bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased impact sensitivity in ageing high explosives; analysis of Amatol extracted from explosive remnants of war
Authors: Novik Geir P. , Christensen Dennis
Published: March 2024

Millions of tonnes of explosive remnants of war remain in nature and their volume is continuously growing. The explosive legacy of wars represents an increasing threat to the environment and societal safety and security. As munitions continue to deteriorate, harmful constituents will eventually leak into the environment, poisoning ecological receptors and contaminating the surrounding soil and groundwater. Moreover, munition deterioration due to exposure to various environmental factors may ultimately cause them to become increasingly sensitive to external stimuli and susceptible to accidental detonation. To thoroughly assess how to address these ageing munitions, we must first establish certain threshold values for safe and secure handling and final disposal of the explosive ordnance. One key factor is to establish how the impact sensitivity of the explosives evolves over time. In the present work, we investigated the high-explosive substance Amatol extracted from ageing explosive remnants of war. The results obtained in the analysis indicate that the high explosives in the examined specimens were generally much more sensitive to impact than previously assumed. Furthermore, the analysis revealed that the standardized methodology of impact sensitivity testing was insufficient for estimating the sensitivities in question, and a more careful statistical analysis is required.
Social evaluative implications of sensory adaptation to human voices
Authors: Neuenswander Kelsey L. , Gillespie Grace S. R. , Lick David J. , Bryant Gregory A. , Johnson Kerri L.
Published: March 2024

People form social evaluations of others following brief exposure to their voices, and these impressions are calibrated based on recent perceptual experience. Participants adapted to voices with fundamental frequency (
f
o
; the acoustic correlate of perceptual pitch) manipulated to be gender-typical (i.e. masculine men and feminine women) or gender-atypical (i.e. feminine men and masculine women) before evaluating unaltered test voices within the same sex. Adaptation resulted in contrastive aftereffects. Listening to gender-atypical voices caused female voices to sound more feminine and attractive (Study 1) and male voices to sound more masculine and attractive (Study 2). Studies 3a and 3b tested whether adaptation occurred on a conceptual or perceptual level, respectively. In Study 3a, perceivers adapted to gender-typical or gender-atypical voices for both men and women (i.e. adaptors pitch manipulated in opposite directions for men and women) before evaluating unaltered test voices. Findings showed weak evidence that evaluations differed between conditions. In Study 3b, perceivers adapted to masculinized or feminized voices for both men and women (i.e. adaptors pitch manipulated in the same direction for men and women) before evaluating unaltered test voices. In the feminized condition, participants rated male targets as more masculine and attractive. Conversely, in the masculinized condition, participants rated female targets as more feminine and attractive. Voices appear to be evaluated according to gender norms that are updated based on perceptual experience as well as conceptual knowledge.
Tympanal ears mediate male–male competition, courtship and mating success in
Bicyclus anynana
butterflies
Authors: Tiong Galen J. L. , Naing Lin , Ng Edwin , Dion Emilie , Monteiro Antónia
Published: March 2024

The presence of intra-specific acoustic communication in diurnal butterflies is not well established. Here, we examined the function of the tympanal ear (Vogel’s organ, VO) in the seasonally polyphenic butterfly
Bicyclus anynana
in the context of sexual signalling. We investigated how the VO and the flanking enlarged veins, which are suggested sound resonance chambers, scale with wing size across sexes and seasonal forms, and how disruptions to the VO alter courtship behaviour and mating outcomes. We found that males have VOs similar in size to females despite having smaller wings, and dry season (DS) male cubital and anal veins do not scale with the wing size. This suggests that the VO plays an important role in males and that cubital and anal veins in DS males may be tuned to amplify specific sound frequencies. Behavioural assays performed with deafened and hearing males of different seasonal forms, in pair and triad settings, showed that deafened DS males, but not wet season males, experienced lower mating success relative to their hearing counterparts. Our study documents a novel function for the wing tympanal membrane in mediating courtship and mating outcomes in diurnal butterflies.
Genomic insights into the population history and adaptive traits of Latin American Criollo cattle
Authors: Ward James A. , Ng'ang'a Said I. , Randhawa Imtiaz A. S. , McHugo Gillian P. , O'Grady John F. , Flórez Julio M. , Browne John A. , Pérez O’Brien Ana M. , Landaeta-Hernández Antonio J. , Garcia Jóse F. , Sonstegard Tad S. , Frantz Laurent A. F. , Salter-Townshend Michael , MacHugh David E.
Published: March 2024

