bluuebunny/crossref_metadata_2025 huggingface dataset:
EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory of a predatory trait
Authors: Quiobe Shiela Pearl , Kalirad Ata , Röseler Waltraud , Witte Hanh , Wang Yinan , Rödelsperger Christian , Sommer Ralf J.
Published: September 2024

Environmental influences on traits and associated transgenerational epigenetic inheritance have widespread implications, but remain controversial and underlying mechanisms poorly understood. We introduce long-term environmental induction experiments on alternative diets inPristionchus pacificus, a nematode exhibiting mouth-form plasticity including predation, by propagating 110 isogenic lines for 101 generations with associated food-reversal experiments. We found dietary induction and subsequent transgenerational memory of the predatory morph and identified a role of ubiquitin ligase EBAX-1/ZSWIM8 in this process.Ppa-ebax-1mutants have no memory andPpa-EBAX-1 destabilizes the clustered microRNA familymiR-2235a/miR-35.Deletions of a cluster of 44 identicalmiR-2235acopies resulted in precocious and extended transgenerational inheritance of the predatory morph. These findings indicate that EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory, suggesting a role for target-directed miRNA degradation.
BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression
Authors: Bell Caitlin F. , Baylis Richard A. , Lopez Nicolas G. , Ma Wei Feng , Gao Hua , Wang Fudi , Bamezai Sharika , Fu Changhao , Kojima Yoko , Adkar Shaunak S. , Luo Lingfeng , Miller Clint L. , Leeper Nicholas J.
Published: September 2024

Background

Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment.

Methods and Results

We use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to ‘resolution phase’ M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect.

Conclusion

As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.
Operant conditioning of cortical waves through a brain-machine interface
Authors: Dogadov Anton A. , Shulz Daniel E. , Ferezou Isabelle , Ego-Stengel Valérie , Estebanez Luc
Published: September 2024

At the surface of the cerebral cortex, activity dynamics measured at a mesoscopic (about 0.1 to 1 mm in mouse cortex) scale are characterized by both spontaneous and behavior-related dynamical waves of synchronized neuronal activity. These waves are thought to participate in information propagation and processing, but remain poorly understood.

To assess if such mesoscopic coordinated neuronal dynamics can be controlled in a goal-directed manner, we implemented a task in which mice are trained to generate waves with specific trajectories in order to obtain rewards. We tracked propagating waves at the surface of the somatosensory-motor cortex of head-fixed mice in real time by means of wide field calcium imaging, and conditioned the delivery of rewards to the detection of wave trajectories responding to specific spatiotemporal criteria.

We found that the majority of the trained mice significantly increased their performance, mainly by increasing the frequency of rewardable waves. As the mice learned to achieve this task, we observed changes in the spatiotemporal patterns of the cortical waves. By revealing that, upon learning, neuronal activity can be shaped at the mesoscopic scale to generate specific waves patterns, our work opens up new perspectives for brain-machine interfacing.
Prediction of Protein Half-lives from Amino Acid Sequences by Protein Language Models
Authors: Sagawa Tatsuya , Kanao Eisuke , Ogata Kosuke , Imami Koshi , Ishihama Yasushi
Published: September 2024

We developed a protein half-life prediction model, PLTNUM, based on a protein language model using an extensive dataset of protein sequences and protein half-lives from the NIH3T3 mouse embryo fibroblast cell line as a training set. PLTNUM achieved an accuracy of 71% on validation data and showed robust performance with an ROC of 0.73 when applied to a human cell line dataset. By incorporating Shapley Additive Explanations (SHAP) into PLTNUM, we identified key factors contributing to shorter protein half-lives, such as cysteine-containing domains and intrinsically disordered regions. Using SHAP values, PLTNUM can also predict potential degron sequences that shorten protein half-lives. This model provides a platform for elucidating the sequence dependency of protein half-lives, while the uncertainty in predictions underscores the importance of biological context in influencing protein half-lives.
Mapping and Modeling Age-Related Changes in Intrinsic Neural Timescales
Authors: Wu Kaichao , Gollo Leonardo Lyra
Published: September 2024

