bluuebunny/crossref_metadata_2025 huggingface dataset:
Fair molecular feature selection unveils universally tumor lineage-informative methylation sites in colorectal cancer
Authors: Li Xuan Cindy , Liu Yuelin , Schäffer Alejandro A. , Mount Stephen M. , Sahinalp S. Cenk
Published: February 2024

In the era of precision medicine, performing comparative analysis over diverse patient populations is a fundamental step towards tailoring healthcare interventions. However, the critical aspect of equitably selecting molecular features across multiple patients is often overlooked. To address this challenge, we introduceFALAFL(FAir muLti-sAmple Feature seLection), an algorithmic approach based on combinatorial optimization.FALAFLis designed to bridge the gap between molecular feature selection and algorithmic fairness, ensuring a fair selection of molecular features from all patient samples in a cohort.

We have appliedFALAFLto the problem of selecting lineage-informative CpG sites within a cohort of colorectal cancer patients subjected to low read coverage single-cell methylation sequencing. Our results demonstrate thatFALAFLcan rapidly and robustly determine the optimal set of CpG sites, which are each well covered by cells across the vast majority of the patients, while ensuring that in each patient a high proportion of these sites have good read coverage. An analysis of theFALAFL-selected sites reveals that their tumor lineage-informativeness exhibits a strong correlation across a spectrum of diverse patient profiles. Furthermore, these universally lineage-informative sites are highly enriched in the inter CpG island regions.

FALAFLintegrates equity considerations into the molecular feature selection from single-cell sequencing data obtained from a patient cohort. We hope that it will help propel equitable healthcare data science practices and contribute to the advancement of our understanding of complex diseases.
A biomimetic fruit fly robot for studying the neuromechanics of legged locomotion
Authors: Goldsmith Clarus A. , Haustein Moritz , Büschges Ansgar , Szczecinski Nicholas S.
Published: February 2024

For decades, the field of biologically inspired robotics has leveraged insights from animal locomotion to improve the walking ability of legged robots. Recently, “biomimetic” robots have been developed to model how specific animals walk. By prioritizing biological accuracy to the target organism rather than the application of general principles from biology, these robots can be used to develop detailed biological hypotheses for animal experiments, ultimately improving our understanding of the biological control of legs while improving technical solutions. In this work, we report the development and validation of the robot Drosophibot II, a meso-scale robotic model of an adult fruit fly,Drosophila melanogaster. This robot is novel for its close attention to the kinematics and dynamics ofDrosophila, an increasingly important model of legged locomotion. Each leg’s proportions and degrees of freedom have been modeled afterDrosophila3D pose estimation data. We developed a program to automatically solve the inverse kinematics necessary for walking and solve the inverse dynamics necessary for mechatronic design. By applying this solver to a fly-scale body structure, we demonstrate that the robot’s dynamics fits those modeled for the fly. We validate the robot’s ability to walk forward and backward via open-loop straight line walking with biologically inspired foot trajectories. This robot will be used to test biologically inspired walking controllers informed by the morphology and dynamics of the insect nervous system, which will increase our understanding of how the nervous system controls legged locomotion.
Exploring Directed Connectivity Patterns of OPM-MEG with Multivariate Transfer Entropy
Authors: Pedersen Mangor , Vashista Geet , Henare Dion , Sowman Paul F.
Published: February 2024

We explored the directed connectivity of magnetoencephalography data recorded via Optically Pumped Magnetometers (OPM-MEG). Ten healthy adult participants were scanned twice while watching a movie in an OPM-MEG system. Beamformer source localisation was employed to obtain source time series within 62 cortical brain regions. Multivariate transfer entropy (mTE) was used to quantify directed connectivity. Our results suggest that out-degree connectivity (node-to-network) was stronger than in-degree (network-to-node). Out-degree display a more heavy-tailed distribution, indicative of brain hubs, whereas in-degree nodes had a distribution closer to a normal distribution. Although in-degree and out-degree nodes were positively correlated, we observed that out-degree connectivity was stronger in somatomotor and attention networks than in other resting-state networks. However, in- and out-degree were both inversely related to the physical distance between nodes, suggesting that directed connectivity is stronger between short-distanced nodes. As OPM-MEG research is likely to expand substantially in the future, we propose that directed connectivity measures may provide additional insights into the underlying mechanisms of brain communication.
MRI mapping of hemodynamics in the human spinal cord
Authors: Hemmerling Kimberly J. , Hoggarth Mark A. , Sandhu Milap S. , Parrish Todd B. , Bright Molly G.
Published: February 2024

