bluuebunny/crossref_metadata_2025 huggingface dataset:
Matrimeres are systemic nanoscale mediators of tissue integrity and function
Authors: Debnath Koushik , Qayoom Irfan , O’Donnell Steven , Ekiert Julia , Wang Can , Sanborn Mark A. , Liu Chang , Rivera Ambar , Cho Ik Sung , Saichellappa Saiumamaheswari , Toth Peter T. , Mehta Dolly , Rehman Jalees , Du Xiaoping , Gao Yu , Shin Jae-Won
Published: March 2024

Tissue barriers must be rapidly restored after injury to promote regeneration. However, the mechanism behind this process is unclear, particularly in cases where the underlying extracellular matrix is still compromised. Here, we report the discovery of matrimeres as constitutive nanoscale mediators of tissue integrity and function. We define matrimeres as non-vesicular nanoparticles secreted by cells, distinguished by a primary composition comprising at least one matrix protein and DNA molecules serving as scaffolds. Mesenchymal stromal cells assemble matrimeres from fibronectin and DNA within acidic intracellular compartments. Drawing inspiration from this biological process, we have achieved the successful reconstitution of matrimeres without cells. This was accomplished by using purified matrix proteins, including fibronectin and vitronectin, and DNA molecules under optimal acidic pH conditions, guided by the heparin-binding domain and phosphate backbone, respectively. Plasma fibronectin matrimeres circulate in the blood at homeostasis but exhibit a 10-fold decrease during systemic inflammatory injuryin vivo. Exogenous matrimeres rapidly restore vascular integrity by actively reannealing endothelial cells post-injury and remain persistent in the host tissue matrix. The scalable production of matrimeres holds promise as a biologically inspired platform for regenerative nanomedicine.
Biomass competition unifies individual and community scaling patterns
Authors: Fant Lorenzo , Ghedini Giulia
Published: March 2024

Both metabolism and growth scale sublinearly with body mass for most species. Ecosystems show the same sublinear scaling between production and total biomass but ecological theory cannot reconcile the existence of these nearly identical scalings at different levels of biological organization. We solve this paradox using marine phytoplankton to connect individual and ecosystem scalings across three orders of magnitude in body size and biomass. Competitive interactions determined by biomass, rather than differences in species size, slow metabolism in a consistent fashion across species that dominates over species-specific peculiarities, resulting in a unique behavior across community compositions. The allometry of ecosystem production thus emerges from this metabolic density-dependence, independently of the equilibrium state or resource regime of the system. Our findings demonstrate the mechanistic basis of ecosystem allometries, unifying aspects of physiology and ecology to explain why growth patterns are so strikingly similar across scales.
MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN ADROSOPHILAMODEL OF NEURODEGENERATION
Authors: Wodrich Andrew P. K. , Harris Brent T. , Giniger Edward
Published: March 2024

Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using aDrosophilamodel of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses, or whether they are simply covariates of pathology that do not alter viability. We find, surprisingly, that increasing mitochondrial H2O2correlates with improved survival. We also find evidence that drugs that alter the mitochondrial glutathione redox potential modulate survival primarily through the compensatory effects they induce rather than through their direct effects on the final mitochondrial glutathione redox potentialper se. We also find that the response to treatment with a redox-altering drug varies dramatically depending on the age at which the drug is administered, the duration of the treatment, and the genotype of the individual receiving the drug. These data have important implications for the design and interpretation of studies investigating the effect of redox state on health and disease as well as on efforts to modify the redox state to achieve therapeutic goals.
A role for δ subunit-containing GABAAreceptors on parvalbumin positive neurons in maintaining electrocortical signatures of sleep states
Authors: Lambert Peter M. , Salvatore Sofia V. , Lu Xinguo , Shu Hong-Jin , Benz Ann , Rensing Nicholas , Yuede Carla M. , Wong Michael , Zorumski Charles F. , Mennerick Steven
Published: March 2024

GABAAreceptors containing δ subunits have been shown to mediate tonic/slow inhibition in the CNS. These receptors are typically found extrasynaptically and are activated by relatively low levels of ambient GABA in the extracellular space. In the mouse neocortex, δ subunits are expressed on the surface of some pyramidal cells as well as on parvalbumin positive (PV+) interneurons. An important function of PV+ interneurons is the organization of coordinated network activity that can be measured by EEG; however, it remains unclear what role tonic/slow inhibitory control of PV+ neurons may play in shaping oscillatory activity. After confirming a loss of functional δ mediated tonic currents in PV cells in cortical slices from mice lackingGabrdin PV+ neurons (PV δcKO), we performed EEG recordings to survey network activity across wake and sleep states. PV δcKO mice showed altered spectral content of EEG during NREM and REM sleep that was a result of increased oscillatory activity in NREM and the emergence of transient high amplitude bursts of theta frequency activity during REM. Viral reintroduction ofGabrdto PV+ interneurons in PV δcKO mice rescued REM EEG phenotypes, supporting an important role for δ subunit mediated inhibition of PV+ interneurons for maintaining normal REM cortical oscillations.

