bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct pathogenic influence of anti-HMGCR+ and anti-SRP+ immune-mediated necrotizing myopathy autoantibodies on engineered muscle function
Authors: Lad Heta , Esteban Ernest Myguel , Tiper Yekaterina , Mahoudeau Alexandrine , Xie Zhuoye , Tendrel Berenice , Allenbach Yves , Benveniste Olivier , Gilbert Penney M.
Published: August 2024

Immune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies. However, the demonstration of a direct pathogenic effect of IMNM patient autoantibodies on skeletal muscle contractile force, independent of the downstream activation of the complement pathway, has yet to be reported. Thus, the goal of this study was to leverage a custom 3D-human skeletal muscle microtissue (hMMT) culture platform, that enables muscle cell contractile apparatus maturation and the analysis of contractile function, to evaluate the direct effect of total immunoglobulins (IgGs) isolated from IMNM patients with amplification of anti-SRP+or anti-HMGCR+autoantibodies. hMMTs capable of force generation were treated with total IgGs, isolated from 3 SRP+ and 3 HMGCR+ patients plasma, and delivered in complement inactivated media for 4 days. hMMT health was then evaluated by quantifying the peak force and contraction kinetics in response to electrical field stimulation and by performing histological analysis of sarcomere and myotube structures. Treating hMMTs with total IgGs from anti-HMGCR+patients resulted in a decline in tetanus contractile force, though sarcomere Z-line architecture analysis revealed no significant influences on sarcomere organization. hMMT treatment with total IgGs from anti-SRP+patients induced muscle atrophy, observed via significantly smaller myotube diameter, but this did not translate to a decline in contractile function. This study demonstrates that anti-SRP and anti-HMGCR autoantibodies exert direct, but distinct influences on IMNM-associated skeletal muscle pathogenesis, which may inform IMNM therapy development.
Imputation of cancer proteomics data with a deep model that learns from many datasets
Authors: Harris Lincoln , Noble William S.
Published: August 2024

Missing values are a major challenge in the analysis of mass spectrometry proteomics data. Missing values hinder reproducibility, decrease statistical power for identifying differentially expressed (DE) proteins and make it challenging to analyze low-abundance proteins. We present Lupine, a deep learning-based method for imputing, or estimating, missing values in tandem mass tag (TMT) proteomics data. Lupine is, to our knowledge, the first imputation method that is designed to learn jointly from many datasets, and we provide evidence that this approach leads to more accurate predictions. We validated Lupine by applying it to TMT data from>1,000 cancer patient samples spanning ten cancer types from the Clinical Proteomics Tumor Atlas Consortium (CPTAC). Lupine outperforms the state of the art for TMT imputation, identifies more DE proteins than other methods, corrects for TMT batch effects, and learns a meaningful representation of proteins and patient samples. Lupine is implemented as an open source Python package.
Racial and Ethnic Differences in Sodium Sources and Sodium Reduction Behaviors among US Adults: NHANES 2017-2020 pre pandemic
Authors: Cheng Jessica , Thorndike Anne N , Yi Stella
Published: August 2024

Background Nearly all US adults exceed sodium recommendations, which increases cardiovascular risk. Understanding racial and ethnic differences in sodium sources and behaviors could lead to nuanced public health messaging, dietary interventions, and clinical guidance to more equitably achieve population-level sodium reduction. Methods Using National Health and Nutrition Examination Survey 2017-2020 pre-pandemic data, racial and ethnic differences in sodium sources and sodium-related behaviors (e.g., salt use at the table and in food preparation, doctor advice to reduce sodium, attempts to reduce sodium, and label reading) were assessed using weighted chi-square. Given the nutrient database?s assumption that rice is salted may be inappropriate for some ethnic groups, we conducted a secondary analysis altering this assumption. Results Pizza, soup, and chicken were top sources of sodium across racial and ethnic groups. For Asian Americans, 4 top sources were unique (e.g., soy-based condiments). Black adults reported the highest rates of reducing sodium (67% vs. 44% among White adults) and receiving physician sodium reduction advice (35% vs.18% among Asian Americans). Asian Americans were the most likely to frequently use salt during food preparation (66% vs. Other Race adults 32%) but reported not using salt at the table (43% vs. 23% among Other Race adults). Assuming rice is unsalted reduces Asian American sodium intake estimates by ~325 mg/day. Conclusions While product reformulation targets and front-of-pack nutrition labeling may help reduce sodium intake across groups, to equitably address sodium intake, culturally appropriate advice on sources of sodium and salt usage may be needed, particularly for Asian Americans.
Synchronous L1 retrotransposition events promote chromosomal crossover early in human tumorigenesis
Authors: Zumalave Sonia , Santamarina Martin , Espasandín Nuria P. , Garcia-Souto Daniel , Temes Javier , Baker Toby M. , Pequeño-Valtierra Ana , Otero Iago , Rodríguez-Castro Jorge , Oitabén Ana , Álvarez Eva G. , Otero Paula , Díaz-Arias Iria , Martínez-Fernández Mónica , Van Loo Peter , Cristofari Gael , Rodriguez-Martin Bernardo , Tubio Jose M. C.
Published: August 2024