Impaired spinal cord vascular function contributes to numerous neurological pathologies, making it important to be able to noninvasively characterize these changes. Here, we propose a functional magnetic resonance imaging (fMRI)-based method to map spinal cord vascular reactivity (SCVR). We used a hypercapnic breath-holding task, monitored with end-tidal CO2(PETCO2), to evoke a systemic vasodilatory response during concurrent blood oxygenation level-dependent (BOLD) fMRI. SCVR amplitude and hemodynamic delay were mapped at the group level in 27 healthy participants as proof-of-concept of the approach, and then in two highly-sampled participants to probe feasibility/stability of individual SCVR mapping. Across the group and the highly-sampled individuals, a strong ventral SCVR amplitude was initially observed without accounting for local regional variation in the timing of the vasodilatory response. Shifted breathing traces (PETCO2) were used to account for temporal differences in the vasodilatory response across the spinal cord, producing maps of SCVR delay. These delay maps reveal an earlier ventral and later dorsal response and demonstrate distinct gray matter regions concordant with territories of arterial supply. The SCVR fMRI methods described here enable robust mapping of spatiotemporal hemodynamic properties of the human spinal cord. This noninvasive approach has exciting potential to provide early insight into pathology-driven vascular changes in the cord, which may precede and predict future irreversible tissue damage and guide the treatment of several neurological pathologies involving the spine.
Lifespan reference curves for harmonizing multi-site regional brain white matter metrics from diffusion MRI
Authors: Zhu Alyssa H. , Nir Talia M. , Javid Shayan , Villalon-Reina Julio E. , Rodrigue Amanda L. , Strike Lachlan T. , de Zubicaray Greig I. , McMahon Katie L. , Wright Margaret J. , Medland Sarah E. , Blangero John E. , Glahn David C. , Kochunov Peter , Håberg Asta K. , Thompson Paul M. , Jahanshad Neda
Published: February 2024

Age-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan with a unique trajectory in the brain, complementing the process of gray matter development and degeneration. Normative modeling can establish lifespan reference curves for typical WM microstructural aging patterns by pooling data from many independent studies that span different age ranges. Here, we create such reference curves by harmonizing and pooling diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three ComBat harmonization methods to create normative curves for regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a widely used metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with neuroscientific knowledge regarding WM maturation peaks. Harmonized FA metrics were used to create lifespan reference curves, which were validated with test-retest data and used to assess the effect of the ApoE4 risk factor for dementia in WM across the lifespan. We found significant associations between ApoE4 and FA in WM regions associated with neurodegenerative disease even in healthy individuals across the lifespan, with regional age-by-genotype interactions. Within-study associations were not affected by normative harmonization, ensuring that large-scale harmonized studies can be conducted across the lifespan, even from distinct age-restricted studies, without compromising individual study findings. Our lifespan reference curves and tools to harmonize new dMRI data to the curves are available through our new Python package, eHarmonize (https://github.com/ahzhu/eharmonize).
Friend, food, or foe: sea anemones discharge fewer nematocysts at familiar anemonefish after delayed mucus adaptation
Authors: Hoepner Cassie M. , Fobert Emily K. , Rudd David , Petersen Oliver , Abbott Catherine A. , da Silva Karen Burke
Published: February 2024

1.

For decades, it has been hypothesized that anemonefishes are able to live within the stinging tentacles of host sea anemone species because the chemical composition of their mucus layer inhibits or lacks the trigger for firing host nematocysts. However, there is very little molecular evidence for this, beyond suggestions that glycans in the mucus could be key. In this study we assessed these hypotheses by testing Bubble-tip anemone (Entacmaea quadricolor) nematocysts in response to three different mucus sources, before and after anemonefish association. We also profiled the corresponding mucus lipid and glycan composition of anemonefish. Host sea anemones significantly reduced nematocyst firing at acclimated anemonefish mucus compared to mucus from unacclimated individuals. Changes in anemonefish mucus glycan composition became distinguishable three weeks after introduction relative to an anemonefish that was not living in association of a host sea anemone. The glycan composition reverted back to a pre-acclimated composition when profiled 24 hours after anemonefish removal from a host sea anemone. Triggering fewer nematocysts through glycan profile alterations may be an important adaptation that has enabled anemonefish to live long-term in a sea anemone host. However, the delay in mucus response indicates it is not the initial mechanism used by anemonefish to enter a host sea anemone without being stung.
Changes in cognition and neuroinflammation in a rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically
Authors: Haller Olivia J. , Semendric Ines , Collins-Praino Lyndsey E. , Whittaker Alexandra L. , George Rebecca P.
Published: February 2024