Intrinsic timescales of brain regions exhibit heterogeneity, escalating with hierarchical levels, and are crucial for the temporal integration of external stimuli. Normal aging, often associated with cognitive deficits, involves progressive neuronal and synaptic loss, shaping brain structure and dynamics. The impact of these structural changes on temporal integration coding in the aged brain remains largely unknown. To address this gap, we mapped differences in intrinsic timescales and gray matter volume (GMV) within brain regions using magnetic resonance imaging (MRI) in young and elderly adults. We found shorter intrinsic timescales across multiple large-scale functional networks in the elderly cohort, and a significant positive association between intrinsic timescales and GMV. Additionally, age-related decline in performance on a visual discrimination task was linked to a reduction in intrinsic timescales in the cuneus. To explain these age-related changes in GMV and intrinsic timescales, we propose an age-dependent model of spiking neuron networks. In younger subjects, brain regions were modeled in a near-critical branching regime, while in elderly subjects, regions had fewer neurons and synapses, pushing the dynamics toward a more subcritical regime. The empirical results were reproduced by the model: Neuronal networks representing brain regions in young subjects exhibited longer intrinsic timescales due to critical slowing down. These findings reveal how age-related structural brain changes may drive alterations in brain dynamics, offering testable predictions and informing future interventions for cognitive decline.
A high-throughput phenotypic screen combined with an ultra-large-scale deep learning-based virtual screening reveals novel scaffolds of antibacterial compounds
Authors: Scalia Gabriele , Rutherford Steven T. , Lu Ziqing , Buchholz Kerry R. , Skelton Nicholas , Chuang Kangway , Diamant Nathaniel , Hütter Jan-Christian , Luescher Jerome-Maxim , Miu Anh , Blaney Jeff , Gendelev Leo , Skippington Elizabeth , Zynda Greg , Dickson Nia , Koziarski Michał , Bengio Yoshua , Regev Aviv , Tan Man-Wah , Biancalani Tommaso
Published: September 2024

The proliferation of multi-drug-resistant bacteria underscores an urgent need for novel antibiotics. Traditional discovery methods face challenges due to limited chemical diversity, high costs, and difficulties in identifying structurally novel compounds. Here, we explore the integration of small molecule high-throughput screening with a deep learning-based virtual screening approach to uncover new antibacterial compounds. Leveraging a diverse library of nearly 2 million small molecules, we conducted comprehensive phenotypic screening against a sensitizedEscherichia colistrain that, at a low hit rate, yielded thousands of hits. We trained a deep learning model, GNEprop, to predict antibacterial activity, ensuring robustness through out-of-distribution generalization techniques. Virtual screening of over 1.4 billion compounds identified potential candidates, of which 82 exhibited antibacterial activity, illustrating a 90X improved hit rate over the high-throughput screening experiment GNEprop was trained on. Importantly, a significant portion of these newly identified compounds exhibited high dissimilarity to known antibiotics, indicating promising avenues for further exploration in antibiotic discovery.
Pro-inflammatory mediators sensitise Transient Receptor Potential Melastatin 3 cation channel (TRPM3) signalling in mouse sensory neurons
Authors: Aguilera-Lizarraga Javier , Lim Tony K. , Pattison Luke A. , Paine Luke W. , Bulmer David C. , Smith Ewan St. John
Published: September 2024

Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can potentiate or sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel’s role in inflammatory pain, the mechanisms driving its sensitisation during inflammation remain poorly understood. Here, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests post-translational modification occurs. Finally, using the model of complete Freund’s adjuvant-induced knee inflammation, we found that pharmacological blockade of TRPM3 does not alleviate inflammatory pain, which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.

Abstract Figure

Graphical abstract
Calculating and Reporting Coefficients of Variation for DIA-based Proteomics
Authors: Brenes Alejandro J.
Published: September 2024

The Coefficient of Variation (CV) is a measure that is frequently used to assess data dispersion for mass spectrometry-based proteomics. In the current era of burgeoning technical developments, there has been an increased focus on using CVs to measure the quantitative accuracy of the new methods. Thus, it has also become important to define a set of guidelines on how to calculate and report the CVs.This perspective shows the effects that the CV equation, as well as software parameters can have on data dispersion and CVs, highlighting the importance of reporting all these variables within the methods section. It also proposes a set of recommendations to calculate and report CVs for technical studies where the main objective is to benchmark technical developments with a focus on precision. To assist in this process a novel R package to calculate CVs ( proteomicsCV ) is also included.
DYF-5 regulates intraflagellar transport by affecting train turnaround
Authors: Mul Wouter , Mitra Aniruddha , Prevo Bram , Peterman Erwin J.G.
Published: September 2024