L1 retrotransposition is a significant source of genomic variation in human epithelial tumours, which can contribute to tumorigenesis. However, fundamental questions about the causes and consequences of L1 activity in cancer genomes remain unresolved, primarily due to the limitations of short-read sequencing technologies. Here, we employ multiplatform sequencing, with an emphasis on long reads, to analyse a fine selection of 10 tumours exhibiting high rates of somatic retrotransposition, encompassing over 6000 events. The analysis of L1 locus-specific single-nucleotide variants reveals a novel panorama of L1 loci activity. Furthermore, examination of the internal structure of somatic L1s uncovers the mechanisms behind their inactivation. A hidden landscape of chromosomal aberrations emerges in the light of long reads, where reciprocal translocations mediated by L1 insertion represent frequent events. Resolution of L1 bridges’ configuration elucidates the mechanisms of their formation, where typically two independent, but synchronous, somatic L1 insertions drive the reciprocal exchange between non-homologous chromosomes. Timing analyses indicate that L1 retrotransposition is an early driver of chromosomal instability, active before the first whole-genome doubling event. Overall, these findings highlight L1 activity as a more significant contributor to tumour genome plasticity than previously recognized, extending its impact beyond simple insertional mutagenesis.
Mitochondrial sites of contact with the nucleus aid in chemotherapy evasion of glioblastoma cells
Authors: Strobbe Daniela , Bueno Mardja , De Vitis Claudia , Hassan Sarah , Faccenda Danilo , Bruqi Krenare , Romano Elena , Pedace Lucia , Yurchenko Andrey A. , Dhoot Gurtej K , Bistrot Ivi J , Klamt Fabio , Lenz Luana S. , Filippi–Chiela Eduardo Cremonese , D’Urso Pietro Ivo , Lally Imogen , Miele Eveline , Falasca Laura , Nikolaev Sergey , Mancini Rita , Roncaroli Federico , Lenz Guido , Campanella Michelangelo
Published: August 2024

Glioblastoma (GBM) is the most common form of a malignant primary brain tumour in adults for which therapeutic options are minimal. The rapid onset of the resistance mechanisms against the chemotherapeutic agent Temozolomide (TMZ), the first line of pharmacological care for patients, prevents the long-term validity of this approach. The underpinning biology for this remains poorly understood thus compromising the efficacy of this approach. The Translocator Protein (TSPO) is an 18kDa ubiquitous cholesterol-binding molecule on the outer membrane of mitochondria (OMM). Upregulated in cancers TSPO is required to form contacts between mitochondria and the nucleus termed: Nucleus Associated Mitochondria (NAM). In GBM tissues as well as in 2D and 3D cell cultures we assayed patterns of TSPO expression (i), autophagy/mitophagy (ii), transcription factors (iii) and susceptibility to TMZ-induced demise (iv). Confocal and ultrastructural imaging detailed the organization and redistribution of the mitochondrial network (v).

Our findings show that TMZ exploits mitochondria via TSPO to aid the formation of NAM which couples the expression of the nuclear transcription factor Sterol regulatory element-binding transcription factor 1 (SREBP1) and the stabilization of YAP/TAZ.

Pharmacological modulation of TSPO counteracts all the above and re-instates susceptibility to TMZ-induced demise. NAM is therefore proposed as a variable in the engagement and execution of pro-survival mechanisms in GBM thus offering a means to both insight into the pathophysiology of this disease and offer novel therapeutic strategies.

Key Points

TMZ exploits TSPO to curb mitochondrial quality control in glioblastoma cells.

TMZ-mediated MRR is associated with the relocation of mitochondria to the nucleus and modulation of transcriptional factors involved in cholesterol metabolism and adaptation to aggressive growth.

TSPO represents a pharmacological target to revert chemoresistance in glioblastoma cells.

Importance of the Study

This study elucidates a mitochondrion-driven mechanism of chemoresistance in human glioblastoma cells, which depends on the mitochondrial translocator protein TSPO. The administration of TSPO ligands restores susceptibility to TMZ by influencing the dynamics of transcriptional factors associated with cholesterol metabolism and mechanical transduction.
Developmental trajectory of thalamus topography during the late preterm and perinatal period in normal development, after premature birth and in congenital heart defects
Authors: Ji Hui , Wu Zhexin , Speckert Anna , Tuura Ruth , Hagmann Cornelia , Latal Beatrice , Knirsch Walter , Jakab Andras
Published: August 2024

The thalamus plays a critical role in neural circuit maturation and brain connectivity. It is well known to show a characteristic topographical organization of local and long-range connectivity, yet developmental changes in this topography remains incompletely understood. Our study aims to first validate the use of diffusion MRI for the topographic delineation of thalamic subdivisions (nuclei), to characterize thalamic topography during development and assess the impact of congenital heart defects (CHD) on thalamus development.

