bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor sialylation controls effective anti-cancer immunity in breast cancer
Authors: Mereiter Stefan , Jonsson Gustav , Oliveira Tiago , Helm Johannes , Hoffmann David , Abeln Markus , Jochum Ann-Kristin , Jochum Wolfram , Kellner Max J. , Feith Marek , Tkalec Vanessa , Wasilewska Karolina , Jiao Jie , Emsenhuber Lukas , Holstein Felix , Obenauf Anna C. , Lordello Leonardo , Scoazec Jean-Yves , Kroemer Guido , Zitvogel Laurence , Ali Omar Hasan , Flatz Lukas , Gerardy-Schahn Rita , Münster-Kühnel Anja , Stadlmann Johannes , Penninger Josef M.
Published: September 2023

Breast cancer is the most common cancer among women. However, the use of immune checkpoint inhibitors, that have revolutionized treatment of multiple cancers, unfortunately remain largely ineffective in most breast cancer patients. Here, we report the most comprehensive glycoproteome map in breast tumor cells, pointing to a key role of sialic acid modifications in mammary cancer. Genetic and pharmacologic inhibition of sialylation repolarizes the tumor microenvironment, leading to a reduction in myeloid-derived suppressor cells and a significant increase in Tcf7+memory and CD8+effector T cells. Mechanistically, sialylation controls cell surface expression of MHC class I and PD-1-ligand on the tumor cells. Functionally, in vivo interference with sialylation on breast cancer cells licenses CD8+T cells to effectively kill the tumors. In multiple immunotherapy-resistant breast tumor models, we also show that the abrogation of sialylation sensitizes to anti-PD-1 immune checkpoint therapy. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers tested and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways of immune evasion. Targeting tumor sialylation licenses immunologically inert mammary tumors to be efficiently eliminated by anti-cancer immunity and sensitizes to immune checkpoint therapy.
Unmasking AlphaFold: integration of experiments and predictions in multimeric complexes
Authors: Mirabello Claudio , Wallner Björn , Nystedt Björn , Azinas Stavros , Carroni Marta
Published: September 2023

Since the release of AlphaFold, researchers have actively refined its predictions and attempted to integrate it into existing pipelines for determining protein structures. These efforts have introduced a number of functionalities and results at the latest Critical Assessment of protein Structure Prediction edition (CASP15), resulting in a marked improvement in the prediction of multimeric protein structures. However, AlphaFold’s capability of predicting large protein complexes is still limited and integrating experimental data in the prediction pipeline is not straightforward. In this study, we introduce AF_unmasked to overcome these limitations. Our results demonstrate that AF_unmasked can integrate experimental information to build larger or hard to predict protein assemblies with high confidence. The resulting predictions can help interpret and augment experimental data. This new approach generates near-perfect structures even when little to no evolutionary information is available and imperfect experimental structures are used as a starting point. AF_unmasked fills incomplete structures by a procedure called“structural inpainting”, which may provide insights into protein dynamics. In summary, AF_unmasked provides an easy-to-use method that efficiently integrates experiments to predict large protein complexes more confidently.

Code

github.com/clami66/AF_unmasked
Tonic and phasic transcutaneous auricular vagus nerve stimulation both evoke rapid and transient pupil dilation
Authors: Skora Lina , Marzecová Anna , Jocham Gerhard
Published: September 2023

Background

Transcutaneous auricular vagus nerve stimulation (tVNS or taVNS) is a non-invasive method of electrical stimulation of the afferent pathway of the vagus nerve, suggested to drive changes in putative physiological markers of noradrenergic activity, including pupil dilation.

Objective

However, it is unknown whether different taVNS modes can map onto the phasic and tonic modes of noradrenergic activity. The effects of taVNS on pupil dilation in humans are inconsistent, largely due to differences in stimulation protocols. Here, we attempted to address these issues.

Methods

We investigated pupil dilation under phasic (1 s) and tonic (30 s) taVNS, in a pre-registered, single-blind, sham-controlled, within-subject cross-over design, in the absence of a behavioural task.

Results

Phasic taVNS induced a rapid increase in pupil size over baseline, significantly greater than under sham stimulation, which rapidly declined after stimulation offset. Tonic taVNS induced a similarly rapid (and larger than sham) increase in pupil size over baseline, returning to baseline within 5 s, despite the ongoing stimulation. Thus, both active and sham tonic modes closely resembled the phasic effect. There were no differences in tonic baseline pupil size, and no sustained effects of stimulation on tonic baseline pupil size.