Significance statement

The impact on cortical EEG of inhibition on PV+ neurons was studied by deleting a GABAAreceptor subunit selectively from these neurons. We discovered unexpected changes at low frequencies during sleep that were rescued by viral reintroduction.
Locus Coeruleus Contrast and Diffusivity: Effects of Age and Relations to Memory
Authors: Bennett Ilana J. , Langley Jason , Sun Andrew , Solis Kitzia , Seitz Aaron R. , Hu Xiaoping P.
Published: March 2024

Neurocognitive aging researchers are increasingly focused on the locus coeruleus, a neuromodulatory brainstem structure that degrades with age. With this rapid growth, the field will benefit from consensus regarding which magnetic resonance imaging (MRI) metrics of locus coeruleus structure are most sensitive to age and cognition. To address this need, the current study acquired magnetization transfer- and diffusion-weighted MRI images in younger and older adults who also completed a free recall memory task. Results revealed significantly larger differences between younger and older adults for maximum than average magnetization transfer-weighted contrast (MTC), axial than mean or radial single-tensor diffusivity (DTI), and free than restricted multi-compartment diffusion (NODDI) metrics in the locus coeruleus; with maximum MTC being the best predictor of age group. Age effects for the MTC and NODDI metrics interacted with sex such that larger age group differences were seen in males than females. Age group differences were also larger for DTI metrics in the rostral, and NODDI metrics in the caudal, locus coeruleus subdivision. Within older adults, however, there were no significant effects of age on any measure of locus coeruleus structure. Finally, independent of age and sex, higher restricted diffusion in the locus coeruleus was significantly related to better (lower) recall variability, but not mean recall. Whereas MTC has been widely used in the literature, our comparison between the average and maximum MTC metrics, and inclusion of DTI and NODDI metrics, make important and novel contributions to our understanding of the aging of locus coeruleus structure.
Proposing a Systematic Lineage Classification Below the Genotype Level for Dengue Serotypes 1 and 2
Authors: Pereira James Siqueira , Ribeiro Gabriela , de Souza Vinicius Carius , Brcko Isabela Carvalho , Ribeiro Igor Santana , De Lima Iago Trezena Tavares , Slavov Svetoslav Nanev , Sampaio Vessoni Sandra Coccuzzo , Elias Maria Carolina , Jerônimo Lima Alex Ranieri
Published: March 2024

Dengue virus (DENV), a mosquito-borne flavivirus, is causing a significant outbreak in Brazil. The recent surge in complete DENV genome sequences necessitates a standardized classification system for an improved understanding of viral dynamics and transmission patterns. Traditionally, DENV classification relies on serotypes and genotypes but lacks a consensus for sub-genotype classification. This hinders comprehensive analyses of viral diversity. We address this gap by proposing a novel lineage classification system for DENV using a semi-automatic workflow, leveraging the use of complete genome sequences to classify and re-evaluate DENV genetic diversity. This system offers a more granular classification scheme compared to current methods. The proposed hierarchical nomenclature, incorporating serotype, genotype, subgenotype, lineage, and sublineage, facilitates precise tracking of viral introductions and evolutionary events. This information might have crucial implications for public health interventions, enabling more targeted control strategies and improved monitoring of vaccine effectiveness during future outbreaks.
Ultrasound pulse repetition frequency preferentially activates different neuron populations independent of cell type
Authors: Sherman Jack , Bortz Emma , Antonio Erynne San , Tseng Hua-an , Raiff Laura , Han Xue
Published: March 2024

Transcranial ultrasound activates mechanosensitive cellular signaling and modulates neural dynamics. Given that intrinsic neuronal activity is limited to a couple hundred hertz and often exhibits frequency preference, we examined whether pulsing ultrasound at physiologic pulse repetition frequencies (PRFs) could selectively influence neuronal activity in the mammalian brain. We performed calcium imaging of individual motor cortex neurons, while delivering 0.35 MHz ultrasound at PRFs of 10, 40, and 140 Hz in awake mice. We found that most neurons were preferentially activated by only one of the three PRFs, highlighting unique cellular effects of physiologic PRFs. Further, ultrasound evoked responses were similar between excitatory neurons and parvalbumin positive interneurons regardless of PRFs, indicating that individual cell sensitivity dominates ultrasound-evoked effects, consistent with the heterogeneous mechanosensitive channel expression we found across single neurons in mice and humans. These results highlight the feasibility of tuning ultrasound neuromodulation effects through varying PRFs.
Skull evolution and lineage diversification in endemic Malagasy carnivorans
Authors: Law Chris J. , Linden Tate J. , Flynn John J.
Published: March 2024