We used local fiber orientation distribution functions, derived from diffusion MRI (dMRI) data, to subdivide the thalamus into seven clusters. We first evaluated the within-subject reproducibility of a dMRI based clustering method across 30 adults scan-rescan datasets (n = 30) using K-means clustering, achieving reproducible segmentation of the thalamus into seven parts. This was applied to a large developmental cohort comprising normally developing infants from the term-born dHCP cohort (n = 68, gestational age [GW] at MRI scan ranging from 37.4 to 44.8 weeks, mean ± SD: 41.4 ± 2.1 weeks) and the Zurich cohort (n = 42, GW at MRI ranging from 39.0 to 48.7 weeks, mean ± SD: 42.55 ± 1.96 weeks). The cohort also included preterm-born dHCP cohort (n = 48, GW at MRI scan ranging from 29.3 to 37.4 corrected gestational weeks, mean ± SD: 34.4 ± 2.02 weeks) and one case of a postmortem fetal specimen (n = 1, GW at MRI = 21 weeks). Cluster volumes were analyzed as a function of age using multivariate linear regression. Differences in cluster volumes between control subjects (n = 42, GW at MRI ranging from 39.0 to 48.7 weeks, mean ± SD: 42.55 ± 1.96 weeks) and newborns with congenital heart disease (CHD) (n = 49, GW at MRI ranging from 37.6 to 42.9 weeks, mean ± SD: 40.23 ± 1.30 weeks) were analyzed using variance analysis, controlling for sex and age at MRI scan.

The clustering on average had a within-subject overlap of 0.811 (Dice overlap metric). While absolute thalamus volumes increased with age, their relative volumes remained stable in the studied developmental period. CHD infants shown reduced absolute volumes in six of the seven thalamic nuclei, with significant increasing in the relative volume of the cluster overlapping with the mediodorsal nucleus.

While the perinatal period comprises rapid developmental events including the maturation of white matter, the topography of thalamic circuitry remains stable. Our study highlights alterations in thalamic topology and potential impacts on brain connectivity in CHD infants. By leveraging local diffusion properties from diffusion MRI, our validated segmentation technique offers a robust, data-centric approach to thalamic delineation.
Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial
Authors: Costa Kevin D. , Wong Andy O. T. , Mak Suet Yee , Roberts Erin G. , Keung Wendy , Correia Claudia , Walentinsson Anna , Christoffersson Jonas , Cheung Alice , Lieu Deborah K. , Jennbacken Karin , Wang Qing-Dong , Hajjar Roger J. , Li Ronald A.
Published: August 2024

Aims

Heart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing. Aligned with FDA Modernization Act 2.0, we aimed to create the firstin vitrohuman-specific mini-heart models of HFpEF, and to test the efficacy of a candidate gene therapy to improve cardiac kinetics and correct the disease phenotype.

Methods and Results

Healthy human pluripotent stem cell-derived ventricular cardiomyocytes were used to bioengineer beating cardiac tissue strips and pumping cardiac chambers. When conditioned with transforming growth factor-β1 and endothelin-1, these mini-heart models exhibited signature disease phenotypes of significantly elevated diastolic force and tissue stiffness, and slowed contraction and relaxation kinetics, with no significant deficit in systolic force or ejection fraction versus unconditioned controls. Bioinformatic analysis of bulk RNA sequencing data from HFpEF mini-heart models and patient ventricular samples identified downregulation of SERCA2a of the calcium signalling pathway as a key differentially expressed gene. After dosage optimization, AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-Hearts.

Conclusions

These findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation. We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.

Translational Perspective

Heart failure with preserved ejection fraction (HFpEF) is a significant and growing global health concern lacking disease-modifying therapeutic options, reflecting inadequate preclinical models of the disease. Aligned with FDA Modernization Act 2.0, we created the firstin vitrohuman-specific mini-heart models of HFpEF, demonstrated phenotypic disease characteristics of elevated stiffness and slowed kinetics, showed transcriptomic consistency with HFpEF patient data, identified SERCA2a as a key downregulated gene, performed dosing titration of SERCA2a gene therapy, and showed improvement of cardiac kinetics post-treatment. The findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF.
Multiple polyploidizations inArabidopsis lyratastabilized by long-range adaptive introgression across Eurasia
Authors: Scott Alison D. , Kolesnikova Uliana , Glushkevich Anna , Steinmann Laura , Tikhomirov Nikita , Pfordt Ursula , Bohutínská Magdalena , Burns Robin , Seregin Alexey P. , Kolar Filip , Schmickl Roswitha , Novikova Polina Yu.
Published: August 2024