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (
Bos taurus
) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (
Bos indicus
) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.
Data-driven discovery of invariant measures
Authors: Bramburger Jason J. , Fantuzzi Giovanni
Published: March 2024

Invariant measures encode the long-time behaviour of a dynamical system. In this work, we propose an optimization-based method to discover invariant measures directly from data gathered from a system. Our method does not require an explicit model for the dynamics and allows one to target specific invariant measures, such as physical and ergodic measures. Moreover, it applies to both deterministic and stochastic dynamics in either continuous or discrete time. We provide convergence results and illustrate the performance of our method on data from the logistic map and a stochastic double-well system, for which invariant measures can be found by other means. We then use our method to approximate the physical measure of the chaotic attractor of the Rössler system, and we extract unstable periodic orbits embedded in this attractor by identifying discrete-time periodic points of a suitably defined Poincaré map. This final example is truly data-driven and shows that our method can significantly outperform previous approaches based on model identification.
Quasi-steady-state modelling and characterization of diffusion-controlled dissolution from polydisperse spheroidal particles, II: characterization
Authors: Wang Yanxing , Wan Hui , Barka Cody , Wei Tie , Shu Fangjun
Published: March 2024

A quasi-steady-state model for accurately predicting the detailed diffusion-dominated dissolution process of polydisperse spheroidal (prolate, oblate and spherical) particle systems was presented in Part I of this study. In the present paper, the dissolution characteristics of typical polydisperse spheroidal particle systems have been extensively investigated. The effects of the distributions of particle size and shape have been studied by examining the detailed dissolution processes, such as the size reduction rates of individual particles, the increase in bulk concentration and the dissolution time of the polydisperse systems. Some important factors controlling the dissolution process, including initial particle concentration, smallest and largest particle sizes, and the smallest and largest Taylor shape parameters, have been identified.
A sex-linked supergene with large effects on sperm traits has little impact on reproductive traits in female zebra finches
Authors: Assersohn Katherine , Morton Oscar , Slate Jon , Hemmings Nicola
Published: March 2024

Despite constituting an essential component of fitness, reproductive success can vary remarkably between individuals and the causes of such variation are not well understood across taxa. In the zebra finch—a model songbird, almost all the variation in sperm morphology and swimming speed is maintained by a large polymorphic inversion (commonly known as a supergene) on the Z chromosome. The relationship between this polymorphism and reproductive success is not fully understood, particularly for females. Here, we explore the effects of female haplotype, and the combination of male and female genotype, on several primary reproductive traits in a captive population of zebra finches. Despite the inversion polymorphism's known effects on sperm traits, we find no evidence that inversion haplotype influences egg production by females or survival of embryos through to hatching. However, our findings do reinforce existing evidence that the inversion polymorphism is maintained by a heterozygote advantage for male fitness. This work provides an important step in understanding the causes of variation in reproductive success in this model species.
Sleep and subjective age: protect your sleep if you want to feel young
Authors: Balter Leonie J. T. , Axelsson John
Published: March 2024

The current studies examined the impact of insufficient sleep and sleepiness on the subjective experience of age. Study 1, a cross-sectional study of 429 participants (282 females (66%), 144 males, 3 other gender; age range 18–70), showed that for each additional day of insufficient sleep in the last 30 days, subjective age increased by 0.23 years. Study 2, an experimental crossover sleep restriction study (
n
= 186; 102 females (55%), 84 males; age range 18–46), showed that two nights of sleep restriction (4 h in bed per night) made people feel 4.44 years older compared to sleep saturation (9 h in bed per night). Additionally, moving from feeling extremely alert (Karolinska Sleepiness Scale (KSS) score of 1) to feeling extremely sleepy (KSS score of 9) was associated with feeling 10 years older in both studies. These findings provide compelling support for insufficient sleep and sleepiness to exert a substantial influence on how old we feel, and that safeguarding sleep is probably a key factor in feeling young.
Xanthomonas rydalmerensis sp. nov., a non-pathogenic member of Group 1 Xanthomonas
Authors: McKnight Daniel J. E. , Wong-Bajracharya Johanna , Okoh Efenaide B. , Snijders Fridtjof , Lidbetter Fiona , Webster John , Haughton Mathew , Darling Aaron E. , Djordjevic Steven P. , Bogema Daniel R. , Chapman Toni A.
Published: March 2024