Conclusions

These results suggest that both phasic- and tonic-like taVNS under the standard stimulation parameters may modulate primarily the phasic mode of noradrenergic activity, as indexed by evoked pupil dilation, over and above somatosensory effects. This result sheds light on the temporal profile of phasic and tonic stimulation, with implications for their applicability in further research.
Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET
Authors: Godbersen Godber M , Falb Pia , Klug Sebastian , Silberbauer Leo R , Reed Murray B , Nics Lukas , Hacker Marcus , Lanzenberger Rupert , Hahn Andreas
Published: September 2023

Functional positron emission tomography (fPET) with [18F]FDG allows one to quantify stimulation-induced dynamics in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires arterial blood sampling, which can cause discomfort for the participant and increases complexity of the experimental protocol. These constraints have limited the widespread applicability of fPET, especially in the clinical routine. Therefore, we introduce a novel approach, which enables the assessment of the dynamics in cerebral glucose metabolism without the need for an input function.

Methods

We tested the validity of a mathematical derivation on the basis of two independent data sets (DS). For DS1, 52 healthy volunteers (23.2 ± 3.3 years, 24 females) completed a visuo-spatial motor coordination task (the video game Tetris®) and for DS2, 18 healthy participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task, both during a [18F]FDG fPET scan. Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as the reference standard. Simplified outcome parameters, such as GLM beta values of task effects and percent signal change (%SC) of both parameters were estimated. These were compared for task-relevant brain regions and on a whole-brain level.

Results

In general, we observed higher agreement with the reference standard for DS1 (radiotracer administration as bolus + constant infusion) compared to DS2 (constant infusion only). Across both data sets, strong correlations were found between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). Additionally, %SC of beta values exhibited excellent agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively.

Conclusion

Task-specific changes in glucose metabolism can be reliably estimated using %SC of GLM beta values, eliminating the need for any blood sampling. This approach streamlines fPET imaging, albeit with the trade-off of being unable to quantify baseline metabolism. The proposed simplification enhances the applicability of fPET, allowing for widespread employment in research settings and clinical investigations.

GRAPHICAL ABSTRACT
Focal acetylcholinergic modulation of the human midcingulo-insular network during attention: Meta-analytic neuroimaging and behavioral evidence
Authors: Chakraborty Sudesna , Lee Sun Kyun , Arnold Sarah M. , Haast Roy A.M. , Khan Ali R. , Schmitz Taylor W.
Published: September 2023

The basal forebrain cholinergic neurons provide acetylcholine to the cortex via large projections. Recent molecular imaging work in humans indicates that the cortical cholinergic innervation is not uniformly distributed, but rather may disproportionately innervate cortical areas relevant to supervisory attention. In this study, we therefore reexamined the spatial relationship between acetylcholinergic modulation and attention in the human cortex using meta-analytic strategies targeting both pharmacological and nonpharmacological neuroimaging studies. We found that pharmaco-modulation of acetylcholine evoked both increased activity in the anterior cingulate and decreased activity in the opercular and insular cortex. In large independent meta-analyses of non-pharmacological neuroimaging research, we demonstrate that during attentional engagement these cortical areas exhibit (1) task-related co-activation with the basal forebrain, (2) task-related co-activation with one another, and (3) spatial overlap with dense cholinergic innervations originating from the BF, as estimated by multimodal PET and MR imaging. Finally, we provide meta-analytic evidence that pharmaco-modulation of acetylcholine also induces a speeding of responses to targets with no apparent tradeoff in accuracy. In sum, we demonstrate in humans that acetylcholinergic modulation of midcingulo-insular hubs of the ventral attention/salience network via basal forebrain afferents may coordinate selection of task relevant information, thereby facilitating cognition and behavior.
BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window
Authors: Lowe Simon A. , Wilson Abigail D. , Aughey Gabriel , Banarjee Animesh , Goble Talya , Simon-Batsford Nell , Sanderson Angelina , Kratschmer Patrick , Balogun Maryam , Gao Hao , Aw Sherry S. , Jepson James E.C.
Published: September 2023

Gain-of-function mutations in BK potassium channels (BK GOF) cause debilitating involuntary limb movements. BK channels modulate action potential shape and neurotransmission in mature neurons, yet some BK GOF mutations also cause neurodevelopmental morbidities. Thus, whether BK GOF impairs limb control by altering the excitation/inhibition of mature motor circuits, or by disrupting their development, remains unclear. To address this issue, we developed a genetic method enabling spatiotemporal control of BK channel expression in neurons of the fruit fly,Drosophila. In concert with high-resolution measurements of limb kinematics, we demonstrate that GOF BK channels act during a narrow neurodevelopmental period to perturb limb control in adult flies. During this period, BK GOF alters synaptic localisation of the key active zone protein Bruchpilot and suppresses excitatory neurotransmission. In a wild-type background, we find that reducing neural activity during neurodevelopment yields similar motor defects to those observed in BK GOF flies. Conversely, enhancing neural excitability during development rescues alterations in limb kinematics in BK GOF flies. Collectively, our results suggest that BK GOF perturbs limb control largely by disrupting activity-dependent aspects of neuronal development.
The glucocorticoid dexamethasone inhibits HIF-1alpha stabilisation and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages
Authors: Clayton Sally A , Lockwood Chloe , O’Neil John D , Daley Kalbinder K , Hain Sofia , Abdelmottaleb Dina , Bolimowska Oliwia O , Tennant Daniel A , Clark Andrew R
Published: September 2023

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis, caused by changes of glucose traffic and metabolism in muscle, liver and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly-used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia- inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on alteration of glucose utilisation.