Intraflagellar transport (IFT) coordinates the transport of cargo in cilia and is essential for ciliary function. CILK1 has been identified as a key regulator of IFT. The mechanism by which it acts has, however, remained unclear. In this study, we use fluorescence imaging and single-molecule tracking in the phasmid cilia of liveC. elegansto study the effect of the CILK1 homolog DYF-5 on the dynamics of the IFT. We show that in the absence of DYF-5, IFT components accumulate at the ciliary tip. kinesin-II is no longer restricted to the proximal segment of the cilium but is present all throughout the cilium, while its velocity is different from that of OSM-3. The frequency of IFT trains is reduced and in particular retrograde trains were rarely observed. In the absence of DYF-5, retrograde transport is vastly reduced, resulting in the accumulation of IFT components at the tip and depletion at the base. The latter results in impeded anterograde train assembly, resulting in fewer trains with irregular composition. Our results show that DYF-5 plays a key role in regulating the turnarounds of IFT trains at the ciliary tip.
Nutritional analysis of commercially available, complete plant- and meat-based dry dog foods in the UK
Authors: Brociek R.A. , Li D. , Broughton R. , Gardner D.S.
Published: September 2024

Background

Adoption of a plant-based diet is a popular lifestyle choice for many owners of canine companion animals. Increasingly, owners would like to feed their canine companions a similar diet. A plant-based dietary pattern has been reported to be associated with some micronutrient deficiencies. Complete dog foods are, by definition, supposed to be nutritionally replete in all macro- and micronutrients. Few studies have reported a full nutritional analysis of complete, dry plant-versus meat-based dog foods.

Method

Here, 31 pet foods (n=19 meat-based, n=6 veterinary and n=6 plant-based) were analysed for total protein content and individual amino acids, fatty acids, major and trace elements, vitamin D and all B-vitamins.

Results

Nutritional composition of meat and plant-based foods were similar, except for iodine and B-vitamins, which were lower in plant-based foods. The majority (66%) of veterinary diets with lower total protein by design, were also deficient in one or more essential amino acids. Isolated instances of non-compliance to nutritional guidelines were observed across all food-groups. Of the tested nutrients 55%, 16%, 24% and 100% of foods met all amino acid, mineral, B-vitamin, and vitamin D guidelines, respectively.

Conclusions

Adopting a plant-based dietary pattern for your companion canine can provide nutritional adequacy with respect to the majority of macro- and micronutrients, but feeding supplemental iodine and B-vitamins should be considered. Veterinary diets, purposely low in crude protein, often have less than optimal essential amino acid composition. These data provide important new information for owners of companion canines being fed plant-based or veterinary diets.
SVbyEye: A visual tool to characterize structural variation among whole-genome assemblies
Authors: Porubsky David , Guitart Xavi , Yoo DongAhn , Dishuck Philip C. , Harvey William T. , Eichler Evan E.
Published: September 2024

Motivation We are now in the era of being able to routinely generate highly contiguous (near telomere-to-telomere) genome assemblies of human and nonhuman species. Complex structural variation and regions of rapid evolutionary turnover are being discovered for the first time. Thus, efficient and informative visualization tools are needed to evaluate and directly observe structural differences between two or more genomes. Results We developed SVbyEye, an open-source R package to visualize and annotate sequence-to-sequence alignments along with various functionalities to process alignments in PAF format. The tool facilitates the characterization of complex structural variants in the context of sequence homology helping resolve the mechanisms underlying their formation. Availability and implementation SVbyEye is available at https://github.com/daewoooo/SVbyEye.
Transcriptomic and Multi-scale Network Analyses Reveal Key Drivers of Cardiovascular Disease
Authors: Tumenbayar Bat-Ider , Pham Khanh , Biber John C. , Drewes Rhonda , Bae Yongho
Published: September 2024