Abundance of polyploidy varies across lineages, evolutionary time and geography, suggesting both genetics and environment play a role in polyploid persistence.Arabidopsis lyrataappears to be the most polyploidy-rich species-complex in theArabidopsisgenus, with multiple origins of autotetraploidy. This is revealed by genomic data from over 400 samples across Eurasia. We found over 30 previously undescribed autotetraploid populations in Siberia with a minimum of two separate origins, independent of those previously reported in Central Europe. The establishment of Siberian tetraploids is mediated by meiotic adaptation at the same genes as in European tetraploidA. lyrataandArabidopsis arenosa,despite high divergence and geographical separation. Haplotype analysis based on synthetic long-read assemblies supports the long-range introgression of adaptive alleles from the tetraploid interspecific pool of EuropeanA. lyrataandA. arenosato tetraploid SiberianA. lyrata. Once evolved, adaptation to polyploidy promotes the establishment of new polyploid lineages through adaptive inter– and intraspecific introgression.
NEBULA101: an open dataset for the study of language aptitude in behaviour, brain structure and function
Authors: Rampinini Alessandra , Balboni Irene , Kepinska Olga , Berthele Raphael , Golestani Narly
Published: August 2024

This paper introduces the “NEBULA101 - Neuro-behavioural Understanding of Language Aptitude” dataset, which comprises behavioural and brain imaging data from 101 healthy adults to examine individual differences in language and cognition. Human language, a multifaceted behaviour, varies significantly among individuals, at different processing levels. Recent advances in cognitive science have embraced an integrated approach, combining behavioural and brain studies to explore these differences comprehensively. The NEBULA101 dataset offers brain structural, diffusion-weighted, task-based and resting-state MRI data, alongside extensive linguistic and non-linguistic behavioural measures to explore the complex interaction of language and cognition in a highly multilingual sample. By sharing this multimodal dataset, we hope to promote research on the neuroscience of language, cognition and multilingualism, enabling the field to deepen its understanding of the multivariate panorama of individual differences and ultimately contributing to open science.
SCRATCH: A programmable, open-hardware, benchtop robot that automatically scratches cultured tissues to investigate cell migration, healing, and tissue sculpting
Authors: Lin Yubin , Silverman-Dultz Alexander , Bailey Madeline , Cohen Daniel J.
Published: August 2024

Despite the widespread popularity of the ‘scratch assay’, where a pipette is dragged through cultured tissue to create an injury gap to study cell migration and healing, the manual nature of the assay carries significant drawbacks. So much of the process depends on individual manual technique, which can complicate quantification, reduce throughput, and limit the versatility and reproducibility of the approach. Here, we present a truly open-source, low-cost, accessible, and robotic scratching platform that addresses all of the core issues. Compatible with nearly all standard cell culture dishes and usable directly in a sterile culture hood, our robot makes highly reproducible scratches in a variety of complex cultured tissues with high throughput. Moreover, we demonstrate how scratching can be programmed to precisely remove areas of tissue to sculpt arbitrary tissue and wound shapes, as well as enable truly complex co-culture experiments. This system significantly improves the usefulness of the conventional scratch assay, and opens up new possibilities in complex tissue engineering and cell biological assays for realistic wound healing and migration research.
EEG During Dynamic Facial Emotion Processing Reveals Neural Activity Patterns Associated with Autistic Traits in Children
Authors: Hill Aron T. , Ford Talitha C. , Bailey Neil W. , Lum Jarrad A. G. , Bigelow Felicity J. , Oberman Lindsay M. , Enticott Peter G.
Published: August 2024

Altered brain connectivity and atypical neural oscillations have been observed in autism, yet their relationship with autistic traits in non-clinical populations remains underexplored. Here, we employ electroencephalography (EEG) to examine functional connectivity, oscillatory power, and broadband aperiodic activity during a dynamic facial emotion processing (FEP) task in 101 typically developing children aged 4-12 years. We investigate associations between these electrophysiological measures of brain dynamics and autistic traits as assessed by the Social Responsiveness Scale, 2nd Edition (SRS-2). Our results revealed that increased FEP-related connectivity across theta (4-7 Hz) and beta (13-30 Hz) frequencies correlated positively with higher SRS-2 scores, predominantly in right-lateralized (theta) and bilateral (beta) cortical networks. Additionally, a steeper 1/f-like aperiodic slope (spectral exponent) across fronto-central electrodes was associated with higher SRS-2 scores. Greater aperiodic-adjusted theta and alpha oscillatory power further correlated with both higher SRS-2 scores and steeper aperiodic slopes. These findings underscore important links between FEP-related brain dynamics and autistic traits in typically developing children. Future work could extend these findings to assess these EEG-derived markers as potential mechanisms underlying behavioural difficulties in autism.
Effects of connectivity hyperalignment (CHA) on estimated brain network properties: from coarse-scale to fine-scale
Authors: Farahani Farzad V. , Nebel Mary Beth , Wager Tor D. , Lindquist Martin A.
Published: August 2024