Five bacterial isolates were isolated from Fragaria × ananassa in 1976 in Rydalmere, Australia, during routine biosecurity surveillance. Initially, the results of biochemical characterisation indicated that these isolates represented members of the genus Xanthomonas. To determine their species, further analysis was conducted using both phenotypic and genotypic approaches. Phenotypic analysis involved using MALDI-TOF MS and BIOLOG GEN III microplates, which confirmed that the isolates represented members of the genus Xanthomonas but did not allow them to be classified with respect to species. Genome relatedness indices and the results of extensive phylogenetic analysis confirmed that the isolates were members of the genus Xanthomonas and represented a novel species. On the basis the minimal presence of virulence-associated factors typically found in genomes of members of the genus Xanthomonas, we suggest that these isolates are non-pathogenic. This conclusion was supported by the results of a pathogenicity assay. On the basis of these findings, we propose the name Xanthomonas rydalmerensis, with DAR 34855T = ICMP 24941 as the type strain.
Parallel maturation of hippocampal memory and CA1 task representations
Authors: Bevandić Juraj , Stella Federico , Ólafsdóttir H. Freyja
Published: March 2024

Hippocampal-dependent memory is known to emerge late in ontogeny and its full development is protracted. Yet, the changes in hippocampal neuronal function that underlie this delayed and gradual maturation remain relatively unexplored. To address this gap, we recorded ensembles of CA1 neurons while charting the development of hippocampal-dependent spatial working memory (WM) in rat pups (∼2-4weeks of age). We found a sharp transition in WM development, with age of inflection varying considerably between individual animals. In parallel with the sudden emergence of WM, hippocampal spatial representations became abruptly task specific, remapping between encoding and retrieval phases of the task. Further, we show how the development of task phase remapping could partly be explained by changes in place field size during this developmental period as well as the onset of precise temporal coordination of CA1 excitatory input. Together, these results suggest that a hallmark of hippocampal memory development may be the emergence of contextually specific CA1 representations driven by the maturation of CA1 micro-circuits.
Exploring the accuracy of ab initio prediction methods for viral pseudoknotted RNA structures
Authors: Medeiros Vasco , Pearl Jennifer M. , Carboni Mia , Er Ece , Zafeiri Stamatia
Published: March 2024

The prediction of tertiary RNA structures is significant to the field of medicine (e.g. mRNA vaccines, genome editing), and the exploration of viral transcripts. Though many RNA folding software exist, few studies have condensed their locus of attention solely to viral pseudoknotted RNA. These regulatory pseudoknots play a role in genome replication, gene expression, and protein synthesis. This study explores five RNA folding engines that compute either the minimum free energy (MFE) or the maximum expected accuracy (MEA). These folding engines were tested against 26 experimentally derived short pseudoknotted sequences (20-150nt) using metrics that are commonly applied to software prediction accuracy (e.g. F1scoring, PPV). This paper reports higher accuracy RNA prediction engines, such as pKiss, when compared to previous iterations of the software, and when compared to older folding engines. They show that MEA folding software does not always outperform MFE folding software in prediction accuracy when assessed with metrics such as percent error, sensitivity, PPV, and F1scoring when applied to viral pseudoknotted RNA. Moreover, the results suggest that thermodynamic model parameters will not ensure accuracy if auxiliary parameters such as Mg2+binding, dangling end options, and H-type penalties are not applied. The observations reported in this paper highlight the quality between differentab initioprediction methods while enforcing the idea that a better understanding of intracellular thermodynamics is necessary for a more efficacious screening of RNAs.