Madagascar is one of the world’s foremost biodiversity hotspots with more than 90% of its species endemic to the island. Malagasy carnivorans are one of only four extant terrestrial mammalian clades endemic to Madagascar. Although there are only eight extant species, these carnivorans exhibit remarkable phenotypic and ecological diversity that is often hypothesized to have diversified through an adaptive radiation. Here, we investigated the evolution of skull diversity in Malagasy carnivorans and tested if they exhibited characteristics of convergence and an adaptive radiation. We found that their skull disparity exceeds that of any other feliform family, as their skulls vary widely and strikingly capture a large amount of the morphological variation found across all feliforms. We also found evidence of shared adaptive zones in cranial shape between euplerid subclades and felids, herpestids, and viverrids. Lastly, contrary to predictions of adaptive radiation, we found that Malagasy carnivorans do not exhibit rapid lineage diversification and only marginally faster rates of mandibular shape evolution, and to a lesser extent cranial shape evolution, compared to other feliforms. These results reveal that exceptional diversification rates are not necessary to generate the striking phenotypic diversity that evolved in carnivorans after their dispersal to and isolation on Madagascar.
Hamstrings are stretched more and faster during accelerative running compared to speed-matched constant speed running
Authors: Gurchiek Reed D. , Teplin Zachary , Falisse Antoine , Hicks Jennifer L. , Delp Scott L.
Published: March 2024

Background

Hamstring strain injuries are associated with significant time away from sport and high reinjury rates. Recent evidence suggests that hamstring injuries often occur during accelerative running, but investigations of hamstring mechanics have primarily examined constant speed running on a treadmill. To help fill this gap in knowledge, this study compares hamstring lengths and lengthening velocities between accelerative running and constant speed overground running.

Methods

We recorded 2 synchronized videos of 10 participants (5 female, 5 male) during 6 accelerative running trials and 6 constant speed running trials. We used OpenCap (a markerless motion capture system) to estimate body segment kinematics for each trial and a 3-dimensional musculoskeletal model to compute peak length and step-average lengthening velocity of the biceps femoris (long head) muscle-tendon unit. To compare running conditions, we used linear mixed regression models with running speed (normalized by the subject-specific maximum) as the independent variable.

Results

At running speeds below 75% of top speed accelerative running resulted in greater peak lengths than constant speed running. For example, the peak hamstring muscle-tendon length when a person accelerated from running at only 50% of top speed was equivalent to running at a constant 88% of top speed. Lengthening velocities were greater during accelerative running at all running speeds. Differences in hip flexion kinematics primarily drove the greater peak muscle-tendon lengths and lengthening velocities observed in accelerative running.

Conclusion

Hamstrings are subjected to longer muscle-tendon lengths and faster lengthening velocities in accelerative running compared to constant speed running. This provides a biomechanical explanation for the observation that hamstring strain injuries often occur during acceleration. Our results suggest coaches who monitor exposure to high-risk circumstances (long lengths, fast lengthening velocities) should consider the accelerative nature of running in addition to running speed.
How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer’s disease brain by a strain-relief mechanism
Authors: Hou Ke , Ge Peng , Sawaya Michael R. , Dolinsky Joshua L. , Yang Yuan , Jiang Yi Xiao , Lutter Liisa , Boyer David R. , Cheng Xinyi , Pi Justin , Zhang Jeffrey , Lu Jiahui , Yang Shixin , Yu Zhiheng , Feigon Juli , Eisenberg David S.
Published: March 2024

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer’s disease (AD). Previously we found thatin vitrothe D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disassembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find assembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.
Splicing-aware resolution of scRNA-Seq data
Authors: Lukyanov D.K. , Egorov E.S. , Kriukova V.V. , Ladell K. , Price D. , Franke A. , Chudakov D.M.
Published: March 2024

Single-cell RNA sequencing (scRNA-Seq) provides invaluable insights in cell biology. Current scRNA-Seq analytic approaches do not distinguish between spliced and unspliced mRNA. RNA velocity paradigm suggests that the presence of unspliced mRNA reflects transitional cell states, informative for studies of dynamic processes such as embryogenesis or tissue regeneration. Alternatively, stable cell subsets may also maintain unspliced mRNA reservoirs for prompt initiation of transcription-independent expression. Based on the latter paradigm, we have developed a method called SANSARA (Splicing-Aware scrNa-Seq AppRoAch) for the splicing-aware analysis of scRNA-Seq data. We employed SANSARA to characterize peripheral blood regulatory T cell (Treg) subsets, revealing the complex interplay between FoxP3 and Helios master transcription factors and other unexpected splicing-informed features. For Th1 and cytotoxic CD4+T cell subsets, SANSARA also revealed substantial splicing heterogeneity across crucial subset-specific genes. SANSARA is straightforward to implement in current data analysis pipelines and opens new dimensions in scRNA-Seq-based discoveries.
AdjuSST: An Adjustable Surface Stiffness Treadmill
Authors: Price Mark , Locurto Dominic , Abdikadirova Banu , Huber Meghan E. , Hoogkamer Wouter
Published: March 2024

