba.Our study discovered that Quercetin-3-(6-Malonylglucoside) and Epigallocatechin gallate recorded excellent binding affinity with Bcl-2. Therefore, we conclude that compounds ofMorus albashould be subjected to further experimental studies (in vitroandin vivo)in order to confirm the findings that they could be used as better options in cancer chemotherapy.
Brain-wide representations of prior information in mouse decision-making
Authors: Findling Charles , Hubert Felix ,   International Brain Laboratory, Acerbi Luigi , Benson Brandon , Benson Julius , Birman Daniel , Bonacchi Niccolò , Bruijns Sebastian , Carandini Matteo , Catarino Joana A , Chapuis Gaelle A , Churchland Anne K , Dan Yang , Davatolhagh Felicia , DeWitt Eric EJ , Engel Tatiana A , Fabbri Michele , Faulkner Mayo , Fiete Ila Rani , Freitas-Silva Laura , Gerçek Berk , Harris Kenneth D , Häusser Michael , Hofer Sonja B , Hu Fei , Huntenburg Julia M , Khanal Anup , Krasniak Chris , Langdon Christopher , Latham Peter E , Lau Petrina Y P , Mainen Zach , Meijer Guido T , Miska Nathaniel J , Mrsic-Flogel Thomas D , Noel Jean-Paul , Nylund Kai , Pan-Vazquez Alejandro , Paninski Liam , Pillow Jonathan , Rossant Cyrille , Roth Noam , Schaeffer Rylan , Schartner Michael , Shi Yanliang , Socha Karolina Z , Steinmetz Nicholas A , Svoboda Karel , Tessereau Charline , Urai Anne E , Wells Miles J , West Steven Jon , Whiteway Matthew R , Winter Olivier , Witten Ilana B , Zador Anthony , Zhang Yizi , Dayan Peter , Pouget Alexandre
Published: July 2023

The neural representations of prior information about the state of the world are poorly understood. To investigate them, we examined brain-wide Neuropixels recordings and widefield calcium imaging collected by the International Brain Laboratory. Mice were trained to indicate the location of a visual grating stimulus, which appeared on the left or right with prior probability alternating between 0.2 and 0.8 in blocks of variable length. We found that mice estimate this prior probability and thereby improve their decision accuracy. Furthermore, we report that this subjective prior is encoded in at least 20% to 30% of brain regions which, remarkably, span all levels of processing, from early sensory areas (LGd, VISp) to motor regions (MOs, MOp, GRN) and high level cortical regions (ACAd, ORBvl). This widespread representation of the prior is consistent with a neural model of Bayesian inference involving loops between areas, as opposed to a model in which the prior is incorporated only in decision-making areas. This study offers the first brain-wide perspective on prior encoding at cellular resolution, underscoring the importance of using large scale recordings on a single standardized task.