Importance

The importance of accurately predicting RNA structures cannot be overstated, particularly in the context of viral biology and the development of therapeutic interventions such as mRNA vaccines and genome editing. Our study addresses the gap in the existing literature by concentrating solely on viral pseudoknotted RNA, which plays a crucial role in viral replication, gene expression, and protein synthesis. Our study sheds light on the debate surrounding minimum free energy (MFE) versus maximum expected accuracy (MEA) models in RNA folding predictions. Contrary to existing beliefs, we found that MEA models do not consistently outperform MFE models, especially in the context of viral pseudoknotted RNAs. Our research contributes to advancing the field of computational biology by providing insights into the efficacy of different prediction methods and emphasizing the need for a deeper understanding of intracellular thermodynamics to improve RNA structure predictions.
Beyond IC50- A computational dynamic model of drug resistance in enzyme inhibition treatment
Authors: Sheehan J. Roadnight , de Wijn Astrid , Freire Thales Souza , Friedman Ran
Published: March 2024

Resistance to therapy is a major clinical obstacle to treatment of cancer and communicable diseases. Chronic myeloid leukaemia (CML) is a blood cancer that is treated with Abl1 inhibitors, and is often seen as a model for targeted therapy and drug resistance. Resistance to the first-line treatment occurs in approximately one in four patients. The most common cause of resistance is mutations in the Abl1 enzyme. Different mutant Abl1 enzymes show resistance to different Abl1 inhibitors and the mechanisms that lead to resistance for various mutation and inhibitor combinations are not fully known, making the selection of Abl1 inhibitors for treatment a difficult task. We developed a model based on information of catalysis, inhibition and pharmacokinetics, and applied it to study the effect of three Abl1 inhibitors on mutants of the Abl1 enzyme. From this model, we show that the relative decrease of product formation rate (defined in this work as “inhibitory reduction prowess”) is a better indicator of resistance than an examination of the size of the product formation rate or fold-IC50values for the mutant. We also examine current ideas and practices that guide treatment choice and suggest a new parameter for selecting treatments that could increase the efficacy and thus have a positive impact on patient outcomes.
Parallel Multilink Group Joint ICA: Fusion of 3D Structural and 4D Functional Data Across Multiple Resting fMRI Networks
Authors: Khalilullah K M Ibrahim , Agcaoglu Oktay , Sui Jing , Duda Marlena , Adali Tülay , Calhoun Vince D
Published: March 2024

Multimodal neuroimaging research plays a pivotal role in understanding the complexities of the human brain and its disorders. Independent component analysis (ICA) has emerged as a widely used and powerful tool for disentangling mixed independent sources, particularly in the analysis of functional magnetic resonance imaging (fMRI) data. This paper extends the use of ICA as a unifying framework for multimodal fusion, introducing a novel approach termed parallel multilink group joint ICA (pmg-jICA). The method allows for the fusion of gray matter maps from structural MRI (sMRI) data to multiple fMRI intrinsic networks, addressing the limitations of previous models. The effectiveness of pmg-jICA is demonstrated through its application to an Alzheimer’s dataset, yielding linked structure-function outputs for 53 brain networks. Our approach leverages the complementary information from various imaging modalities, providing a unique perspective on brain alterations in Alzheimer’s disease. The pmg-jICA identifies several components with significant differences between HC and AD groups including thalamus, caudate, putamen with in the subcortical (SC) domain, insula, parahippocampal gyrus within the cognitive control (CC) domain, and the lingual gyrus within the visual (VS) domain, providing localized insights into the links between AD and specific brain regions. In addition, because we link across multiple brain networks, we can also compute functional network connectivity (FNC) from spatial maps and subject loadings, providing a detailed exploration of the relationships between different brain regions and allowing us to visualize spatial patterns and loading parameters in sMRI along with intrinsic networks and FNC from the fMRI data. In essence, developed approach combines concepts from joint ICA and group ICA to provide a rich set of output characterizing data-driven links between covarying gray matter networks, and a (potentially large number of) resting fMRI networks allowing further study in the context of structure/function links. We demonstrate the utility of the approach by highlighting key structure/function disruptions in Alzheimer’s individuals.
Bone Mineralization Regulation: Using Zebrafish as a Model to Study ANKH-associated Mineralization Disorders
Authors: Wathuliyadde Nuwanthika , Willmore Katherine E. , Kelly Gregory M.
Published: March 2024