Cardiovascular diseases (CVDs) and pathologies are often driven by changes in molecular signaling and communication, as well as in cellular and tissue components, particularly those involving the extracellular matrix (ECM), cytoskeleton, and immune response. The fine-wire vascular injury model is commonly used to study neointimal hyperplasia and vessel stiffening, but it is not typically considered a model for CVDs. In this paper, we hypothesize that vascular injury induces changes in gene expression, molecular communication, and biological processes similar to those observed in CVDs at both the transcriptome and protein levels. To investigate this, we analyzed gene expression in microarray datasets from injured and uninjured femoral arteries in mice two weeks post-injury, identifying 1,467 significantly and differentially expressed genes involved in several CVDs such as including vaso-occlusion, arrhythmia, and atherosclerosis. We further constructed a protein-protein interaction network with seven functionally distinct clusters, with notable enrichment in ECM, metabolic processes, actin-based process, and immune response. Significant molecular communications were observed between the clusters, most prominently among those involved in ECM and cytoskeleton organizations, inflammation, and cell cycle. Machine Learning Disease pathway analysis revealed that vascular injury-induced crosstalk between ECM remodeling and immune response clusters contributed to aortic aneurysm, neovascularization of choroid, and kidney failure. Additionally, we found that interactions between ECM and actin cytoskeletal reorganization clusters were linked to cardiac damage, carotid artery occlusion, and cardiac lesions. Overall, through multi-scale bioinformatic analyses, we demonstrated the robustness of the vascular injury model in eliciting transcriptomic and molecular network changes associated with CVDs, highlighting its potential for use in cardiovascular research.
Biofabrication of engineered tissues by 3D bioprinting of tissue specific high cell-density bioinks
Authors: Jeon Oju , Park Hyoeun , Leach J. Kent , Alsberg Eben
Published: September 2024

Bioprinting of high cell-density bioinks is a promising technique for cellular condensation-based tissue engineering and regeneration medicine. However, it remains difficult to create precisely controlled complex structures and organization of tissues with high cell-density bioink-based bioprinting for tissue specific condensation. In this study, we present newly biofabricated tissues from directly assembled, tissue specific, high cell-density bioinks which have been three-dimensionally printed into a photocrosslinkable and biodegradable hydrogel microparticle supporting bath. Three types of tissue specific high cell-density bioinks have been prepared with individual stem cells or stem cell aggregates by incorporation of growth factor-loaded gelatin microparticles. The bioprinted tissue specific high cell-density bioinks in the photocrosslinked microgel supporting bath condense together and differentiate down tissue-specific lineages to form multi-phase tissues (e.g., osteochondral tissues). By changing the growth factors and cell types, these tissue specific high cell-density bioinks enable engineering of various functional tissues with controlled architecture and organization of cells.
Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease
Authors: Jacob Ikechukwu B. , Lawal Akinkunmi O. , Mahmoud Salma S. , Kopsack Emerson M. , Reynolds Erin S. , Meng Qinghe , Fan Hongkuan , Massa Paul T. , Thangamani Saravanan , Jia Hongpeng , Wang Guirong
Published: September 2024

Abstract

COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (SFTPA1andSFTPA2) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A2, 6A4) and SP-A2 (variants 1A0, 1A3). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infectionin vivo. Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A2(6A2), hACE2/6A4(6A4), hACE2/1A0(1A0), and hACE2/1A3(1A3), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 103PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A0mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A0, and 6A2mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such asMyD88,Stat3,IL-18, andJak2in the lungs of KO and 1A0mice. However,Mapk1was significantly downregulated in 6A2versus 1A0mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1β were comparatively higher in the lungs and sera of KO and 1A0mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.
Visually-evoked activity and variable modulation of auditory responses in the macaque inferior colliculus
Authors: Schmehl Meredith N. , Herche Jesse L. , Groh Jennifer M.
Published: September 2024

How multisensory cues affect processing in early sensory brain areas is not well understood. The inferior colliculus (IC) is an early auditory structure that is visually responsive (Porter et al. 2007; Bulkin and Groh 2012a, 2012b), but little is known about how visual signals affect the IC’s auditory representation. We explored how visual cues affect both spiking and local field potential (LFP) activity in the IC of two monkeys performing a task involving saccades to auditory, visual, or combined audiovisual stimuli. We confirm that LFPs are sensitive to the onset of fixation lights as well as the onset of visual targets presented during steady fixation. The LFP waveforms evoked by combined audiovisual stimuli differed from those evoked by sounds alone. In single-unit spiking activity, responses were weak when visual stimuli were presented alone, but visual stimuli could modulate the activity evoked by sounds in a stronger way. Such modulations could involve either increases or decreases in activity, and whether increases or decreases were observed was variable and not obviously correlated with the responses evoked by visual or auditory stimuli alone. These findings indicate that visual stimuli shape the IC’s auditory representation in flexible ways that differ from those observed previously in multisensory areas.