GRAPHICAL ABSTRACT
Subnet Communicability: Diffusive Communication Across the Brain Through a Backbone Subnetwork
Authors: Parlett Jonathan , Jeyapratap Abhishek , Shokoufandeh Ali , Tunc Birkan , Osmanlioglu Yusuf
Published: September 2023

One of the fundamental challenges in modern neuroscience is understanding the interplay between the brain’s functional activity and its underlying structural pathways. To address this question, we propose a novel communication pattern calledsubnet communicability, which models diffusive communication between pairs of regions through a small, intermediary subnetwork of brain regions as opposed to spreading messages through the entire network. We demonstrate that subnet communicability strengthens coupling between the structural and functional connectomes better than previous models, including communicability. Over two large datasets, we show that the optimal subnetwork is consistent across the population. Subnet communicability provides new insights into structure-function coupling in the brain and offers a balance between redundancy in message passing and economy of brain wiring.
GPFN: Prior-Data Fitted Networks for Genomic Prediction
Authors: Ubbens Jordan , Stavness Ian , Sharpe Andrew G.
Published: September 2023

Genomic Prediction (GP) methods predict the breeding value of unphenotyped individuals in order to select parental candidates in breeding populations. Among models for GP, classical linear models have remained consistently popular, while more complex nonlinear methods such as deep neural networks have shown comparable accuracy at best. In this work we propose the Genomic Prior-Data Fitted Network (GPFN), a new paradigm for GP. GPFNs perform amortized Bayesian inference by drawing hundreds of thousands or millions of synthetic breeding populations during the prior fitting phase. This allows GPFNs to be deployed without requiring any training or tuning, providing predictions in a single inference pass. On three populations of crop plants across two different crop species, GPFNs perform significantly better than the linear baseline on 13 out of 16 traits. On a challenging between-families NAM prediction task, the GPFN performs significantly better in 3 locations while only falling behind in one. GPFNs represent a completely new direction for the field of genomic prediction, and have the potential to unlock levels of selection accuracy not possible with existing methods.
Rapid evolution ofWolbachiagenomes in mosquito cell culture
Authors: Martinez Julien , Sinkins Steve P.
Published: September 2023

Wolbachiabacterial symbionts are widespread across arthropods where they cause reproductive manipulations and/or confer fitness benefits such as protection against viral pathogens. Their self-spreading ability coupled with their antiviral effect has been harnessed in health programmes to curb the transmission of dengue virus. Comparative genomics ofWolbachiastrains has been a useful tool to understand the general trends in the evolution of the symbiont genome; however, short-term evolutionary processes occurring within hosts remain poorly explored. Understanding these short-term dynamics is necessary to provide a more complete picture ofWolbachiaevolution and will inform ongoingWolbachia-based disease control interventions. Here we generated six new mosquito cell lines by introducing a range ofWolbachiastrains fromDrosophilainto the symbiont-freeAedes albopictusAa23 cell line. Following transinfection, we tracked temporal variation inWolbachiadensity and identifiedde novomutations through re-sequencing of the symbiont genome. Several mutations were associated with major shifts in bacterial density. Moreover, signs of parallel evolution across cell lines, combined with an excess of non-synonymous mutations, indicate thatWolbachiaevolution in cell culture is dominated by selective processes rather than genetic drift. Our results also provide new candidate genes likely to be involved in symbiont density regulation. Altogether, our study demonstrates that cell culture is a valuable tool to investigate symbiont short-term evolution, identify the genetic basis of bacterial density variation and for the generation of new higher-density variants for use in control programmes.
Biological warfare between two bacterial viruses in a genomic archipelago sheds light on the spread of CRISPR-Cas systems
Authors: Rubio Alejandro , Garzón Andrés , Moreno-Rodriguez Antonio , Pérez-Pulido Antonio J.
Published: September 2023

CRISPR-Cas systems are acquired immunity systems of bacteria and archaea that prevent infection by phages and other mobile genetic elements. It is currently known that this defense system has also been co-opted by viruses. These viruses could use CRISPR-Cas systems to compete against other rival viruses. We have discovered a virus in the bacteriumAcinetobacter baumanniithat incorporates a CRISPR-Cas system into an integration hotspot of the host genome. Once integrated, this could prevent the infection of the most frequent viruses in this bacterial species, especially one that competes with the CRISPR-Cas system itself for the same integration site. This latter virus is prevalent in strains of the species belonging to the so-called Global Clone 2, which causes the most frequent outbreaks worldwide. Knowledge of this new viral warfare using CRISPR-Cas systems, known to limit the entry of antibiotic resistance genes into bacteria, could be useful in the fight against the infections they cause. But it would also shed light on the way in which these defense systems expand in bacteria.
Decoding Nucleosome-Depleted Regions: Insights from Epigenetic Marks, Nucleosome Size, and Thermodynamic Modelling
Authors: Tartour Kévin , Barbier Jérémy , Hungyo Kharerin , Sassolas Fabien , Vaillant Cédric , Padmanabhan Kiran , Audit Benjamin
Published: September 2023