Chemotherapy-induced cognitive impairment (CICI) affects up to 75% of cancer survivors between 6-months and 20-years post-treatment. Impairments include memory loss, learning difficulties, inability to concentrate and a decrease in processing speed, all of which can negatively impact quality of life. Several mechanisms are proposed to drive these impairments, with evidence implicating neuroinflammation as a key contributor. However, the time course over which impairments occur is less well-established. Several preclinical studies have focused on acute (0-7 days) and sub-acute (8-days to 12-weeks) time-points following chemotherapy, but few have investigated more longer-term time-points. This study therefore aimed to understand the evolution of cognitive changes following methotrexate (MTX) or 5-flurouracil (5-FU) chemotherapy treatment, assessing three time-points: acute (96-hour), sub-acute (31-days) and chronic (93-days). Further, we investigated whether alterations in cognition were associated with concomitant changes in neuroinflammation, assessed via astrocytic reactivity. Female Sprague Dawley rats received two intraperitoneal injections of MTX, 5-FU or saline and were assessed on the novel object recognition, 5-choice serial reaction time task and Barnes maze. Hippocampal (HIPP) and pre-frontal cortex (PFC) tissue was examined for GFAP expression. Results indicate that both MTX and 5-FU exposure were associated with impairments in spatial memory, task acquisition, and processing speed at 31-days, with impairment ameliorated by 93-days post-treatment. While MTX and 5-FU increased GFAP expression across all time-points, with the largest changes at 96-hours and 31-days, drug-specific and region-specific variations were noted. These results provide valuable insight into the complexity of the neuroinflammatory response in CICI. While neuroinflammation may be a promising therapeutic target, further work is required to fully understand this response, including which aspects to target and at what time-points, to ensure optimal outcomes for cancer patients treated with chemotherapy.
Facilitate integrated analysis of single cell multiomic data by binarizing gene expression values
Authors: Misra Rohan , Ferrena Alexander , Zheng Deyou
Published: February 2024

The identity of a cell type can be revealed by its transcriptome and epigenome profiles, both of which can be in flux temporally and spatially, leading to distinct cell states or subtypes. The popular and standard workflow for single cell RNA-seq (scRNA-seq) data analysis applies feature selection, dimensional reduction, and clustering on the gene expression values quantified by read counts, but alternative approaches using a simple classification of a gene to “on” and “off” (i.e., binarization of the gene expression) has been proposed for classifying cells and other downstream analyses. Here, we demonstrate that a direct concatenation of the binarized scRNA-seq data and the standard single cell ATAC-seq data is sufficient and effective for integrated clustering analysis, after applying term-frequency-inverse document frequency (TF-IDF) and single value decomposition (also called latent semantic indexing, LSI) algorithms to the combined data, when the two modalities of omic data are collected using paired multiomic technology. This proposed approach avoids the need for converting scATAC-seq data to gene activity scores for combined analysis and furthermore enables a direct investigation into the contribution of each data type to resolving cell type identity.
Prediction of neural activity in connectome-constrained recurrent networks
Authors: Beiran Manuel , Litwin-Kumar Ashok
Published: February 2024