New & Noteworthy

We find that the inferior colliculus, a primarily auditory brain area, displays distinct population-level responses to visual stimuli. We also find that visual cues can influence the auditory responses of individual neurons. Together, the results provide insight into how relatively early sensory areas may play a role in combining multiple sensory modalities to refine the perception of complex environments.
Neuro-musculoskeletal modeling reveals muscle-level neural dynamics of adaptive learning in sensorimotor cortex
Authors: DeWolf Travis , Schneider Steffen , Soubiran Paul , Roggenbach Adrian , Mathis Mackenzie
Published: September 2024

The neural activity of the brain is intimately coupled to the dynamics of the body. Yet how our hierarchical sensorimotor system dynamically orchestrates the generation of movement while adapting to incoming sensory information remains unclear. In mice, the extent of encoding from posture to muscle-level features across the motor (M1) and primary sensory forelimb (S1) cortex and how these are shaped during learning are unknown. To address this, we built a large-scale model that captures hypothesized neural computations and use this to control a novel 50-muscle model of the adult forelimb amenable to studying motor control and learning in a physics simulation environment. We show that we can imitate 3D limb kinematics collected during a joystick task by solving inverse kinematics and deriving a sensorimotor control model that drives the same actions. Using the internal computations from our model, we find that populations of layer 2/3 M1 and S1 neurons encode high-level position, and lower-level muscle space and proprioceptive dynamics. During adaptive learning, these functionally distinct neurons map onto specific computational motifs. Strikingly, S1 neurons more prominently encode sensorimotor prediction errors. Moreover, we find that neural latent dynamics differentially change in S1 vs. M1 during this within-session learning. Together, our results provide a new model of how neural dynamics in cortex enables adaptive learning.
Distinct roles of general anesthesia activated CeA neurons in acute versus late phase of neuropathic pain
Authors: Zhao Junli , Furutani Kenta , McGinnis Aidan , Mathew Joseph P , Wang Fan , Ji Ru-Rong
Published: September 2024

A previous study discovered a distinct population of GABAergic neurons in thecentralamygdala (CeA) that can be activated bygeneralanesthesia (CeAGA) and exert analgesic functions (Hua et al., 2020). To independently reproduce these prior findings and to investigate the electrophysiological properties of CeAGAneurons, we first used 1.2% isoflurane to induce c-Fos activation in the mouse brain and validated theFosexpression by RNAscopein situhybridization. Indeed, isoflurane induced robust Fos expression in CeA and these Fos+CeAGAneurons are GABAergic neurons (Vgat+). We next used Fos-TRAP2 method (different from the CANE method used in the prior study) to label CeAGAneurons (tdTomato+). Ourex vivoelectrophysiological recordings in brain slices revealed that compared to Fos-negative CeA neurons, CeAGAneurons had significantly higher excitability and exhibited distinct patterns of action potentials. Chemogenetic activation of Fos-TRAPed CeAGAneurons was effective at increasing pain thresholds in naïve mice and mice with early-phase neuropathic pain 2 weeks after spared nerve injury (SNI). However, the same chemogenetic activation of CeAGAneurons only had modest analgesia in the late phase of SNI at 8 weeks, although it was highly effective in reducing chronic pain-associated anxiety behaviors at this stage. We found that Fos-negative CeA neurons, but not CeAGAneurons, exhibited increased excitability in the late-phase of SNI, suggesting that chronic pain causes a shift in the relative activity of the CeA microcircuit. Interestingly, Fos-negative neurons exhibited much higher expression of K+-Cl−cotransporter-2 (KCC2), and KCC2 expression was downregulated in the CeA in the late-phase of neuropathic pain. These results support the idea that targeting CeAGAneurons may provide therapeutic benefits for pain relief and chronic pain-associated anxiety. Our findings also suggest distinct roles of CeAGAneurons in regulating physiological pain, acute pain, and chronic pain with a possible involvement of KCC2.
Direct and indirect genetic pathways between parental neuroticism and offspring emotional problems across development: evidence from 7 cohorts across 5 European nations
Authors: Sallis Hannah M. , Costantini Ilaria , Chuong Melisa T. , Kantojärvi Katri , Wootton Robyn E. , Jones Hannah J. , Sirignano Lea , Frank Josef , Streit Fabian , Witt Stephanie H. , Zillich Lea , Gilles Maria , Ask Helga , Kwong Alex S. F. , Adams Mark J , Tilling Kate , Lawlor Deborah A. , Timpson Nicholas J. , Paunio Tiina , Havdahl Alexandra , McIntosh Andrew M. , Stein Alan , James Deborah , Pearson Rebecca M.
Published: September 2024