Humans have the remarkable ability to manage foot-ground interaction seamlessly across terrain changes despite the high dynamic complexity of the task. Understanding how adaptation in the neuromotor system enables this level of robustness in the face of changing interaction dynamics is critical for developing more effective gait retraining interventions. We developed an adjustable surface stiffness treadmill (AdjuSST) to trigger these adaptation mechanisms and enable studies to better understand human adaptation to changing foot-ground dynamics. The AdjuSST system makes use of fundamental beam-bending principles; it controls surface stiffness by controlling the effective length of a cantilever beam. The beam acts as a spring suspension for the transverse endpoint load applied through the treadmill. The system is capable of enforcing a stiffness range of 15-300kN/m within 340 ms, deflecting linearly downwards up to 10 cm, and comfortably accommodating two full steps of travel along the belt. AdjuSST offers significant enhancements in effective walking surface length compared to similar systems, while also maintaining a useful stiffness range and responsive spring suspension. These improvements enhance our ability to study locomotor control and adaptation to changes in surface stiffness, as well as provide new avenues for gait rehabilitation.
Foldclass and Merizo-search: embedding-based deep learning tools for protein domain segmentation, fold recognition and comparison
Authors: Kandathil Shaun M , Lau Andy M C , Buchan Daniel W A , Jones David T
Published: March 2024

The availability of very large numbers of protein structures from accurate computational methods poses new challenges in storing, searching and detecting relationships between these structures. In particular, the new-found abundance of multi-domain structures in the AlphaFold structure database introduces challenges for traditional structure comparison methods. We address these challenges using a fast, embedding-based structure comparison method called Foldclass which detects structural similarity between protein domains. We demonstrate the accuracy of Foldclass embeddings for homology detection. In combination with a recently developed deep learning-based automatic domain segmentation tool Merizo, we develop Merizo-search, which first segments multi-domain query structures into domains, and then searches a Foldclass embedding database to determine the top matches for each constituent domain. Combining the ability of Merizo to accurately segment complete chains into domains, and Foldclass to embed and detect similar domains, Merizo-search can be used to detect per-domain similarities for complete chains. We anticipate that these tools will enable a number of analyses using the wealth of predicted structural data now available. Foldclass and Merizo-search are available at https://github.com/psipred/merizo_search. Merizo-search is also available on the PSIPRED web server at http://bioinf.cs.ucl.ac.uk/psipred.
Development of AI-assisted microscopy frameworks through realistic simulation in pySTED
Authors: Bilodeau Anthony , Michaud-Gagnon Albert , Chabbert Julia , Turcotte Benoit , Heine Jörn , Durand Audrey , Lavoie-Cardinal Flavie
Published: March 2024

The integration of artificial intelligence (AI) into microscopy systems significantly enhances performance, optimizing both the image acquisition and analysis phases. Development of AI-assisted super-resolution microscopy is often limited by the access to large biological datasets, as well as by the difficulties to benchmark and compare approaches on heterogeneous samples. We demonstrate the benefits of a realistic STED simulation platform,pySTED, for the development and deployment of AI-strategies for super-resolution microscopy. The simulation environment provided bypySTEDallows the augmentation of data for the training of deep neural networks, the development of online optimization strategies, and the training of reinforcement learning models, that can be deployed successfully on a real microscope.
COCONUT: An analysis of coiled-coil regions in proteins
Authors: Soni Neelesh , Madhusudhan M. S.
Published: March 2024

Motivation

The molecular rules determine the strength and orientation (parallel or antiparallel) of interacting coiled-coil helices in protein-protein interactions. Interpreting these rules is crucial for identifying novel protein-protein interactions, designing competitive binders, and constructing large assemblies containing coiled-coil domains. This study establishes the molecular principles that dictate the strength and orientation of coiled-coil interactions, providing insights relevant to these applications.

Results

We examined how hydrophobic contacts determine structural specificity within coiled-coil dimers. Our analysis revealed that the hydrophobic core densities differ between parallel and antiparallel dimer confirmations, highlighting their importance in stabilizing different structural arrangements. We developedCOiled-COil aNalysisUTility (COCONUT), a computational platform with machine learning models, validated for predictive capabilities in various applications. Using COCONUT’s pipeline for coiled-coil analysis and modeling, we predicted the orientation of substitution-sensitive coiled-coil dimer, identified residue pairings in non-canonical coiled-coil heterodimer, and constructedn-strandedcoiled-coil model. These results demonstrate COCONUT’s utility as a computational framework for interpreting and modeling coiled-coil structures.