Elucidating the global and local rules that govern genome-wide nucleosome organisation and chromatin architecture remains a critical challenge. Thermodynamic modelling based on DNA elastic properties predicts the presence of sequence-encoded nucleosome-inhibiting energy barriers (NIEBs) along vertebrate genomes. They delineatein vivonucleosome-depleted regions (NDRs) flanked by 2-3 well positioned nucleosomes. Here, we compared mouse NIEBs to NDRs observed at CTCF binding sites and active TSSs to reveal specific chromatin organizations. We uncover in MNase-seq chromatin profiles the presence of particles of subnucleosomal length specifically positioned at the border of NIEBs with an enrichment of H3.3 and its modification H3.3 S31Ph, whereas the positioning of nucleosomes bearing H3K27ac appears insensitive to NIEBs. Surprisingly, post-translational modifications affect the size distribution of nucleosomes as seen by MNase digestion and so likely their breathing capability. We implemented an extension of our thermodynamic model allowing for variable particle size and suggest that subnucleomes at NIEB borders would result from the recruitment of chromatin remodellers at NIEBs. Our findings provide new insights into the mechanisms by which the DNA sequence and epigenetic marks shape the nucleosome positioning and breathing.
Mechanical and elemental characterization of ant mandibles: consequences for bite mechanics
Authors: Klunk Cristian L. , Heethoff Michael , Hammel Jörg U. , Gorb Stanislav N. , Krings Wencke
Published: September 2023

Chewing with the mandibles is a food processing behavior observed in most current insect lineages. Mandible morphology has an essential role in biting behavior and food processing capacity. However, the mandible cuticle can have regional differences in its mechanical properties, associated or not with the accumulation of elements that increase cuticle stiffness. The effects of such a heterogeneous distribution of cuticle material properties in the mandible responses to biting loading are still poorly explored in chewing insects. Here we measured the elemental composition and material properties of workers of an ant species,Formica cunicularia, and tested the effects of the cuticular variation in Young’s modulus (E) under bite-loading with Finite Element Analysis (FEA). We divided worker mandibles into four regions that we expect would vary in elemental composition and material properties, namely the masticatory margin, mandible blade, ventral (VMA), and dorsal (DMA) mandibular articulations with the head. Specifically, we expect the masticatory margin will show higher cuticular hardness (H) and E values, followed by the mandibular joints and the mandible blade. We also predict that such cuticle material properties variation is functionally relevant under bite-loading, changing stress patterns when compared to the mechanical responses of a mandible with a homogeneous distribution of material properties. To measure elemental composition, we used energy disperse X-ray spectroscopy, while H and E were accessed through nanoindentation tests. Mandible mechanical responses to bite-loading were tested with FEA, comparing a mandible with a homogeneous versus a heterogeneous E distribution. As expected, the mandibular regions showed distinct proportions of relevant elements, like Cu and Zn, with the masticatory margin showing the higher levels of those elements, followed by the mandibular articulations with the head and the mandible blade. The same pattern was observed regarding the values of cuticle H and E. When incorporated into FEA, this variation in E effectively changed mandible stress patterns, leading to a higher concentration of stresses in the stiffer mandibular regions, letting the softer mandible blade with relatively lower stress levels. Our results demonstrated the relevance of cuticle heterogeneity in mechanical properties to deal with bite-loading demands and suggest that the accumulation of transition metals such as Cu and Zn has a relevant correlation with such mechanical characteristics of the mandible in this ant species.
Modeling the evolution of segment trees reveals deficiencies in current inferential methods for genomic reassortment
Authors: Lin Qianying , Goldberg Emma E. , Leitner Thomas , Molina-París Carmen , King Aaron A. , Romero-Severson Ethan O.
Published: September 2023