Disentangling direct and indirect genetic pathways underlying the intergenerational transmission of emotional problems could guide preventative strategies and further the understanding of the role of parental mental health in children’s outcomes. This study aimed to estimate the extent to which genetic pathways that aredirect(via child genotype) andindirect(e.g., via parental phenotype) explain the well-established association between parent and child emotional problems. We leveraged data from seven European cohort studies with a combined population of Ntrios=15,475. Polygenic scores were calculated for parental and offspring neuroticism, as it represents a dispositional trait underlying emotional problems. Emotional problems in offspring were measured using validated scales across various developmental stages from early childhood to adulthood. We used neuroticism polygenic scores within a structural equation modelling framework to distinguish between direct genetic pathways from parental genotype to offspring outcome (acting through offspring genotype), and indirect genetic pathways (acting through parental phenotype and associated environment). Standard errors for direct genetic, indirect genetic and total effects were bootstrapped and meta-analyses pooled effect estimates at three developmental stages (childhood: 3-4 years, adolescence: 11-13 years, adulthood: 18+ years). We found evidence suggesting an indirect genetic pathway between mothers and child emotional problems during early childhood (pooled estimate, mean difference in standardised child emotional problems score per 1SD increase in maternal PGS for neuroticism=0.04, 95% CI: 0.01, 0.07). This association attenuated over child development, while direct genetic pathways strengthened. High attrition rates, measurement error and low variance explained by polygenic scores may have altered precision of the estimates, influencing the interpretation of the results. However, we provide the first multi-cohort study to provide evidence for anindirectgenetic pathway from maternal neuroticism to early child emotional problems. This suggests that there are likely processesotherthan direct genetic pathways involved in the intergenerational transmission of emotional problems, highlighting the importance of timely support to prevent and reduce emotional issues in mothers as a preventative strategy for emotional difficulties.
Exploring the intersection between orthostatic hypotension and daytime sleepiness in Parkinson’s disease
Authors: Mahajan Abhimanyu , Duque Kevin R. , Dwivedi Alok K. , Abanto Jesus , Marsili Luca , Hill Emily J. , Saraf Ameya , McDonald Kelsey J. , Arowosegbe Adebukunola , Deraz Heba A. , Bloemer Aaron , Espay Alberto J.
Published: September 2024

Introduction

Daytime sleepiness, reported in about 50% of patients with Parkinson’s disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and co-morbidites on this relationship is inadequate.

Methods

Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS; ESS score > 10). The primary exposure variable was orthostatic hypotension (OH). Linear and logistic regression analyses followed by moderated graphical network analyses were conducted to explore the complex association between OH and ESS. Edge weight from graphical network analysis indicates the strength of the association.

Results

Data on 453 subjects with PD were analyzed. Median disease duration was 5.8 years and nearly 90% were H&Y stage <3. OH was not associated with EDS. OH was associated with depression (edge weight, 0.22) in cognitively impaired patients but not in cognitively normal patients. In addition, depression was associated with ESS (edge weight, 0.37; moderation weight, 0.22) in cognitively impaired patients to a greater extent than in cognitively normal patients (edge weight, 0.22).

Conclusions

OH is not directly associated with daytime sleepiness in early, treated PD. However, OH seems to be associated with ESS via depression in cognitively impaired patients. This complex relationship deserves additional study.
Conspiratorial thinking in a 50-state survey of American adults
Authors: Perlis Roy H. , Uslu Ata , Barroilhet Sergio A. , Vohringer Paul A. , Santillana Mauricio , Baum Matthew A. , Druckman James N. , Ognyanova Katherine , Lazer David
Published: September 2024

Background

While the NIMH Research Domain Criteria framework stresses understanding how neuropsychiatric phenotypes vary across populations, little is known outside of small clinical cohorts about conspiratorial thoughts as an aspect of cognition.

Methods

We conducted a 50-state non-probability internet survey conducted in 6 waves between October 6, 2022 and January 29, 2024, with respondents age 18 and older. Respondents completed the American Conspiratorial Thinking Scale (ACTS) and the 9-item Patient Health Questionnaire (PHQ-9). Survey-weighted regression models were used to examine sociodemographic and clinical associations with ACTS score, and associations with vaccination status.

Results

Across the 6 survey waves, there were 123,781 unique individuals. After reweighting, a total of 78.6% of respondents somewhat or strongly agreed with at least one conspiratorial idea; 19.0% agreed with all four of them. More conspiratorial thoughts were reported among those age 25 - 54, males, individuals who finished high school but did not start or complete college, those with household income between $25,000 and $50,000 per year, and those who reside in rural areas, as well as those with greater levels of depressive symptoms. Endorsing more conspiratorial thoughts was associated with a significantly lower likelihood of being vaccinated against COVID-19.