Recent gains in functional magnetic resonance imaging (fMRI) studies have been driven by increasingly sophisticated statistical and computational techniques and the ability to capture brain data at finer spatial and temporal resolution. These advances allow researchers to develop population-level models of the functional brain representations underlying behavior, performance, clinical status, and prognosis. However, even following conventional preprocessing pipelines, considerable inter-individual disparities in functional localization persist, posing a hurdle to performing compelling population-level inference. Persistent misalignment in functional topography after registration and spatial normalization will reduce power in developing predictive models and biomarkers, reduce the specificity of estimated brain responses and patterns, and provide misleading results on local neural representations and individual differences. This study aims to determine how connectivity hyperalignment (CHA)—an analytic approach for handling functional misalignment—can change estimated functional brain network topologies at various spatial scales from the coarsest set of parcels down to the vertex-level scale. The findings highlight the role of CHA in improving inter-subject similarities, while retaining individual-specific information and idiosyncrasies at finer spatial granularities. This highlights the potential for fine-grained connectivity analysis using this approach to reveal previously unexplored facets of brain structure and function.
Are super-predators also super-scary? A systematic review and meta-analysis of animal responses to human interactions
Authors: Dsouza Shawn , Shanker Kartik , Thaker Maria
Published: August 2024

Human induced rapid environmental change has been recognized as a global threat to natural systems and the organisms that inhabit them. Human hunters and fishers interact with animals in natural spaces as predators, and are more effective in capturing prey and reducing populations than natural predators overall. On the other hand, seemingly benign interactions with humans, such as tourism, may also be perceived as threatening and have negative impacts on animal populations. Here, we provide a synthesis of the current knowledge of the combined effects of lethal and non-lethal human interactions on the behavioural responses of animals in natural spaces. We conducted a systematic review and meta-analysis of literature published over the past three decades, and built a dataset to determine the relative effect of lethal and non-lethal human interactions on foraging, vigilance, and movement behaviors of wild animals. Lethal human interactions included hunting, fishing, and retaliatory killing in response to conflict, and non-lethal human interactions were distinguished as active (snorkeling, scuba diving, pedestrians, hiking, and tourists) or passive (roads, human settlements, sonar, and boat traffic). We also considered how the trophic level of the species and body size could influence the effect of human interactions on animal behavior. Our findings show that lethal human interactions had a significant effect on the behaviors of animals, causing animals that are actively hunted by humans to increase vigilance, reduce foraging, and alter movements. Both active and passive non-lethal interactions had weaker and non-significant effects on altering these behaviours of animals. Overall, our meta-analysis shows that the impact of non-lethal human activities in eliciting fear-driven behavioural changes in prey does not seem to have broad empirical support. It also suggests that the intensity of effect of the “human super-predator” may depend on the trophic level of affected species, or the history of the human-animal interactions in that landscape, In order to understand the nuances of these effects, systematic studies across more species and geographic regions are needed.
Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I
Authors: Neumann Bryan , McCarthy Stephen , Gonen Shane
Published: August 2024

Voltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaVisoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarised potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-NaV1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDIwas unresolvable. We find that Protoxin-I binds to and displaces the VSDIIS3-S4 linker, hindering translocation of the S4IIhelix during activation.
Exploration of Natural Products for Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia Through Ligand-Based Pharmacophore Screening and Molecular Dynamic Simulation Approaches
Authors: Das Uddalak , Regati Dheemanth , Kumar Jitendra , Sowdhamini R.
Published: August 2024

Background

Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are prevalent drivers of acute myeloid leukemia (AML). While targeted therapies exist, resistance can emerge. This study explored the potential of natural products to identify novel dual IDH inhibitors.

Methods

In-silicoscreening of the COCONUT database was performed using Lipinski’s Rule of Five. Pharmacophore modelling identified crucial features for IDH binding. Docking simulations with Glide (Schrödinger) assessed binding affinity, followed by MM-GBSA calculations for free energy estimation. The most promising candidate underwent ADME/T and toxicity analysis. Finally, molecular dynamics (MD) simulations evaluated the stability of protein-ligand complexes and binding interactions, followed by trajectory analysis using DCCM and PCA.

Results

The study identified Ternstroside D (CNP0166496) as a potential dual inhibitor for IDH1 and IDH2 mutations. Docking simulations and MM-GBSA calculations predicted favourable binding affinities. MD simulations revealed stable protein-ligand complexes, and in-silico ADME/T analysis suggested good drug-like properties and a favorable safety profile for CNP0166496.

Conclusion

Thisin-silicostudy provides compelling evidence for Ternstroside D (CNP0166496) as a promising dual inhibitor for IDH1 and IDH2 mutations in AML. Furtherin-vitroandin-vivostudies are warranted to validate these findings.
Route Learning and Transport of Resources during Colony Relocation in Australian Desert Ants
Authors: Deeti Sudhakar , McLean Donald James , Murray Trevor , Cheng Ken
Published: August 2024

Many ant species are able to respond to dramatic changes in local conditions by relocating the entire colony to a new location. While we know that careful learning walks enables the homing behavior of foraging ants to their original nest, we do not know whether additional learning is required to navigate to the new nest location. To answer this question, we investigated the nest relocation behavior of a colony of Australian desert antsMelophorus bagotithat relocated their nest in response to heavy rainfall in the semi-desert terrain of Alice Springs. We identified five types of behavior: exploration between nests (Old-to-New nest and New-to-Old nest), transport from Old to New nest, and re-learning walks at Old and New nests. Initially, the workers performed relearning walks at the Old nest and exploratory walks between the Old and New nests. Once they completed the exploratory walks, the workers transported resources and brood to the new nest. Finally, we observed the workers performing relearning walks at the New nest. While the relearning walks at the Old nest were slow and appear to enable exploratory walks to the New nest, the relearning walks at the new nest were faster and appeared to enable homing from foraging trips. These observations shed insight on how learning helps these ants to respond to sudden changes in their environment.