Availability and implementation

COCONUT is an open-source and free Python package available herehttps://github.com/neeleshsoni21/COCONUT. The documentation is available in the source code and here:https://neeleshsoni21.github.io/COCONUT/
Essential Dynamics of CB1Receptor-Agonist Complexes: Implications for Signalling Bias
Authors: Fellner Daniel M. J. , Glass Michelle , Furkert Daniel P.
Published: March 2024

The CB1cannabinoid receptor is implicated in a broad range of physiological processes and disease states, however CB1-targeting drugs in clinical use remain based on tetrahydrocannabinol (THC). Ligands that exhibit functional selectivity for different intracellular signalling pathways are currently an area of rapid development, and hold significant potential as therapeutic agents. Improved understanding of the exact molecular mechanisms underpinning biased activation of intracellular effector proteins for CB1is necessary to enable drug development of biased CB1ligands into candidates for treatment of human disease. Using molecular dynamics, this study shows that CB1conformations resulting from activation by the orthosteric ligands CP55940, Δ9-THC or 5F-MDMB-PICA exhibit differences in the dynamic organisation of key residues and receptor substructures involved in coupling to G proteins and β-arrestins, that leads to selective activation of downstream signalling pathways. The identification of conformationally distinct CB1-agonist complexes that demonstrate different functional profiles provides an important step in unravelling the molecular determinants for biased signalling, and lays a platform for future rational design of novel therapeutic leads.
Unravelling the glycome in human intervertebral disc degeneration: Aberrant glycosylation modulates inflammation and metabolism
Authors: Joyce Kieran , Scheper Aert F. , Phyo Aung Myat , O’Flaherty Roisin , Drake Richard , Devitt Aiden , Marchetti-Deschmann Martina , Saldova Radka , Pandit Abhay
Published: March 2024

Intervertebral disc (IVD) degeneration is one of the major contributing causes of low back pain (LBP), a common health issue that imposes a significant socio-economic burden on society. Previous work has demonstrated a dysregulated glycome in animal models of IVD degeneration; however, the role of glycosylation in pathogenesis is unknown. The objective of this study was to characterise altered glycan expression in IVD degeneration and elucidate the functional role of this response. Glycans in human healthy (n=6) and degenerated IVD (n=6) were examined through UPLC-MS and MALDI-IMS. These findings were correlated with proteomic analysis by LC-MS and functionalin vitrostudies using RNA sequencing. IVD degeneration was associated with a hypersialylatedN-glycome, predominantly α-2,6 linked sialic acid. Confirming hypersialylation, we investigated sialylation’s functional role through mechanistic studies using a sialylation inhibitor (3Fax-peracetyl Neu5Ac). Sialylation inhibitionin vitromodulated inflammatory and metabolic pathways, demonstrating a functional role for glycosylation in IVD degeneration.

Brief summary

IVD degeneration is associated with altered glycosylation, a potential target for new therapies.
Frequency-specific changes in prefrontal activity associated with maladaptive belief updating in volatile environments in euthymic bipolar disorder
Authors: Ivanova Marina , Germanova Ksenia , Dmitry Petelin , Ragimova Aynur , Kopytin Grigory , Volel Beatrice , Nikulin Vadim , Ruiz Maria Herrojo
Published: March 2024

Bipolar disorder (BD) involves altered reward processing and decision-making, with inconsistencies across studies. Here, we integrated hierarchical Bayesian modelling with magnetoencephalography (MEG) to characterise maladaptive belief updating in this condition. First, we determined if previously reported increased learning rates in BD stem from a heightened expectation of environmental changes. Additionally, we examined if this increased expectation speeds up belief updating in decision-making, associated with modulation of rhythmic neural activity within the prefrontal, orbitofrontal, and anterior cingulate cortex (PFC, OFC, ACC). Twenty-two 22 euthymic BD and 27 healthy control (HC) participants completed a reward-based motor decision-making task in a volatile setting. Hierarchical Bayesian modelling revealed BD participants anticipated greater environmental volatility, resulting in a more stochastic mapping from beliefs to actions and paralleled by lower win rates and a reduced tendency to repeat rewarded actions than HC. Despite this, BD individuals adjusted their expectations of action-outcome contingencies more slowly, but both groups invigorated their actions similarly. On a neural level, while healthy individuals exhibited an alpha-beta suppression and gamma increase during belief updating, BD participants showed dampened effects, extending across the PFC, OFC, and ACC regions. This was accompanied by an abnormally increased beta-band directed information flow in BD. Overall, the results suggest euthymic BD individuals anticipate environmental change without adequately learning from it, contributing to maladaptive belief updating. Alterations in frequency-domain amplitude and functional connectivity within the PFC, OFC, and ACC during belief updating underlie the computational effects and could serve as potential indicators for predicting relapse in future research.
The homeobox transcription factor Cux1 coordinates postnatal epithelial developmental timing but is dispensable for lung organogenesis and regeneration
Authors: Zhao Barbara , Socha Jacob , Toth Andrea , Fernandes Sharlene , Warheit-Niemi Helen , Ruff Brandy , Khurana Hershey Gurgit K , VanDussen Kelli , Swarr Daniel , Zacharias William J.
Published: March 2024