Craniometaphyseal Dysplasia (CMD) is a rare skeletal disorder that can result from mutations in theANKHgene. This gene encodes progressive ankylosis (ANK), which is responsible for transporting inorganic pyrophosphate (PPi) and ATP from the intracellular to the extracellular environment, where PPi inhibits bone mineralization. When ANK is dysfunctional, as in patients with CMD, the passage of PPi to the extracellular environment is reduced, leading to excess mineralization, particularly in bones of the skull. Zebrafish may serve as a promising model to study the mechanistic basis of CMD. Here we provide a detailed analysis of the zebrafish ankh paralogs, ankha and ankhb, in terms of their phylogenic relationship with ANKH in other vertebrates as well as their spatiotemporal expression patterns during zebrafish development. We found a closer evolutionary relationship exists between the zebrafish ankhb protein and its human and other “higher” vertebrate counterparts. Furthermore, we noted distinct temporal expression patterns withankhamore prominently expressed in early development stages, andankhbexpression at larval growth stages. Whole mountin situhybridization was used to compare spatial expression patterns of each paralog during bone development. Both paralogs showed strong expression in the craniofacial region as well as the notochord and somites, with only subtle patterning differences. Given the substantial overlap in spatiotemporal expression ofankhaandankhb, the exact roles of these genes remain speculative. However, this study lays the groundwork for functional analyses of each ankh paralog and the potential of using zebrafish to find possible targeted therapies for CMD.
ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology
Authors: Mimar Sayat , Paul Anindya S. , Lucarelli Nicholas , Border Samuel , Santo Briana A. , Naglah Ahmed , Barisoni Laura , Hodgin Jeffrey , Rosenberg Avi Z , Clapp William , Sarder Pinaki ,   the Kidney Precision Medicine Project
Published: March 2024

Artificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing. Applied to WSIs, AI has created opportunities for improved disease diagnostics and prognostics with the ultimate goal of enhancing precision medicine and resulting patient care.

The National Institutes of Health (NIH) has recognized the importance of developing standardized principles for data management and discovery for the advancement of science and proposed the Findable, Accessible, Interoperable, Reusable, (FAIR) Data Principles1with the goal of building a modernized biomedical data resource ecosystem to establish collaborative research communities. In line with this mission and to democratize AI-based image analysis in digital pathology, we propose ComPRePS: an end-to-end automatedComputationalRenalPathologySuite which combines massive scalability, on-demand cloud computing, and an easy-to-use web-based user interface for data upload, storage, management, slide-level visualization, and domain expert interaction. Moreover, our platform is equipped with both in-house and collaborator developed sophisticated AI algorithms in the back-end server for image analysis to identify clinically relevant micro-anatomic functional tissue units (FTU) and to extract image features.
LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients
Authors: Frenger Quentin , Lucas Julie , Petitdemange Arthur , Path Luisa , Wadier Nadège , Depauw Sabine , Giorgiutti Stéphane , Gong Yazhuo , Merlin Hélène , Meyer Aurore , Herber Mathilde , Jaquel Léa , Mertz Philippe , Felten Renaud , Chatelus Emmanuel , Dieudonne Yannick , Guffroy Aurélien , Arnaud Laurent , Poindron Vincent , Gottenberg Jacques-Eric , Sibilia Jean , Korganow Anne-Sophie , Martin Thierry , Gros Frédéric
Published: March 2024

Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called “noncanonical” autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly inATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment.

Key messages

Polymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE

While autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc

We show here that autophagy is comparable between PBMCs from patients and matched controls

We find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients

As LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation
Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes
Authors: Pino Diego Chillón , Badonyi Mihaly , Semple Colin A. , Marsh Joseph A.
Published: March 2024

Advances in structure determination and computational modelling are enabling us to study the protein structural context of human genetic variants at an unprecedented scale. Here, we investigate millions of human cancer-associated missense mutations in terms of their structural locations and predicted perturbative effects. We find that, while cancer-driving mutations have properties similar to other known disease-causing mutations, this is obscured by the abundance of passenger mutations in cancer sequencing datasets. Nevertheless, by considering the collective properties of mutations at the level of individual proteins, we identify distinct mutational signatures associated with tumour suppressors and oncogenes. Tumour suppressors are enriched in structurally damaging mutations, consistent with loss-of-function mechanisms. In contrast, oncogene mutations tend to be structurally mild, reflecting selection for gain-of-function driver mutations and against loss-of-function mutations. Although oncogenes are difficult to distinguish from genes with no role in cancer using only structural damage, we find that an alternate metric based on the clustering of mutations in three-dimensional space is highly predictive of oncogenes, particularly when mutation recurrence is considered. These observations allow us to identify novel candidate driver genes and speculate about their molecular roles, which we expect to have general utility in the analysis of cancer sequencing data.
CrossModal Correspondence based MultisensoryIntegration: A pilot study showing how HAV cues can modulate the reaction time
Authors: Banerjee Swati , Shumkova Daria
Published: March 2024

We live in a multisensory world, where all our senses work together for giving us a fulfilling experience of the environment that we are in or during our use of immersive technologies.