Reassortment is an evolutionary process common in viruses with segmented genomes. These viruses can swap whole genomic segments during cellular co-infection, giving rise to new viral variants. Large-scale genome rearrangements, such as reassortment, have the potential to quickly generate new phenotypes, making the understanding of viral reassortment important to both evolutionary biology and public health research. In this paper, we argue that reassortment cannot be reliably inferred from incongruities between segment phylogenies using the established remove-and-rejoin or coalescent approaches. We instead show that reassortment must be considered in the context of a broader population process that includes the dynamics of the infected hosts. Using illustrative examples and simulation we identify four types of evolutionary events that are difficult or impossible to reconstruct with incongruence-based methods. Further, we show that these specific situations are very common and will likely occur even in small samples. Finally, we argue that existing methods can be augmented or modified to account for all the problematic situations that we identify in this paper. Robust assessment of the role of reassortment in viral evolution is difficult, and we hope to provide conceptual clarity on some important methodological issues that can arise in the development of the next generation of tools for studying reassortment.
Perinatal Morphine Exposure Induces Long-Term Changes in the Intestinal Microbiota of Male and Female Rats
Authors: Harder Hannah J. , Dauriat Charlène J.G. , Chassaing Benoit , Murphy Anne Z.
Published: September 2023

The increased use of opioids by women of reproductive age has resulted in a dramatic rise in number of infants exposed to opioidsin utero. Although perinatal opioid exposure (POE) has been associated with an elevated risk of infection and hospitalization later in life, the mechanism(s) by which opioids influence immune development and maturation is not fully elucidated. Alterations in the intestinal microbiota composition, which leads to changes in immune training and maturation, could be at play. Chronic opioid use in adults is associated with a proinflammatory and pathogenic microbiota composition; therefore, we hypothesized here thatin uteromorphine exposure could negatively affect intestinal microbiota composition, leading to alterations in immune system function. We report that a clinically-relevant model of perinatal opioid exposure, in rats, induces profound intestinal microbiota dysbiosis that is maintained into adulthood. Furthermore, microbial maturity was reduced in morphine-exposed offspring. This suggests that increased risk of infection observed in children exposed to opioids during gestation may be a consequence of microbiota alterations with downstream impact on immune system development. Further investigation of how perinatal morphine induces dysbiosis will be critical to the development of early life interventions designed to ameliorate the increased risk of infection observed in these children.
Independent Influences of Movement Distance and Visual Distance on Fitts' Law
Authors: Al-Fawakhiri Naser , McDougle Samuel D.
Published: September 2023

Fitts’ Law is one among a small number of psychophysical laws. However, a fundamental variable in Fitts’ Law – the movement distance, D – confounds two quantities: the physical distance the effector has to move to reach a goal, and the visually perceived distance to that goal. While these two quantities are functionally equivalent in everyday motor behavior, decoupling them might improve our understanding of the factors that shape speed-accuracy tradeoffs. Here we leveraged the phenomenon of visuomotor gain adaptation to de-confound movement and visual distance during goal-directed reaching. We found that movement distance and visual distance can influence movement times, supporting a variant of Fitts’ Law that considers both. The weighting of movement versus visual distance was modified by restricting movement range and degrading visual feedback. These results may reflect the role of sensory context in early stages of motor planning.

Public Significance

You will automatically slow your movement when picking up a needle five inches away versus a handkerchief three inches away. This fact is elegantly formalized by Fitts’ Law, which mathematically relates movement duration to movement difficulty. However, one of the fundamental variables in the law – the distance of a planned movement – is ambiguous: Is it the actual distance the hand must move that biases movement duration, or is it the visually perceived distance? We decoupled these variables, finding that Fitts’ Law is shaped by both quantities, and that the influence of one versus the other may be related to the relevance of visual information. We believe our “addendum” to Fitts’ Law is timely, as everyday motor behavior has become increasingly enmeshed with virtual environments that abstract our movements into digital realities.
A neural signature for the subjective experience of threat anticipation under uncertainty
Authors: Liu Xiqin , Jiao Guojuan , Zhou Feng , Kendrick Keith M , Yao Dezhong , Xiang Shitong , Jia Tianye , Zhang Xiaoyong , Zhang Jie , Feng Jianfeng , Becker Benjamin
Published: September 2023

Uncertainty about potential future threats and the associated anxious anticipation represents a key feature of anxiety. However, the neural systems that underlie the subjective experience of threat anticipation under uncertainty remain unclear. Combining a novel uncertain shock anticipation paradigm that allows precise modulation of the level of momentary anxious arousal during functional magnetic resonance imaging (fMRI) with multivariate predictive modeling, we trained a brain model that accurately predicted the intensity of subjective experience of anxious arousal on the population and individual level. In a series of analyses utilizing available fMRI datasets, we further demonstrate that the signature specifically predicted anxious anticipation and was not sensitive in predicting pain, general anticipation or unspecific arousal. The signature was functionally and spatially distinguishable from representations of subjective fear or negative affect. We developed a sensitive, generalizable, and specific neuromarker for subjective anxious arousal experienced during uncertain threat anticipation that can facilitate model development and clinical translation.
Effect of Menstrual Cycle and Menopause on Human Gastric Electrophysiology
Authors: Lim Alexandria H , Varghese Chris , Sebaratnam Gabrielle , Schamberg Gabriel , Calder Stefan , Gharibans Armen , Andrews Christopher N , Foong Daphne , Ho Vincent , Ishida Shunichi , Imai Yohsuke , Wise Michelle R , O’Grady Greg
Published: September 2023