Lung epithelial progenitors use a complex network of known and predicted transcriptional regulators to influence early lung development. Here, we evaluate the function of one predicted regulator, Cux1, that we identified from transcriptional regulatory analysis of the SOX9+distal lung progenitor network. We generated a new Cux1-floxed mouse model and created an epithelial-specific knockout of Cux1 using Shh-Cre (Cux1ShhCre-LOF). Postnatal Cux1ShhCre-LOFanimals recapitulate key skin phenotypic features found in prior constitutive Cux1 knockout animals, confirming functionality of the new floxed model. Postnatal Cux1ShhCre-LOFmice displayed subtle alveolar simplification and a transient delay in alveologenesis without persistent lung phenotypes or alterations in lung epithelial cell allocation. Cux1ShhCre-LOFmice developed failure to thrive in their second and third weeks of life due to delayed ileal maturation, which similarly resolves by postnatal day 35. Finally, we challenged Cux1ShhCre-LOFwith influenza-mediated lung injury to demonstrate that Cux1ShhCre-LOFmice undergo productive alveolar regeneration that is indistinguishable from WT animals. Together, these findings indicate that epithelial-specific loss of Cux1 leads to transient developmental delays in the skin, lung, and intestine without defects in definitive organogenesis.

One-Sentence Summary

Deletion of key DNA binding domains leads to loss of Cux1 function in the lung, intestine, and skin characterized by transient failure to thrive without significant adult disease.
Integration of CTCF Loops, Methylome, and Transcriptome in Differentiating LUHMES as a Model for Imprinting Dynamics of the 15q11-q13 Locus in Human Neurons
Authors: Fugon Orangel J Gutierrez , Sharifi Osman , Heath Nicholas G , Soto Daniela C , Gomez J. Antonio , Yasui Dag H , Mendiola Aron Judd P. , O'Geen Henriette , Beitnere Ulrika , Tomkova Marketa , Haghani Viktoria , Dillon Greg , Segal David J , LaSalle Janine
Published: March 2024

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
Effects of early life adversity and adolescent basolateral amygdala activity on corticolimbic connectivity and anxiety behaviors
Authors: Cody Caitlyn R. , Artur de la Villarmois Emilce , Miguelez Fernandez Anabel , Lardizabal Janelle , McKnight Chaney , Tseng Kuei , Brenhouse Heather C.
Published: March 2024

Early postnatal development of corticolimbic circuitry is shaped by the environment and is vulnerable to early life challenges. Prior work has shown that early life adversity (ELA) leads to hyperinnervation of glutamatergic basolateral amygdala (BLA) projections to the prefrontal cortex (PFC) in adolescence. While hyperinnervation is associated with later-life anxiety behaviors, the physiological changes underpinning corticolimbic and behavioral impacts of ELA are not understood. We tested whether postsynaptic BLA-driven PFC activity is enhanced in ELA-exposed animals, using the maternal separation (MS) model of ELA. PFC local-field potential following BLA stimulation was facilitated in MS-exposed adolescents. Since ELA increases activity of the early-developing BLA, while the PFC exhibits protracted development, we further examined impacts of glutamatergic BLA activity during early adolescence on later-life PFC innervation and heightened anxiety. In early adolescence, MS-exposed animals exhibited decreased anxiety-like behavior, and acute adolescent BLA inhibition induced behaviors that resembled those of MS animals. To examine long-lasting impacts of adolescent BLA activity on innervation, BLA-originating axonal boutons in the PFC were quantified in late adolescence after early adolescent BLA inhibition. We further tested whether late adolescent BLA-PFC changes were associated with anxious reactivity expressed as heightened acoustic startle responses. MS rearing increased BLA-PFC innervation and threat reactivity in late adolescence, however early adolescent BLA inhibition was insufficient to prevent MS effects, suggesting that earlier BLA activity or post-synaptic receptor rearrangement in the PFC drives altered innervation. Taken together, these findings highlight both pre- and postsynaptic changes in the adolescent BLA-PFC circuit following ELA.
Mapping the genomic landscape of peach and almond with PrunusMap
Authors: Ksouri Najla , Moreno María Ángeles , Contreras-Moreira Bruno , Gogorcena Yolanda
Published: March 2024

High throughput sequencing is accelerating plant breeding. Genotyping, quantitative trait locus or genome-wide association analyses are essential to locate alleles of interest in germplasm collections. These applications require accurately mapping nucleotide markers within growing collections of reference genome sequences. PrunusMap (https://prunusmap.eead.csic.es) is a user-friendly Web application designed to facilitate these tasks toPrunusbreeders. It efficiently aligns markers and locates SNPs on peach and almond genomes, providing lists of nearby genes and curated proteins. It can align all markers from a genetic map in one step, producing their physical positions. By searching multiple maps, it can also solve the problem of finding equivalent gene identifiers across different annotations. Three intuitive tools, “Find markers”, “Align sequences” and “Locate by position”, are available to accelerate mapping analyses, particularly for users with limited bioinformatics expertise. New genomes, annotations or marker sets will be added based on their interest to the community.
Exploring dynamic brain oscillations in motor imagery and low-frequency sound
Authors: Dupont W. , Poulin-Charronnat B. , Madden-Lombardi C. , Jacquet T. , Pfister P. , Dos Anjos T. , Lebon F.
Published: March 2024