We develop a theory of connectome-constrained neural networks in which a student network is trained to reproduce the activity of a ground-truth teacher, representing a neural system for which a connectome is available. Unlike standard paradigms with unconstrained connectivity, here the two networks have the same connectivity but different biophysical parameters, reflecting uncertainty in neuronal and synaptic properties. We find that a connectome is often insufficient to constrain the dynamics of networks that perform a specific task, illustrating the difficulty of inferring function from connectivity alone. However, recordings from a small subset of neurons can remove this degeneracy, producing dynamics in the student that agree with the teacher. Our theory can also prioritize which neurons to record from to most efficiently predict unmeasured network activity. Our analysis shows that the solution spaces of connectome-constrained and unconstrained models are qualitatively different and provides a framework to determine when such models yield consistent dynamics.
Prevalence of Depression and Associated Socio-economic Outcomes during Violent Conflict: A Matched Analysis for Palestine Using Nationally Representative Survey and Conflict Event Data
Authors: Ronzani Piero , Stojetz Wolfgang , Stammel Nadine , Boettche Maria , Zardetto Diego , Fenzl Sarah , Salhab Maen , Anderson Jessica M. , Finn Arden , Aghajanian Alia , Brück Tilman
Published: February 2024

Background

Mental health risks are high in conflict settings, but mental health research mostly focuses on non-conflict settings. Survey data from active conflict settings often suffer from low response rates, unrepresentative samples, and a lack of detailed information on the roots and implications of poor mental health. We overcome these challenges by analyzing nationally representative evidence on the prevalence, sources, and socio-economic correlates of depression, a highly disabling and costly public health issue, in an active conflict setting.

Methods

We analyze nationally and sub-nationally representative geocoded survey data from the Palestinians’ Psychological Conditions Survey, collected from 5,877 Palestinian individuals in West Bank and Gaza in 2022. We calculate representative depression statistics, disaggregate by sub-areas and across socio-demographic groups, and estimate the associations with geocoded violent conflict event data as well as survey-based trauma exposure across conflict types and socio-economic outcomes.

Findings

58 percent (SE=2·21) of adults in Palestine exhibit depressive symptoms. Prevalence is highest in Gaza (71 percent, SE=2·70), increases with exposure to violent conflict and traumatic events, and is associated with worse socio-economic outcomes. The associated losses for 2022 are equivalent to 732,555 Years Lost in Disability, representing 8·9 percent of Palestine’s GDP.

Interpretation

Those exposed to violence and traumatic events are disproportionately affected by depression in conflict settings, which may fuel poverty and instability. Scalable investments in mental health in conflict settings promise to not only support well-being but also strengthen productivity and social cohesion for a given level of violence.

Funding

The study received funding by the World Bank’s State and Peace Building Trust Fund.
SIGNAL-seq: Multimodal Single-cell Inter- and Intra-cellular Signalling Analysis
Authors: Opzoomer James W. , O’Sullivan Rhianna , Sufi Jahangir , Madsen Ralitsa , Qin Xiao , Basiarz Ewa , Tape Christopher J.
Published: February 2024

We present SIGNAL-seq (Split-pool Indexing siG-Nalling AnaLysis by sequencing): a multiplexed splitpool combinatorial barcoding method that simultaneously measures RNA and post-translational modifications (PTMs) in fixed single cells from 3D models. SIGNAL-seq PTM measurements are equivalent to mass cytometry and RNA gene detection is analogous to split-pool barcoding scRNA-seq. By measuring both mRNA ligand-receptor pairs and PTMs in single cells, SIGNAL-seq can simultaneously uncover inter- and intra-cellular regulation of tumour microenvironment plasticity.
MICROCOSM FABRICATION PLATFORM FOR LIVE MICROSCOPY OF PLANT-SOIL SYSTEMS
Authors: Liu Yangminghao , Patko Daniel , de le Mata Alberto Llora , Dong Xingshui , Peral Emma Gomez , He Xinhua , Ameduri Bruno , Ladmiral Vincent , MacDonald Michael P , Dupuy Lionel X
Published: February 2024