Discussion

A substantial proportion of US adults endorsed at least some conspiratorial thinking, which varied widely across population subgroups. The extent of correlation with non-vaccination suggests the importance of considering such thinking in designing public health strategies.
Using correlative and mechanistic species distribution models to predict vector-borne disease risk for the current and future environmental and climatic change: a case study of West Nile Virus in the UK
Authors: Withers A. J. , Croft S. , Budgey R. , Warren D. , Johnson N.
Published: September 2024

Globally, vector-borne diseases have significant impacts on both animal and human health, and these are predicted to increase with the effects of climate change. Understanding the drivers of such diseases can help inform surveillance and control measures to minimise risks both now and in the future. In this study, we illustrate a generalised approach for assessing disease risk combining species distribution models of vector and wildlife hosts with data on livestock and human populations using the potential emergence of West Nile Virus (WNV) in the UK as a case study. Currently absent in the UK, WNV is an orthoflavivirus with a natural transmission cycle betweenCulexmosquitos (Cx. pipiensandCx. modestus) and birds. It can spread into non-target hosts (e.g., equids, humans) via mosquito bites where it can cause febrile disease with encephalitis and mortality in severe cases. We compared six correlative species distribution models and selected the most appropriate for each vector based on a selection of performance measures and compared this to mechanistic species distribution models and known distributions. We then combined these with correlative species distribution models of representative avian hosts, equines, and human population data to predict risk of WNV occurrence. Our findings highlighted areas at greater risk of WNV due to higher habitat suitability for both avian hosts and vectors, and considered how this risk could change by 2100 under a best-case Shared Socioeconomic Pathway (SSP1) and worst-case (SSP5) future climate scenario. Generally, WNV risk in the future was found to increase in south-eastern UK and decrease further north. Overall, this paper presents how current and future vector distributions can be modelled and combined with projected host distributions to predict areas at greater risk of novel diseases. This is important for policy decision making and contingency preparedness to enable adaptation to changing environments and the resulting shifts in vector-borne diseases that are predicted to occur.
Practice Reshapes the Geometry and Dynamics of Task-tailored Representations
Authors: Kikumoto Atsushi , Shibata Kazuhisa , Nishio Takahiro , Badre David
Published: September 2024

Extensive practice makes task performance more efficient and precise, leading to automaticity. However, theories of automaticity differ on which levels of task representations (e.g., low-level features, stimulus-response mappings, or high-level conjunctive memories of individual events) change with practice, despite predicting the same pattern of improvement (e.g., power law of practice). To resolve this controversy, we built on recent theoretical advances in understanding computations through neural population dynamics. Specifically, we hypothesized that practice optimizes the neural representational geometry of task representations to minimally separate the highest-level task contingencies needed for successful performance. This involves efficiently reaching conjunctive neural states that integrate task-critical features nonlinearly while abstracting over non-critical dimensions. To test this hypothesis, human participants (n = 40) engaged in extensive practice of a simple, context-dependent action selection task over 3 days while recording EEG. During initial rapid improvement in task performance, representations of the highest-level, context-specific conjunctions of task-features were enhanced as a function of the number of successful episodes. Crucially, only enhancement of these conjunctive representations, and not lower-order representations, predicted the power-law improvement in performance. Simultaneously, over sessions, these conjunctive neural states became more stable earlier in time and more aligned, abstracting over redundant task features, which correlated with offline performance gain in reducing switch costs. Thus, practice optimizes the dynamic representational geometry as task-tailored neural states that minimally tesselate the task space, taming their high-dimensionality.
Endogenous Regulator of G protein Signaling 14 (RGS14) suppresses cocaine-induced emotionally motivated behaviors in female mice
Authors: Bramlett Sara N. , Foster Stephanie L. , Weinshenker David , Hepler John R.
Published: September 2024