Statement of significance

In this study, we examined one nest of red honey ants,Melophorus bagoti, in Central Australia relocating their nest after a spell of heavy rainfall, which, we presumed, damaged the nest that the colony was living in. After the new nest some 20 m away was mostly dug, we examined the behaviors that orchestrated the move. Workers did a bit of learning of the route to the new nest before transporting any resources. They executed short loops around the old nest, mostly aimed in the direction of the new nest, known as relearning walks. Then they walked back and forth between the old and new nests without carrying any resources, a process we called exploration walks. Then the workers undertook the laborious process of moving house, that is, transporting workers unfamiliar with the route, larvae, and pupae to the new nest. After this stage, we observed ants doing more relearning walks at the new nest in preparation for foraging from their new home. These relearning walks covered all directions around the nest. Our study showed for the first time the importance of the process of learning in nest relocation, a key response to extreme environmental challenges, broadening the role of learning in the lives of these social insects.
A novel baseline-effect shift tracking model for more sensitive detection of differences in the effects of closely related dopamine transporter inhibitor/ sigma receptor antagonist drug combinations on psychostimulant use
Authors: Paul Reshma , Gandhi Roshni M , Job Martin O
Published: August 2024

Background

For the purpose of improving the ability to distinguish the activity of closely related drugs on psychostimulant use to enable more specific drug effect characterization, we have developed a new model termed the baseline-effect shift tracking (BEST) model. BEST compares/contrasts the baseline-drug activity relationship(s).

Aim

To compare the current model to our BEST model to determine which was more effective in distinguishing the effects of combinations of a dopamine transporter inhibitor (methylphenidate, MPD) and selective sigma1 (BD1063) and non-selective sigma (BD1008) receptor antagonists on cocaine consumption.

Methods

Male Sprague Dawley rats were trained to self-administer cocaine (n = 9, 0.32 mg/kg/infusion) or sucrose pellets (n = 6, 20 mg pellets/delivery). We determined the effects for cocaine/sucrose of combinations of MPD (1 mg/kg i.p) and 1) BD1063 (0, 3.2, 10 mg/kg i.p), and 2) BD1008 (0, 3.2, 10 mg/kg i.p) on a) consumption at zero price (Q0), and b) essential value (eValue, demand elasticity) estimated using behavioral economic analysis of within-session demand curves, and c) the total intake under the price response curve (TIPR). We compared the models using ANOVA/ regression analysis.

Results

The current model did not detect any differences in the effects of these drug combinations on cocaine/ sucrose taking behavior. For cocaine, but not for sucrose, the BEST model detected differences in the effects of these drug combinations on TIPR in subjects with higher baseline activity.

Conclusion

BEST model (with TIPR analysis) is more sensitive than the current models in differentiating drug effects on cocaine consumption.
The ERGtools2 package: A Toolset for Processing and Analysing Visual Electrophysiology Data
Authors: Lindner Moritz
Published: August 2024

Introduction

Visual electrophysiology techniques play a key role in assessing the functional integrity of the visual pathway. Recent advancements and applications demand flexible analysis tools. Heren, ERGtools2, an open-source R package designed for processing and analysing visual electrophysiology data is introduced.

Methods

A dataset comprising Electroretinogram (ERG) recordings from both eyes of C57Bl/6J mice, subjected to standard ISCEV stimuli, was used to present the functionality of ERGtools2. ERGtools2 stores and organizes all recordings, metadata, and measurement information from individual examination in a single object, maintaining raw data throughout the analysis process.

Results

A standard workflow is presented exemplifying how ERGtools2 can be used to efficiently import, pre-process and analyse ERG data. Following this workflow, basic ERG measurements likeaandB-wave amplitudes and visualisation of a single exam as well as group statistics are obtained. Moreover, special use cases are described, including for the handling of noisy data and the storage of data in the HDF5 format to ensure long-term preservation and accessibility. ERGtools2 also provides a graphical interface.