Biological processes in soil pores are critical to crop nutrition and productivity, but live observations of these processes at that scale have been difficult to accomplish. To address this challenge, we have developed new techniques for the fabrication of microcosms dedicated to live imaging of the rhizosphere which incorporate the ability to control water content in transparent soil. Chambers were assembled using poly(dimethyl siloxane) (PDMS) parts fabricated by injection moulding and subsequently joined to glass slides. The control of liquid fluxes in the microcosm was achieved by syringes passing through the PDMS parts or through custom made PDMS sponges. We then tested various low refractive index materials for the fabrication of transparent soils and carried out live microscopy using Fluorescence Light Sheet microscopy. The proposed fabrication techniques are modular and enabled the construction of a wide range of experimental systems, including split chamber systems for the control of water content in soil, heterogeneous distribution of water content, monitoring of dye tracers, and live observation of plant roots. Using the techniques, we show how plant roots increase water infiltration through increased permeability of dry soil layers. This study therefore establishes that material property control and microfabrication in model rhizosphere systems can greatly enhance our understanding of plant-soil interactions.
Regulation of host metabolism and defense strategies to survive neonatal infection
Authors: Wu Ziyuan , Tien Nguyen Tran Nam , Bæk Ole , Zhong Jingren , Klabunde Björn , Nguyen Tinh Thu , Yen Nguyen Thi Hai , Long Nguyen Phuoc , Nguyen Duc Ninh
Published: February 2024

Two distinct defense strategies, resistance and tolerance, enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on tolerance to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to resistance that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between tolerance and resistance in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non- survivors inStaphylococcus epidermidis(S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Relative to non-survivors, survivors displayed elevated resistance during the early phase of infection, followed by stronger tolerance in later stages. Conversely, animals succumbing to sepsis showed clear signs of respiratory and metabolic acidosis, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the tolerance phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics supported the finding of enhanced mitochondrial metabolism in survivors. Our findings suggest a link between mitochondrial metabolism, disease tolerance, and ultimately improved survival during infections in newborns. Metabolic regulations related to tolerance may be exploited to discover novel therapeutics for neonatal infection.

Conflict-of-interest statement

The authors have declared that no conflict of interest exists.
In-Vivo and In-Vitro Toxicity Evaluation of 2,3-Dimethylquinoxaline: an Antimicrobial Found in a Traditional Herbal Medicine
Authors: Alfadil Abdelbagi , Alsamhan Hamoud , Ali Ahmed , Alkreathy Huda , Alrabia Mohammad , fatani Asif , A Ibrahem Karem
Published: February 2024

2,3-dimethylquinoxaline (DMQ) is a broad-spectrum antimicrobial phytochemical. This study aims to assess its toxicological profile.In vitrostudies conducted in appropriate cell cultures, included assessment of cardiotoxicity, nephrotoxicity, and hepatotoxicity.An in vivostudy was conducted in mice to determine acute oral toxicity (AOT), and subacute oral toxicity (SAOT). Acute dermal toxicity (ADT) was conducted in rats. Allin-vitrotoxicity studies of DMQ had negative results at concentrations ≤100 µM except for a non-significant reduction in the ATP in human hepatocellular carcinoma cell culture. The median lethal dose of DMQ was higher than 2000 mg/kg. All animals survived the scheduled necropsy and none showed any alteration in clinical signs. Biochemistry analysis revealed a significant difference between the satellite and control groups, showing an increase in platelet counts and white blood cell counts by 99.8% and 188.8%, respectively. Histology revealed enlargement of renal corpuscles; hyperplasia of testosterone-secreting cells; and dilatation of coronaries and capillaries. The present data suggests an acceptable safety profile of DMQ in rodents except for thrombocytosis, leukocytosis, and histological changes in high doses that need further investigation.
Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson’s disease model rats
Authors: Usami Nayuka , Maegawa Hiroharu , Niwa Hitoshi
Published: February 2024