Addictive drugs hijack the neuronal mechanisms of learning and memory in motivation and emotion processing circuits to reinforce their own use. Regulator of G-protein Signaling 14 (RGS14) is a natural suppressor of post-synaptic plasticity underlying learning and memory in the hippocampus. The present study used immunofluorescence and RGS14 knockout mice to assess the role of RGS14 in behavioral plasticity and reward learning induced by chronic cocaine in emotional-motivational circuits. We report that RGS14 is strongly expressed in discrete regions of the ventral striatum and extended amygdala in wild-type mice, and is co-expressed with D1 and D2 dopamine receptors in neurons of the nucleus accumbens (NAc). Of note, we found that RGS14 is upregulated in the NAc in mice with chronic cocaine history following acute cocaine treatment. We found significantly increased cocaine-induced locomotor sensitization, as well as enhanced conditioned place preference and conditioned locomotor activity in RGS14-deficient mice compared to wild-type littermates. Together, these findings suggest that endogenous RGS14 suppresses cocaine-induced plasticity in emotional-motivational circuits, implicating RGS14 as a protective agent against the maladaptive neuroplastic changes that occur during addiction.
The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis
Authors: Pape Daniel J. , Falls-Hubert Kelly C. , Merrill Ronald A. , Ahmed Adnan , Qian Qingwen , McGivney Gavin R. , Sobieralski Paulina , Rauckhorst Adam J. , Yang Ling , Taylor Eric B.
Published: September 2024

Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and13C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.
Escaping the drug-bias trap: using debiasing design to improve interpretability and generalization of drug-target interaction prediction
Authors: Zhang Pei-Dong , Ma Jianzhu , Chen Ting
Published: September 2024

Considering the high cost associated with determining reaction affinities through in-vitro experiments, virtual screening of potential drugs bound with specific protein pockets from vast compounds is critical in AI-assisted drug discovery. Deep-leaning approaches have been proposed for Drug-Target Interaction (DTI) prediction. However, they have shown overestimated accuracy because of the drug-bias trap, a challenge that results from excessive reliance on the drug branch in the traditional drug-protein dual-branch network approach. This casts doubt on the interpretability and generalizability of existing Drug-Target Interaction (DTI) models. Therefore, we introduce UdanDTI, an innovative deep-learning architecture designed specifically for predicting drug-protein interactions. UdanDTI applies an unbalanced dual-branch system and an attentive aggregation module to enhance interpretability from a biological perspective. Across various public datasets, UdanDTI demonstrates outstanding performance, outperforming state-of-the-art models under in-domain, cross-domain, and structural interpretability settings. Notably, it demonstrates exceptional accuracy in predicting drug responses of two crucial subgroups of Epidermal Growth Factor Receptor (EGFR) mutations associated with non-small cell lung cancer, consistent with experimental results. Meanwhile, UdanDTI could complement the advanced molecular docking software DiffDock. The codes and datasets of UdanDTI are available athttps://github.com/CQ-zhang-2016/UdanDTI.
A case is not a case is not a case - challenges and solutions in determining urolithiasis caseloads using the digital infrastructure of a clinical data warehouse
Authors: Schönthaler Martin , Hempen Noah , Weymann Maria , von Bargen Maximilian Ferry , Glienke Maximilian , Elsässer Antonia , Behrens Max , Binder Harald , Binder Nadine
Published: September 2024

Background

To provide more evidence in urolithiasis research, we have established the German Nationwide Register for RECurrent URolithiasis (RECUR) using local clinical data warehouses (CDWH). For RECUR and other registers relying on digitalized clinical data, it is crucial to ensure the data’s reliability for answering scientific questions. In this work, we aim to compare the results of different CDWH-based queries on urolithiasis cases next to manual case extraction from the primary source.

Methods

Sources for data extraction included the Medical Center University of Freiburg (MCUF) hospital information system (HIS), MCUF performance data (a clinical data set with merged data from patients including data from vari-ous time points throughout their treatment), and MCUF reimbursement data. We extracted data on caseloads in urolithiasis algorithmically (performance and reimbursement data) and compared those to a reference group compiled of man-ually extracted data from the local HIS and algorithmically extracted data.

Results

Algorithmic extraction based on performance data resulted in correct and complete case identification as compared to the reference group. The case numbers from manual extraction from HIS data and algorithmic extraction from reimbursement data differed by 14% and 12%, respectively. The reasons for devi-ations in HIS data included human errors and a lack of data availability from different wards. Deviations in reimbursement data arose primarily due to the merging of cases in the context of reimbursement mechanisms. As the CDWH at MCUF is part of the German Medical Informatics Initiative (MII), the results can be transferred to other medical centers with similar CDWH structure.

Conclusions

The current study provides firm evidence of the importance of clearly defining a study’s target variable, e.g., urolithiasis cases, and a thorough understanding of the data sources and modes used to extract the target data. Our work clearly shows that, depending on various data sources, a case is not a case is not a case.