Chronic gastroduodenal symptoms disproportionately affect females of childbearing age; however, the effect of menstrual cycling on gastric electrophysiology is poorly defined. To establish the effect of the menstrual cycle on gastric electrophysiology, healthy subjects underwent non-invasive Body Surface Gastric Mapping (BSGM; 8×8 array), with validated symptom logging App (Gastric AlimetryⓇ, New Zealand). Participants were premenopausal females in follicular (n=26) and luteal phases (n=18). Postmenopausal females (n=30) and males (n=51) were controls. Principal gastric frequency (PGF), BMI-adjusted amplitude, Gastric Alimetry Rhythm Index (GA-RI), fasted-fed amplitude ratio (ff-AR), meal response curves, and symptom burden were analysed. Menstrual cycle-related electrophysiological changes were then transferred to an established anatomically-accurate computational gastric fluid dynamics model (meal viscosity 0.1 Pas), to predict the impact on gastric mixing and emptying. PGF was significantly higher in the luteal vs. follicular phase (mean 3.21 cpm, SD (0.17) vs. 2.94 cpm, SD (0.17), p<0.001) and vs. males (3.01 cpm, SD (0.2), p<0.001). In the computational model, this translated to 8.1% higher gastric mixing strength and 5.3% faster gastric emptying for luteal versus follicular phases. Postmenopausal females also exhibited higher PGF than females in the follicular phase (3.10 cpm, SD (0.24) vs. 2.94 cpm, SD (0.17), p=0.01), and higher BMI-adjusted amplitude (40.7 µV (33.02-52.58) vs. 29.6 µV (26.15-39.65), p<0.001), GA-RI (0.60 (0.48-0.73) vs. 0.43 (0.30-0.60), p=0.005), and ff-AR (2.51 (1.79-3.47) vs. 1.48 (1.21-2.17), p=0.001) than males. There were no differences in symptoms. These results define variations in gastric electrophysiology with regard to human menstrual cycling and menopause.

New and Noteworthy

This study evaluates gastric electrophysiology in relation to the menstrual cycle using a novel non-invasive high-resolution methodology, revealing substantial variations in gastric activity with menstrual cycling and menopause. Gastric slow wave frequency is significantly higher in the luteal versus follicular menstrual phase. Computational modelling predicts that this difference translates to higher rates of gastric mixing and emptying in the luteal phase, which is consistent with previous experimental data evaluating menstrual cycling effects on gastric emptying.
Simultaneous estimation of gene regulatory network structure and RNA kinetics from single cell gene expression
Authors: Jackson Christopher A , Beheler-Amass Maggie , Tjärnberg Andreas , Suresh Ina , Hickey Angela Shang-mei , Bonneau Richard , Gresham David
Published: September 2023

Cells respond to environmental and developmental stimuli by remodeling their transcriptomes through regulation of both mRNA transcription and mRNA decay. A central goal of biology is identifying the global set of regulatory relationships between factors that control mRNA production and degradation and their target transcripts and construct a predictive model of gene expression. Regulatory relationships are typically identified using transcriptome measurements and causal inference algorithms. RNA kinetic parameters are determined experimentally by employing run-on or metabolic labeling (e.g. 4-thiouracil) methods that allow transcription and decay rates to be separately measured. Here, we develop a deep learning model, trained with single-cell RNA-seq data, that both infers causal regulatory relationships and estimates RNA kinetic parameters. The resultingin silicomodel predicts future gene expression states and can be perturbed to simulate the effect of transcription factor changes.

We acquired model training data by sequencing the transcriptomes of 175,000 individualSaccharomyces cerevisiaecells that were subject to an external perturbation and continuously sampled over a one hour period. The rate of change for each transcript was calculated on a per-cell basis to estimate RNA velocity. We then trained a deep learning model with transcriptome and RNA velocity data to calculate time-dependent estimates of mRNA production and decay rates. By separating RNA velocity into transcription and decay rates, we show that rapamycin treatment causes existing ribosomal protein transcripts to be rapidly destabilized, while production of new transcripts gradually slows over the course of an hour.