Pain is a major non-motor symptom of Parkinson’s disease (PD). The alterations in the descending pain inhibitory system (DPIS) have been reported to trigger hyperalgesia in PD patients. However, the underlying mechanisms remain unclear. In the current study, dopaminergic nigrostriatal lesions were induced in rats by injecting 6-hydroxydopamine (6-OHDA) into their medial forebrain bundle. The neural mechanisms underlying changes in nociception in the orofacial region of 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad. The 6-OHDA-lesioned rats were seen to exhibit increased frequency of face-rubbing and more c-Fos immunoreactive (c-Fos-IR) cells in the trigeminal spinal subnucleus caudalis (Vc), confirming hyperalgesia. Examination of the number of c-Fos-IR cells in the DPIS nuclei [including the midbrain ventrolateral periaqueductal gray, the locus coeruleus, the nucleus raphe magnus, and paraventricular nucleus (PVN)] showed that 6-OHDA-lesioned rats exhibited a significantly lower number of c-Fos-IR cells in the magnocellular division of the PVN (mPVN) after formalin injection compared to sham-operated rats. Moreover, the 6-OHDA-lesioned rats also exhibited significantly lower plasma oxytocin (OT) concentration and percentage of oxytocin-immunoreactive (OT-IR) neurons expressing c-Fos protein in the mPVN and dorsal parvocellular division of the PVN (dpPVN), which secrete the analgesic hormone OT upon activation by nociceptive stimuli, when compared to the sham-operated rats. The effect of OT on hyperalgesia in 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad after intracisternal administration of OT, and the findings showed a decrease in the frequency of face rubbing and the number of c-Fos-IR cells in the Vc. In conclusion, these findings confirm presence of hyperalgesia in PD patients, potentially due to suppression of the analgesic effects of OT originating from the PVN.
Woman the Hunter? Female foragers sometimes hunt, yet gendered divisions of labor are real
Authors: Venkataraman Vivek , Hoffman Jordie , Hames Raymond B. , Stibbard-Hawkes Duncan N.E. , Kramer Karen , Kelly Robert , Farquharson Kyle , Hagen Edward H. , Hewlett Barry S. , Davis Helen Elizabeth , Glowacki Luke , Jang Haneul , Syme Kristen , Starkweather Katie , Lew-Levy Sheina
Published: February 2024

Gendered divisions of labor are a feature of every known contemporary hunter-gatherer (forager) society. While gender roles are certainly flexible, and prominent and well-studied cases of female hunting do exist, it is more often men who hunt. A new study (Anderson et al., 2023) surveyed ethnographically known foragers and found that women hunt in 79% of foraging societies, with big-game hunting occurring in 33%. Based on this single type of labor, which is one among dozens performed in foraging societies, the authors question the existence of gendered division of labor altogether. As a diverse group of hunter-gatherer experts, we find that claims that foraging societies lack or have weak gendered divisions of labor are contradicted by empirical evidence. We conducted an in-depth examination of Anderson et al. (2023) data and methods, finding evidence of sample selection bias and numerous coding errors undermining the paper’s conclusions. Anderson et al. (2023) have started a useful dialogue to ameliorate the popular misconception that women never hunt. However, their analysis does not contradict the wide body of empirical evidence for gendered divisions of labor in foraging societies. Furthermore, a myopic focus on hunting diminishes the value of contributions that take different forms and downplays the trade-offs foragers of both sexes routinely face. We caution against ethnographic revisionism that projects Westernized conceptions of labor and its value onto foraging societies.
High sensitivity cameras can lower spatial resolution in high-resolution optical microscopy
Authors: Ortkrass Henning , Müller Marcel , Engdahl Anders Kokkvoll , Holst Gerhard , Huser Thomas
Published: February 2024

High-resolution optical fluorescence microscopies and, in particular, super-resolution fluorescence microscopy, are rapidly adopting highly sensitive cameras as their referred photodetectors. Camera-based parallel detection facilitates high-speed live cell imaging with the highest spatial resolution. Here, we show that the drive to use ever more sensitive, photon-counting image sensors in cameras can, however, have detrimental effects on spatial resolution that many researchers are not aware of. Typical parameters which influence the selection of image sensors are pixel size, quantum efficiency, signal-to-noise performance, dynamic range, and frame rate of the sensor. A parameter that is, however, often overlooked, is the sensor’s modulation transfer function (MTF). We have determined the wavelength-specific MTF of front- and back-illuminated image sensors and evaluated how it affects the spatial resolution that can be achieved in high fluorescence microscopy modalities. We find significant differences in image sensor performance for sensors that cause the resulting spatial resolution to vary with up to 28%. This result shows that the choice of image sensor has significant impact on the imaging performance of all camera-based optical microscopy modalities.
Reliably Measuring Learning-Dependent Distractor Suppression with Eye Tracking
Authors: Kim Andy J. , Grégoire Laurent , Anderson Brian A.
Published: February 2024