While both motor imagery (MI) and low-frequency sound listening have independently demonstrated the ability to modulate brain activity, there remains an unexplored frontier regarding the potential synergistic effects that may arise from their combined application. Any further modulation derived from this combination may be relevant for motor learning and/or rehabilitation. We conducted an experiment probing the electrophysiological activity of brain during these processes. By means of EEG, we recorded alpha and beta band power amplitude, which serve as markers of brain activity. Twenty volunteers were instructed to i) explicitly imagine finger flexion/extension movements in a kinaesthetic modality, ii) listen to low-frequency sounds, iii) imagine finger flexion while listening to low-frequency sounds, and iv) stay at rest. We observed a bimodal distribution, suggesting the presence of variability in brain activity across participants during both MI and low-frequency sound listening. One group of participants (12 individuals) displayed increased alpha power within contralateral sensorimotor and ipsilateral medial parieto-occipital regions during MI. Another group (8 individuals) exhibited a decrease in alpha and beta band power within sensorimotor areas. Interestingly, low-frequency sound listening elicited a similar pattern of brain activity within both groups. Surprisingly, the combination of MI and sound listening did not result in additional changes in alpha and beta power amplitudes compared to these processes in isolation, regardless of group. Altogether, these findings shed significant insight into the brain activity and its variability generated during MI and low-frequency sound listening. Nevertheless, it appears that the simultaneous engagement of MI and low-frequency sound listening could not further modulate alpha power amplitude, possibly due to concurrent cortical activations. This prompts us to inquire whether administering these interventions sequentially could uncover any additional modulation.
Multitasking practice eliminates modality-based interference by separating task representations in sensory brain regions
Authors: Mueckstein Marie , Görgen Kai , Heinzel Stephan , Granacher Urs , Rapp Michael A. , Stelzel Christine
Published: March 2024

The debate on the neural basis of multitasking costs evolves around neural overlap between concurrently performed tasks. Recent evidence suggests that training-related reductions in representational overlap in fronto-parietal brain regions predict multitasking improvements. Cognitive theories assume that overlap of task representations may lead to unintended information exchange between tasks (i.e., crosstalk). Modality-based crosstalk was suggested as a source for multitasking costs in multisensory settings. Robust findings of increased costs for certain modality mappings may be explained by crosstalk between the stimulus modality in one task and sensory action consequences in the concurrently performed task. Whether modality-based crosstalk emerges from representational overlap in general fronto-parietal multitasking regions or modality-specific regions is not known yet. In this functional neuroimaging study, we investigate neural overlap in multitasking performance, focusing on modality compatibility by employing multivariate pattern analysis and modality-specific practice interventions in three groups (total N = 54). We observed significant differences between modality compatible and modality incompatible single-task representations, specifically in the auditory cortex but not in fronto-parietal regions. Notably, improved auditory decoding accuracy related to modality incompatible tasks was predictive of performance gains in the corresponding dual task along with complete elimination of modality-specific dual-task costs. This predictive relationship was evident only in the group practicing modality incompatible mappings, suggesting that specific practice on task sets with modality overlap influenced both neural representations and subsequent multitasking performance. This study contributes to the integration of cognitive theory and neuroscience and the role of task representations in dual-task interference.

Significance

In a society dominated by multitasking, understanding its neurocognitive basis and plasticity is crucial for key aspects of work-related and everyday tasks. We investigate the neural mechanisms behind multitasking limitations, offering insights for targeted cognitive interventions. The study builds upon established theories of cognitive multitasking and imaging research, addressing the concept of modality-based crosstalk - the unintended exchange of modality-based information between tasks. Through functional brain imaging and pattern analysis, we examined how neural task representations contribute to performance costs in dual tasks with varying degrees of modality overlap. Notably, our findings demonstrate a practice-related decrease in neural overlap which is associated with substantial multitasking improvements, specifically in the auditory cortex, emphasizing the contribution of sensory regions to flexible multidimensional task representations.
HIPI: Spatially Resolved Multiplexed Protein Expression Inferred from H&E WSIs
Authors: Zeira Ron , Anavy Leon , Yakhini Zohar , Rivlin Ehud , Freedman Daniel
Published: March 2024