The neural network framework we present is designed to explicitly model causal regulatory relationships between transcription factors and their genes, and shows superior performance to existing models on the basis of recovery of known regulatory relationships. We validated the predictive power of the model by perturbing transcription factorsin silicoand comparing transcriptome-wide effects with experimental data. Our study represents the first step in constructing a complete, predictive, biophysical model of gene expression regulation.
TreeProfiler: A command-line tool for computing and visualizing phylogenetic profiles against large trees
Authors: Deng Ziqi , Hernández-Plaza Ana , Huerta-Cepas Jaime
Published: September 2023

Phylogenetic profiling is a common bioinformatics approach used to study the distribution of traits across species or, more broadly, along the topology of a phylogenetic tree. Originally proposed as a technique for establishing functional relationships between various genes through their correlated presence/absence patterns, phylogenetic profiling is currently considered a powerful exploration tool for investigating the evolutionary distribution of nearly any trait across both gene or species phylogenies. However, computing and visualizing phylogenetic profiles based on large trees is a laborious task. First, traits need to be mapped against tree nodes, which usually requires the implementation ofad hocscripts or substantial manual work. Second, tree mapping is often limited to leaf nodes, neglecting the usefulness of profiling traits against internal tree nodes. Lastly, graphical exploration of large phylogenetic tree-based profiles is challenging, as plotting usually requires complex manual adjustments and most visualization tools cannot scale to the size and complexity of current datasets. To address these limitations, we have developed TreeProfiler, a command line tool designed to facilitate both the automated annotation of large trees using a wide range of data sources, and the visual exploration of these annotations as phylogenetic profiles. TreeProfiler enables seamless annotation of massive trees and data tables, including built-in support for functional data, taxonomic information, multiple sequence alignments and protein domain architectures. Importantly, TreeProfiler expands its annotation capabilities beyond tree leaves, enabling the annotation of internal nodes with summarized or consensus information under each branch. Additionally, TreeProfiler offers a predefined set of graphical layouts that are based on the ETE Toolkit v4.0 library. TreeProfiler offers unique capabilities that extend and facilitate the use of phylogenetic profiling techniques for a broad landscape of scenarios and for a wide community of researchers interested in evolutionary analysis. To demonstrate its value, we showcase TreeProfiler by automatically profiling multiple data sources across a large bacterial phylogeny including 45,555 species, and by exploring functional and taxonomic annotations over a large gene family tree. TreeProfiler is available athttps://github.com/compgenomicslab/TreeProfiler.
Bias in data-driven estimates of the replicability of univariate brain-wide association studies
Authors: Burns Charles D. G. , Fracasso Alessio , Rousselet Guillaume A.
Published: September 2023

Recent studies have used big neuroimaging datasets to answer an important question: how many subjects are required for reproducible brain-wide association studies? These data-driven approaches could be considered a framework for testing the reproducibility of several neuroimaging models and measures. Here we test part of this framework, namely estimates of statistical errors of univariate brain-behaviour associations obtained from resampling large datasets with replacement. We demonstrate that reported estimates of statistical errors are largely a consequence of bias introduced by random effects when sampling with replacement close to the full sample size. We show that future meta-analyses can largely avoid these biases by only resampling up to 10% of the full sample size. We discuss implications that reproducing mass-univariate association studies requires tens-of-thousands of participants, urging researchers to adopt other methodological approaches.
Brief Apnea and Hypoventilation Reduces Seizure Duration and Shifts Seizure Location for Several Hours in a Model of Severe Traumatic Brain Injury
Authors: Rodriguez Lara Frances , Sunkavalli Praneel , Mikaelian Michael , Golemb Bryan , Staley Kevin , Costine-Bartell Beth
Published: September 2023

Objective

Seizures are difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). In our multifactorial, severe TBI model (cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, seizures induced with kainic acid, and brief apnea and hypoventilation), we observed that brief apnea with hypoventilation (A&H) after induced seizure acutely interrupted seizures, leading us to hypothesize that brief A&H might reduce seizure duration beyond the brief hypoxia and hypercapnia for several hours thereafter. The effects of the timing of A&H on seizure duration and location might inform the pathophysiology of this hypoxic-ischemic injury as well as potential treatments.

Methods

Piglets (1 week or 1 month old) received multi-factorial injuries. Apnea and hypoventilation (1 min apnea, 10 min hypoventilation; A&H) was induced either before or after seizure induction, or as a control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, mechanically ventilated, and epidural EEG was recorded for an average of 18 hours after seizure induction.

Results

In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures though most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 hours, seizures transitioned to interictal epileptiform discharges regardless of timing of A&H.

Significance

Even brief A&H may alter traumatic seizures We will address the possibility of induced spreading depolarization prior to preclinical investigations of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.
TheSilene latifoliagenome and its giant Y chromosome
Authors: Moraga Carol , Branco Catarina , Rougemont Quentin , Veltsos Paris , Jedlička Pavel , Muyle Aline , Hanique Melissa , Tannier Eric , Liu Xiaodong , Mendoza-Galindo Eddy , Lemaitre Claire , Fields Peter D. , Cruaud Corinne , Labadie Karine , Belser Caroline , Briolay Jerome , Santoni Sylvain , Cegan Radim , Linheiro Raquel , de la Vega Ricardo C. Rodríguez , Adam Gabriele , Filali Adil El , Mossion Vinciane , Boualem Adnane , Tavares Raquel , Chebbi Amine , Cordaux Richard , Fruchard Cécile , Prentout Djivan , Velt Amandine , Spataro Bruno , Delmotte Stephane , Weingartner Laura , Toegelová Helena , Tulpová Zuzana , Cápal Petr , Šimková Hana , Štorchová Helena , Krüger Manuela , Abeyawardana Oushadee A. J. , Taylor Douglas R. , Olson Matthew S. , Sloan Daniel B. , Karrenberg Sophie , Delph Lynda F. , Charlesworth Deborah , Giraud Tatiana , Bendahmane Abdelhafid , Genova Alex Di , Madoui Amin , Hobza Roman , Marais Gabriel A. B.
Published: September 2023