Discussion

ERGtools2 provides a comprehensive, flexible, and device-independent solution for visual electrophysiology data analysis. Its emphasis on maintaining raw data integrity, combined with advanced processing and analysis capabilities, makes it a useful tool for preclinical and clinical research applications. The open-source nature and the use of open data formats promote reproducibility and data sharing in visual neurosciences.
An alternative mechanism for activation of innate immune signaling by MDA5
Authors: Quack Salina , Maity Sourav , America Pim P. B. , Klein Misha , del Valle Alba Herrero , Singh Rahul , Smitskamp Quinte , Papini Flavia S. , Broedersz Chase P. , Roos Wouter H. , Modis Yorgo , Dulin David
Published: August 2024

Long double-stranded (ds) RNA in the cytosol acts as a potent inflammatory molecule recognized by the receptor MDA5, triggering the innate immune response. Mutations in MDA5 affecting dsRNA recognition can lead to increased infection sensitivity or autoimmune disease. The current model proposes that MDA5 nucleoprotein filament assembly-disassembly dynamics regulates long dsRNA recognition and signaling. We show that MDA5 preferentially loads onto dsRNA via a 3’ recessed end and uses ATP hydrolysis to translocate towards the 5’-end until obstructed, such as by another MDA5 on the opposite strand. Multiple MDA5 monomers accumulate at the blockade, forming a partial filament that extrudes the associated RNA in single-stranded loops and thereby compacting the MDA5-RNA complex. The compacted state is further stabilized by oligomerization of the MDA5’s caspase recruitment domain (CARD) and can withstand significant forces, offering an alternative intermediate in the activation of MDA5-dependent innate immunity.
The evolution of wasp mimicry and biogeography in the genus Temnostoma (Diptera: Syrphidae)
Authors: Hadrava Jiří , Klečka Jan , Moran Kevin , Klečková Irena , Kelso Scott , Etzbauer Claudia , Skevington Jeffrey H. , Mengual Ximo
Published: August 2024

One of the most remarkable examples of Batesian mimicry occurs in the genus Temnostoma Le Peletier & Audinet-Serville, 1828 (Diptera: Syrphidae). Adults of this genus have an overall resemblance to hymenopterans combined with behavioural mimicry (they move the fore legs in front of the head mimicking hymenopteran antennae). While some species of Temnostoma are considered perfect mimics of social wasps, other species have a darker colour pattern and are rather imperfect mimics. Both colour morphs are widespread through the Holarctic. Here, we infer for the first time the evolutionary history of the genus with special focus on the evolution of mimicry and biogeography. With material covering 75 % of known species of Temnostoma and both colour morphs from each biogeographical region, we inferred a molecular phylogeny based on six molecular markers (mitochondrial protein-coding COI gene, nuclear 28s rRNA gene, and four nuclear protein-coding genes: AATS, CK1, TULP, and RBP-15). Using Bayesian inference, we obtained a highly resolved phylogenetic tree supporting the monophyly of the genus Temnostoma as a sister group of genus Takaomyia Hervé-Bazin, 1914. Within Temnostoma, Te. daochus and Te. barberi (two Nearctic species with strikingly different mimicry patterns) were found to be closely related to each other and together form a lineage sister to the rest of the genus. Our results suggest that the behavioural mimicry of wasp antennae is a plesiomorphic state inherited from a common ancestor that includes the genera Temnostoma and Takaomyia. Within Temnostoma, the dark colour pattern (imperfect mimicry) appeared to be an ancestral state and perfect wasp mimicry evolved two times independently within the genus. In some species inhabiting northern parts of the Holarctic, secondary darkening and consequent degradation of the wasp mimicry appeared. This indicates high evolutionary plasticity and ongoing selection pressure on morphological characters related to mimicry in hover flies.
The evolution of reversible plasticity in stable environments
Authors: Walasek Nicole , Panchanathan Karthik , Frankenhuis Willem E.
Published: August 2024

Phenotypic plasticity– the capacity of a genotype to develop into different phenotypes depending on environmental inputs – is widespread in nature. Although theconstructionof phenotypes is often the focus of research, many animals are also able todeconstructphenotypic adjustments. Organisms routinely use suchreversible plasticityto adjust to changes in their social or physical environment. For example, various invertebrates are able to deconstruct defensive morphologies previously built to defend against predators. Theory that explores the selection pressures favoring reversibility is scarce. Existing theory has almost exclusively focused on traits that develop instantaneously rather than incrementally, as is common with many morphological traits. Here, we present a model of the evolution of reversible plasticity when organisms develop incrementally. In our model, organisms repeatedly sample cues to infer the environmental state – which varies between generations but is stable across the lifetime – and incrementally adjust their phenotype to match their environment. Organisms have the possibility to deconstruct phenotypic adjustments. We assume two different modes of phenotypic deconstruction: Organisms can either deconstruct phenotypic adjustments incrementally or completely deconstruct all phenotypic adjustments in one time period. We highlight two results. First, while plasticity in construction is typically highest early in ontogeny, the highest levels of plasticity in deconstruction typically occur in mid-ontogeny. Second, contrasting previous models, we find that reversibility evolves frequently in stable environments and in species with shorter lifespans. Our model thus shows that reversibility does not require environmental change. Rather, reversibility may be favored when organisms are uncertain about the environmental state because the environment can change across generations. Our work illustrates the capacity for reversibility in species who experience environmental changes for the first time in their lives.
ANLN directly interacts with PCNA to regulate UV induced translesion synthesis
Authors: Tong Bei-Bei , Cao Yu-Fei , Wen Bing , Fu Teng , Deng Dan-Xia , Yang Qian-Hui , Wu Yu-Qiu , Zou Hua-Yan , Liao Lian-Di , Xu Li-Yan , Li En-Min
Published: August 2024