For gaining more insight into the temporal scale understanding of the integration phenomenon EEG based BCI can give us the understanding of the transient changes in the brain.

In this study, we investigated the potential of incorporating haptics into crossmodal correspondence based research to induce MSI effect through either the active touch users’ feedback or crossmodal correspondences with visual and auditory modalities, such as Kiki Bouba effect.

We designed two experiments:

Visual stimuli were presented on a standard computer monitor, and auditory stimuli were delivered through computer dynamics. Participants responded using left or right hand by pressing either CapsLock or Enter buttons respectively. Visual cue consisted of a red circle displayed randomly either on the left or on the right side of the screen. Auditory cue was a brief high tone presented through left or right headphones for 500 ms. Text stimuli that appeared on the screen instructed participants to respond with their left or right hand. Before each trial there was a fixation central cross displayed for 500 ms.

This experiment was inspired by previous studies on Kiki-Bouba correspondence. Visual stimuli consisted of 4 shapes - circle, triangle, polygon with 6 vertices, and star - presented on a computer screen. Locations of the visual stimuli were randomized. Auditory stimuli were generated using the Online Tone Generator website (https://onlinetonegenerator.com/). 2 sets of sounds were used: the first set included sine, triangle, square, and sawtooth waveforms, each at a frequency of 500 Hz; the second set included sawtooth waveforms at frequencies of 50 Hz, 300 Hz, 600 Hz, and 2000 Hz (summarised in Table 2).

Results suggested that it is indeed possible to achieve this type of integration without relying on complex haptic devices. Introducing haptics into BCI technologies through feedback touch or crossmodal correspondances holds potential to improve the user experience and information transfer rate (ITR).

Participants, as expected, showed the lowest reaction times in congruent sequential test and the highest – in incongruent HAV cues based test. This indicates the importance preference for sequential cue presentation over simultaneous one. The time was significantly higher in case of Incongruent Haptic cues.
Computational Exploration of Protein Structure Dynamics and RNA structural Consequences ofPKD1Missense Variants: Implications in ADPKD Pathogenesis
Authors: Devi Chandra , Ranjan Prashant , Raj Sonam , Das Parimal
Published: March 2024

Autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by the formation of fluid-filled cysts within the kidneys, leading to progressive renal dysfunction, is primarily caused by mutations inPKD1, a gene encoding for the protein polycystin-1 (PC1). Understanding the structural consequences ofPKD1variants is crucial for elucidating disease mechanisms and developing targeted therapies. In this study, we analyzed the effects of nine missensePKD1variants, including c.6928G>A p.G2310R, c.8809G>A p.E2937K, c.2899T>C p.W967R, c.6284A>G p.D2095G, c.6644G>A p.R2215Q, c.7810G>A p.D2604N, c.11249G>C p.R3750P, c.1001C>T p.T334M, and c.3101A>G p.N1034S on RNA structures, their interactions utilizing computational tools. We also explain the effects of these variants on PC1 protein dynamics, stability, and interactions using molecular dynamics (MD) simulation. These variants are located at crucial domains such as the REJ domain, PKD domains, and cation channel domain, potentially compromising PC1’s function and contributing to ADPKD pathogenesis. Findings reveal substantial deviations in RNA structures and their interactions with other proteins or RNAs and also protein structure and dynamics for variants such as c.8809G>A (p.E2937K), c.11249G>C (p.R3750P), c.3101A>G (p.N1034S), c.6928G>A (p.G2310R), c.6644G>A (p.R2215Q) suggesting their potential implications in disease etiology. The study also suggests that although certain variants may have minimal effects on RNA conformations, their observed alterations in MD simulations indicate potential impact on protein structure dynamics highlighting the importance of evaluating the functional consequences of genetic variants by considering both RNA and protein levels. This study offers valuable perspectives of the utility of studying the structure dynamics through computational tools in prioritizing the variants for their functional implications and understanding the molecular mechanisms underlying ADPKD pathogenesis and developing therapeutic interventions.