In some species, the Y is a tiny chromosome but the dioecious plantSilene latifoliahas a giant ∼550 Mb Y chromosome, which has remained unsequenced so far. Here we used a hybrid approach to obtain a high-quality maleS. latifoliagenome. Using mutants for sexual phenotype, we identified candidate sex-determining genes on the Y. Comparative analysis of the sex chromosomes with outgroups showed the Y is surprisingly rearranged and degenerated for a ∼11 MY-old system. Recombination suppression between X and Y extended in a stepwise process, and triggered a massive accumulation of repeats on the Y, as well as in the non-recombining pericentromeric region of the X, leading to giant sex chromosomes.

One-Sentence Summary

This work uncovers the structure, function, and evolution of one of the largest giant Y chromosomes, that of the model plantSilene latifolia, which is almost 10 times larger than the human Y, despite similar genome sizes.
tidytcells: standardizer for TCR/MHC nomenclature
Authors: Nagano Yuta , Chain Benjamin
Published: September 2023

T cell receptors (TCRs) underpin the diversity and specificity of T cell activity. As such, TCR repertoire data is valuable both as an adaptive immune biomarker, and as a way to identify candidate therapeutic TCRs. Analysis of TCR repertoires relies heavily on computational analysis, and therefore it is of vital importance that the data is standardized and computer-readable. However in practice, the usage of different abbreviations and non-standard nomenclature in different datasets makes this data pre-processing non-trivial.tidytcellsis a lightweight, platform-independent Python package that provides easy-to-use standardization tools specifically designed for TCR nomenclature. The software isopen-sourcedunder the MIT license and is available to install from thePython Package Index (PyPI).
Epigenetic modification and characterization of theMGMTpromoter region using CRISPRoff in glioblastoma cells
Authors: Weber Remi , Weller Michael , Reifenberger Guido , Vasella Flavio
Published: September 2023

The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) promoter region is a critical predictor of response to alkylating agents in glioblastoma. However, current approaches to study theMGMTstatus focus on analyzing models with non-identical backgrounds. Here, we present an epigenetic editing approach using CRISPRoff to introduce site-specific CpG methylation in theMGMTpromoter region of glioma cell lines. Sanger sequencing revealed successful introduction of methylation, effectively generating differently methylated glioma cell lines with an isogenic background. The introduced methylation resulted in reduced MGMT mRNA and protein levels. Furthermore, the cell lines withMGMTpromoter region methylation exhibited increased sensitivity to temozolomide, consistent with the impact of methylation on treatment outcomes in patients with glioblastoma. This precise epigenome-editing approach provides valuable insights into the functional relevance ofMGMTpromoter regional methylation and its potential for prognostic and predictive assessments, as well as epigenetic-targeted therapies.
Oncogenic functions of the m6A demethylase FTO in breast cancer cells involving translational upregulation of C/EBPβ-LIP
Authors: Zuidhof Hidde R. , Müller Christine , Kortman Gertrud , Wardenaar René , Stepanova Ekaterina , Loayza-Puch Fabricio , Calkhoven Cornelis F.
Published: September 2023

N6-methyladenosine (m6A) is a prevalent posttranscriptional mRNA modification involved in the regulation of transcript turnover, translation, and other aspects of RNA fate. The modification is mediated by multicomponent methyltransferase complexes (so-called writers) and is reversed through the action of the m6A-demethylases fat mass and obesity-associated (FTO) and alkB homolog 5 (ALKBH5) (so-called erasers). FTO promotes cell proliferation, colony formation and metastasis in models of triple-negative breast cancer (TNBC). However, little is known about genome-wide or specific downstream regulation by FTO. Here, we examined changes in the genome-wide transcriptome and translatome following FTO-knockdown in TNBC cells. Unexpectedly, FTO knockdown had a limited effect on the translatome, while transcriptome analysis revealed that genes related to extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) are being regulated through yet unidentified mechanisms. Differential translation of the CEBPB mRNA into the C/EBPβ transcription factor isoform C/EBPβ-LIP is known to act pro-oncogenic in TNBC cells through regulation of EMT genes. Here we show that FTO is required for efficient C/EBPβ-LIP expression, suggesting that FTO has oncogenic functions through regulation of C/EBPβ-LIP.