Solid tumors are characterized by complex interactions between the tumor, the immune system and the microenvironment. These interactions and intra-tumor variations have both diagnostic and prognostic significance and implications. However, quantifying the underlying processes in patient samples requires expensive and complicated molecular experiments. In contrast, H&E staining is typically performed as part of the routine standard process, and is very cheap. Here we present HIPI (H&E Image Interpretation and Protein Expression Inference) for predicting cell marker expression from tumor H&E images. We process paired H&E and CyCIF images taken from serial sections of colorectal cancers to train our model. We show that our model accurately predicts the spatial distribution of several important cell markers, on both held-out tumor regions as well as new tumor samples taken from different patients. Moreover, using only the tissue image morphology, HIPI is able to colocalize the interactions between different cell types, further demonstrating its potential clinical significance.
Micron-resolution fiber mapping in histology independent of sample preparation
Authors: Georgiadis Marios , auf der Heiden Franca , Abbasi Hamed , Ettema Loes , Nirschl Jeffrey , Moein Taghavi Hossein , Wakatsuki Moe , Liu Andy , Ho William Hai Dang , Carlson Mackenzie , Doukas Michail , Koppes Sjors A. , Keereweer Stijn , Sobel Raymond A. , Setsompop Kawin , Liao Congyu , Amunts Katrin , Axer Markus , Zeineh Michael , Menzel Miriam
Published: March 2024

Detailed knowledge of the brain’s nerve fiber network is crucial for understanding its function in health and disease. However, mapping fibers with high resolution remains prohibitive in most histological sections because state-of-the-art techniques are incompatible with their preparation. Here, we present a micron-resolution light-scattering-based technique that reveals intricate fiber networks independent of sample preparation for extended fields of view. We uncover fiber structures in both label-free and stained, paraffin-embedded and deparaffinized, newly-prepared and archived, animal and human brain tissues – including whole-brain sections from the BigBrain atlas. We identify altered microstructures in demyelination and hippocampal neurodegeneration, and show key advantages over diffusion magnetic resonance imaging, polarization microscopy, and structure tensor analysis. We also reveal structures in non-brain tissues – including muscle, bone, and blood vessels. Our cost-effective, versatile technique enables studies of intricate fiber networks in any type of histological tissue section, offering a new dimension to neuroscientific and biomedical research.
Baselining the Buzz Trastuzumab-HER2 Affinity, and Beyond
Authors: Chinery Lewis , Hummer Alissa M. , Mehta Brij Bhushan , Akbar Rahmad , Rawat Puneet , Slabodkin Andrei , Quy Khang Le , Lund-Johansen Fridtjof , Greiff Victor , Jeliazkov Jeliazko R. , Deane Charlotte M.
Published: March 2024

1

There is currently considerable interest in the field ofde novoantibody design, and deep learning techniques are now regularly applied to optimise antibody properties such as binding affinity. However, robust baselines within this field have not kept up with recent developments.

In this study, we generate a dataset of over 524,000 Trastuzumab variants and use this to show that standard computational methods such as BLOSUM, AbLang, ESM, and Protein-MPNN can be used to design diverse antibody libraries from just a single starting sequence. These novel libraries are predicted to be enriched in binding variants and experimental validation of 700 of these designs is ongoing. We also demonstrate that, even with only a very small number of experimental data points, simple machine learning classifiers can be trained in seconds to accurately pre-screen future designs. This pre-screening maintains library diversity and saves experimental time and money.
Capture of Human Neuromesodermal and Posterior Neural Tube Axial Stem Cells
Authors: Kelle Dolunay , Ugur Enes , Rusha Ejona , Shaposhnikov Dmitry , Livigni Alessandra , Horschitz Sandra , Davoudi Mahnaz , Blutke Andreas , Bushe Judith , Sterr Michael , Arkhipova Ksenia , Tak Benjamin , de Vries Ruben , Hochane Mazène , Spruijt Britte , Ali Aicha Haji , Lickert Heiko , Feuchtinger Annette , Koch Philipp , Mann Matthias , Leonhardt Heinrich , Wilson Valerie , Drukker Micha
Published: March 2024

The spinal cord, nerves, and skeletal muscles arise from neuromesodermal progenitors (NMPs). We have developed a growth-factor screening strategy, utilizing ES and iPS cells, facilitating the indefinite self-renewal of two types of human axial stem cells (AxSCs), closely resembling mouse NMPs (NM-AxSCs) and posterior neural tube progenitors (N-AxSCs). Under specific regimens— Wnt/CHIR99021, FGF2, and TGF-β inhibitor SB431542 (CFS) and excluding FGF2 (CS), respectively—these AxSCs self-renew and sustain telomeres. Single cell transcriptomics and proteomics have revealed expression of posterior growth-zone and dorsoventral neural tube markers in NM-AxSCs, and correspondingly, differentiation to a wide spectrum of neural tube neurons and myocytes. N-AxSCs rapidly matured into dorsal sensory subsets and neural crest. Crucially, neither AxSC type produces teratomas, and analogous mouse NM-AxSCs integrated successfully into the neural tube and somites. Capturing of AxSCs from patient and GMP ES / iPS cells without transgenesis unveils ontogeny and promises modeling and therapy in neuropathies.