Anillin (ANLN) is a cytoskeletal binding protein involved in mitosis. ANLN is located in the nucleus during interphase and in the cytoplasmic contractile rings during mitosis. Our previous studies found that ANLN is abnormally overexpressed in esophageal squamous cell carcinoma (ESCC), promoting cell division by regulating contractile ring localization. However, the exact function of ANLN in the nucleus remains unclear. Here, we found that the expression of ANLN in the nucleus is associated with poor prognosis in ESCC patients, rather than in the cytoplasm. Protein mass spectrometry and bioinformatics analysis revealed that ANLN is related to DNA synthesis, and proliferating cell nuclear antigen (PCNA) is found to be a potential interacting protein of ANLN. PCNA directly interacts with the PIP box domain of ANLN and co-localizes in the nucleus. ANLN promotes DNA replication and S phase progression in a PCNA dependent manner and independent with the cytoskeletal function of ANLN. Importantly, ANLN is involved in transletion synthesis (TLS), a type of DNA synthesis under stress, by promoting PCNA monoubiquitination at K164 residue. Mechanistically, ANLN binds and recruits the E3 ligase RAD18 to promote PCNA monoubiquitination and DNA polymerase eta loading under UV radiation conditions. Consistently, depletion of ANLN leads to increased genomic instability and increased sensitivity to UV radiation. The findings of the study showed that ANLN in the nucleus as a protein scaffold is involved in UV induced DNA synthesis pathway, providing new insights into the function and mechanism of ANLN in cancer cells.
The Effect of THz Electromagnetic Field on the Conductance of Potassium and Sodium Channels
Authors: Song Zigang , Xue Lingfeng , Ouyang Qi , Song Chen
Published: August 2024

Ion channels are essential to various physiological processes and their defects are associated with many diseases. Previous research has revealed that Terahertz electromagnetic field can alter the channel conductance by affecting the motion of chemical groups of ion channels, and hence regulate the electric signals of neurons. In this study, we conducted molecular dynamics simulations to systematically investigate the effects of terahertz electromagnetic fields on the conductance of voltage-gated potassium and sodium channels, particularly focusing on the bound ions in the selectivity filters that have not been studied previously. Our results identified multiple new characteristic frequencies and showed that 1.4, 2.2, or 2.9 THz field increases the conductance of Kv1.2, and 2.5 or 48.6 THz field increases the conductance of Nav1.5. The conductance-enhancing effects are specific to the frequencies and directions of the electric field, which are determined by the intrinsic oscillation motions of the permeating ions in the selectivity filter or certain chemical groups of the ion channels. The amplitude of the THz field positively correlates with the change in ion conductance. Therefore, this study demonstrates that THz fields can specifically regulate ion channel conductances, which may carry great potential in biomedical applications.
Onset of infectiousness explains differences in transmissibility acrossMycobacterium tuberculosislineages
Authors: Windels Etthel M. , Agüí Cecilia Valenzuela , de Jong Bouke C. , Meehan Conor J. , Loiseau Chloé , Goig Galo A. , Zwyer Michaela , Borrell Sonia , Brites Daniela , Gagneux Sebastien , Stadler Tanja
Published: August 2024

Mycobacterium tuberculosiscomplex (MTBC) lineages show substantial variability in virulence, but the epidemiological consequences of this variability have not been studied in detail. Here, we aimed for a lineage-specific epidemiological characterization by applying phylodynamic models to genomic data from different countries, representing the most abundant MTBC lineages. Our results show that all lineages are associated with similar durations and levels of infectiousness, resulting in similar reproductive numbers. However, L1 and L6 are associated with a delayed onset of infectiousness, leading to longer periods between subsequent transmission events. Together, our findings highlight the role of MTBC phylogenetic diversity in tuberculosis disease progression and transmission.
Glioblastoma stem cells show transcriptionally correlated spatial organization
Authors: Ayyadhury Shamini , Sachamitr Patty , Kushida Michelle M. , Park Nicole I , Coutinho Fiona J. , Whitley Owen , Prinos Panagiotis , Arrowsmith Cheryl H. , Dirks Peter B. , Pugh Trevor J. , Bader Gary D.
Published: August 2024

Glioblastoma (GBM) is an aggressive brain cancer with a poor survival rate. Despite hundreds of clinical trials, there is no effective targeted therapy. Glioblastoma stem cells (GSCs) are an important GBM model system. In culture, these cells form spatial structures that share morphological aspects with their source tumors. We collected 17,000 phase contrast images of 15 patient-derived GSC lines growing to confluence. We find that GSCs grow in characteristic multicellular patterns depending on their transcriptional state. Interpretable computer vision algorithms identified specific image features that predict transcriptional state across multiple cell confluency levels. This relationship will be useful in developing GSC screens where image features can be used to identify how GSC biology changes in response to perturbations simply by imaging cultured cells on plates.