GRAPHICAL ABSTRACT
Low-Cost Robotic Manipulation of Live Microtissues for Cancer Drug Testing
Authors: Stepanov Ivan , Gottshall Noah R. , Ahmadianyazdi Alireza , Sinha Daksh , Lockhart Ethan J. , Nguyen Tran N.H. , Hassan Sarmad , Horowitz Lisa F. , Yeung Raymond S. , Gujral Taranjit S. , Folch Albert
Published: March 2024

The scarcity of human biopsies available for drug testing is a paramount challenge for developing new therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly-prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.

Teaser

A low-cost robot for handling microtissues and catalyzing their use in cancer drug evaluation and personalized oncology.
The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice
Authors: Zarate Sara M. , Garcia Roger C. , Pandey Gauri , Srinivasan Rahul
Published: March 2024

The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating estrogen mediates this effect, we employ two mouse models aimed at depleting systemically circulating estrogen: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating estrogen in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of estrogen depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson’s disease.
Single cell resolution analysis of multi-tissue derived human iNKT cells reveals novel transcriptional paradigms
Authors: Jayasinghe Reyka G. , Hollingsworth Derek , Boonchalermvichian Chaiyaporn , Gupta Biki , Yan Hao , Baker Jeanette , Dejene Beruh , Weinberg Kenneth I , Negrin Robert S. , Mavers Melissa
Published: March 2024

Invariant natural killer T (iNKT) cells are evolutionarily conserved innate lymphocytes important for host defense against pathogens. Further, they are increasingly recognized to play a role in tumor immune surveillance and in protection against graft versus host disease, and they are of particular importance as a universal donor for cellular therapies. Therefore, a thorough understanding of the biology of iNKT cells is critical. Murine studies have revealed the existence of transcriptionally and functionally distinct subsets, similar to T helper cell subsets. However, a comprehensive study of human iNKT cell heterogeneity is lacking. Herein, we define the transcriptomic heterogeneity of human iNKT cells derived from multiple immunologically relevant tissues, including peripheral blood, cord blood, bone marrow, and thymus, using single cell RNA-sequencing. We describe human iNKT cells with a naïve/precursor transcriptional pattern, a Th2-like signature, and Th1/17/NK-like gene expression. This combined Th1/17 pattern of gene expression differs from previously described murine iNKT subsets in which Th1- and Th17- like iNKT cells are distinct populations. We also describe transcription factors regulating human iNKT cells with distinct gene expression patterns not previously described in mice. Further, we demonstrate a novel T effector memory RA+(TEMRA)-like pattern of expression in some human iNKT cells. Additionally, we provide an in-depth transcriptional analysis of human CD8+iNKT cells, revealing cells with two distinct expression patterns—one consistent with naïve/precursor cells and one consistent with Th1/17/NK-like cells. Collectively, our data provide critical insights into the transcriptional heterogeneity of human iNKT cells, providing a platform to facilitate future functional studies and to inform the development of iNKT-based cellular therapies.
Gene regulatory network co-option is sufficient to induce a morphological novelty inDrosophila
Authors: Rice Gavin , Gaitan-Escudero Tatiana , Charles-Obi Kenechukwu , Zeitlinger Julia , Rebeiz Mark
Published: March 2024

Identifying the molecular origins by which new morphological structures evolve is one of the long standing problems in evolutionary biology. To date, vanishingly few examples provide a compelling account of how new morphologies were initially formed, thereby limiting our understanding of how diverse forms of life derived their complex features. Here, we provide evidence that the large projections on theDrosophila eugracilisphallus that are implicated in sexual conflict have evolved through co-option of the trichome genetic network. These unicellular apical projections on the phallus postgonal sheath are reminiscent of trichomes that cover theDrosophilabody but are up to 20-fold larger in size. During their development, they express the transcription factor Shavenbaby, the master regulator of the trichome network. Consistent with the co-option of the Shavenbaby network during the evolution of theD. eugracilisprojections, somatic mosaic CRISPR/Cas9 mutagenesis shows thatshavenbabyis necessary for their proper length. Moreover, mis-expression of Shavenbaby in the sheath ofD. melanogaster, a naïve species that lacks these extensions, is sufficient to induce small trichomes. These induced extensions rely on a genetic network that is shared to a large extent with theD. eugracilisprojections, indicating its co-option but also some genetic rewiring. Thus, by leveraging a genetically tractable evolutionarily novelty, our work shows that the trichome-forming network is flexible enough that it can be co-opted in a new context, and subsequently refined to produce unique apical projections that are barely recognizable compared to their simpler ancestral beginnings.
Novel non-immunogenic trained immunity inducing small molecule with improved anti-tumor properties
Authors: Ajit Jainu , Knight Hannah Riley , Chen Qing , Solanki Ani , Shen Jingjing , Kahn Aaron P. Esser
Published: March 2024

Trained immunity refers to the non-specific innate immune memory response triggered by the epigenetic and metabolic rewiring of innate immune cells. A strengthened innate immune system significantly improves disease resistance. However, very few trained immunity-inducing molecules have been identified. Almost all molecules for training are primarily immunogenic and then subsequently induce training. Non-immunogenic molecules that induce training could be employed in therapies without the concern of adverse inflammatory reactions. We identified a small molecule, A1155463, that modulates cellular metabolism to induce trained immunity in macrophagesin-vitro. We show that nanomolar concentrations of these compounds uniquely alter only cellular metabolism without leading to apoptosis. We further observed that these compounds could induce training in anin-vivomodel in mice. A1155463 training improved anti-tumor resistance to B16.F10 melanoma cells. The effect was enhanced upon combination with checkpoint therapy. In summary, we report the discovery of a novel trained immunity-inducing small molecule with enhanced anti-tumor properties.
Basal ganglia output coding - entopeduncular nucleus - of contextual kinematics and reward in the freely moving mouse
Authors: Verma-Rodríguez Anil K , Ramírez-Jarquín Josué O , Rossi-Pool Román , Tecuapetla Fatuel
Published: March 2024

The entopeduncular nucleus (EPN) is often termed as one of the output nuclei of the basal ganglia owing to their highly convergent anatomy. The rodent EPN has been implicated in reward and value coding whereas the primate analogue internal Globus Pallidus has been found to be modulated by some movements and in some circumstances. In this study we sought to understand how the rodent EPN might be coding kinematic, reward, and difficulty parameters, particularly during locomotion. Furthermore, we aimed to understand the level of movement representation: whole-body or specific body parts. To this end, mice were trained in a freely moving two-alternative forced choice task with two periods of displacement (return and go trajectories) and performed electrophysiological recordings together with video-based tracking. We found 1) robust reward coding but not difficulty. 2) Spatio-temporal variables better explain EPN activity during movement compared to kinematic variables, while both types of variables were more robustly represented in reward-related movement. 3) Reward sensitive units encode kinematics similarly to reward insensitive ones. 4) Population dynamics that best account for differences between these two periods of movement can be explained by allocentric references like distance to reward port. 5) The representation of paw and licks is not mutually exclusive, discarding a somatotopic muscle-level representation of movement in the EPN. Our data suggest that EPN activity represents movements and reward in a complex way: highly multiplexed, influenced by the objective of the displacement, where trajectories that lead to reward better represent spatial and kinematic variables. Interestingly, there are intertwining representations of whole-body movement kinematics with single paw and licking variables. Further, reward sensitive units encode kinematics similarly to reward insensitive ones, challenging the notion of distinct pathways for reward and movement processing.

Significance Statement

The entopeduncular nucleus is one of the main outputs of the basal ganglia whose activity has been hypothesized to be inversely correlated with movement. This study examines motor and reward coding simultaneously, finding that besides the great level of multiplexing of these variables, spatio-temporal coding is better represented than kinematic coding. The level of movement representation seems to be greatly influenced by the goal of a movement, with spatially biased variables influencing the population dynamics of this nucleus. Further, we uncover the coexistence of EPN modulation by movement at different timescales and body parts. The simple overall activity of this output nucleus cannot explain kinematic coding, challenging leading theories of basal ganglia function.
Palmitoylation regulates norepinephrine transporter trafficking and expression and is potentially involved in the pathogenesis of postural orthostatic tachycardia syndrome
Authors: Brown Christopher R. , Foster James D.
Published: March 2024

Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasisviareuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. Previous research has outlined that NET activity and trafficking is modulatedviareversible post-translational modifications like phosphorylation and ubiquitylation. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is another post-translational modification responsible for numerous biological mechanisms. In this study, we reveal that NET is dynamically palmitoylated and inhibition of this modification with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP), results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely with a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted WT hNET palmitoylation and elevated NET protein levels. The POTS associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable fragments. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of POTS.