In the field of psychological science, behavioral performance in computer-based cognitive tasks often exhibits poor reliability. The absence of reliable measures of cognitive processes contributes to non-reproducibility in the field and impedes investigation of individual differences. Specifically in visual search paradigms, response time-based measures have shown poor test-retest reliability and internal consistency across attention capture and distractor suppression, but one study has demonstrated the potential for oculomotor measures to exhibit superior reliability. Therefore, in this study, we investigated three datasets to compare the reliability of learning-dependent distractor suppression measured via distractor fixations (oculomotor capture) and latency to fixate the target (fixation times). Our findings reveal superior split-half reliability of oculomotor capture compared to that of fixation times regardless of the critical distractor comparison, with the reliability of oculomotor capture in most cases falling within the range that is acceptable for the investigation of individual differences. We additionally find that older adults have superior oculomotor reliability compared with young adults, potentially addressing a significant limitation in the aging literature of high variability in response time measures due to slower responses. Our findings highlight the utility of measuring eye movements in the pursuit of reliable indicators of distractor processing and the need to further test and develop additional measures in other sensory domains to maximize statistical power, reliability, and reproducibility.
Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome
Authors: Thirimanne H. Nayanga , Bonnin Damian Almiron , Nuechterlein Nicholas , Arora Sonali , Jensen Matt , Parada Carolina A. , Qiu Chengxiang , Szulzewsky Frank , English Collin W , Chen William C , Sievers Philipp , Nassiri Farshad , Wang Justin Z. , Klisch Tiemo J , Aldape Kenneth D , Patel Akash J , Cimino Patrick J , Zadeh Gelareh , Sahm Felix , Raleigh David R. , Shendure Jay , Ferreira Manuel , Holland Eric C
Published: February 2024

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.
A circadian behavioral analysis suite for real-time classification of daily rhythms in complex behaviors
Authors: Perry Logan J. , Perez Blanca E. , Wahba Larissa Rays , Nikhil KL , Lenzen William C. , Jones Jeff R.
Published: February 2024

Measuring animal behavior over long timescales has been traditionally limited to behaviors that are easily measurable with real-time sensors. More complex behaviors have been measured over time, but these approaches are considerably more challenging due to the intensive manual effort required for scoring behaviors. Recent advances in machine learning have introduced automated behavior analysis methods, but these often overlook long-term behavioral patterns and struggle with classification in varying environmental conditions. To address this, we developed a pipeline that enables continuous, parallel recording and acquisition of animal behavior for an indefinite duration. As part of this pipeline, we applied a recent breakthrough self-supervised computer vision model to reduce training bias and overfitting and to ensure classification robustness. Our system automatically classifies animal behaviors with a performance approaching that of expert-level human labelers. Critically, classification occurs continuously, across multiple animals, and in real time. As a proof-of-concept, we used our system to record behavior from 97 mice over two weeks to test the hypothesis that sex and estrogen influence circadian rhythms in nine distinct home cage behaviors. We discovered novel sex- and estrogen-dependent differences in circadian properties of several behaviors including digging and nesting rhythms. We present a generalized version of our pipeline and novel classification model, the “circadian behavioral analysis suite,” (CBAS) as a user-friendly, open-source software package that allows researchers to automatically acquire and analyze behavioral rhythms with a throughput that rivals sensor-based methods, allowing for the temporal and circadian analysis of behaviors that were previously difficult or impossible to observe.
Short periods of decreased water flow may modulate long-term ocean acidification in reef-building corals
Authors: Martins Catarina P.P. , Simancas-Giraldo Susana M. , Schubert Patrick , Wall Marlene , Wild Christian , Wilke Thomas , Ziegler Maren
Published: February 2024

Ocean acidification (OA) poses a major threat to reef-building corals. Although water flow variability is common in coral reefs and modulates coral physiology, the interactive effects of flow and OA on corals remain poorly understood. Therefore, we performed a three-month OA experiment investigating the effect of changes in flow on coral physiology. We exposed the reef-building coralsAcropora cytherea,Pocillopora verrucosa, andPorites cylindricato control (pH 8.0) and OA (pH 7.8) conditions at moderate flow (6 cm s-1) and monitored OA effects on growth. Throughout the experiment, we intermittently exposed all corals to low flow (2 cm s-1) for 1.5 h and measured their photosynthesis:photosynthesis (P:R) ratio under low and moderate flow. On average, corals under OA calcified 18 % less and grew 23 % less in surface area than those at ambient pH. We observed species-specific interactive effects of OA and flow on coral physiology. P:R ratios decreased after 12 weeks of OA inA. cytherea(22 %) andP. cylindrica(28 %) under moderate flow, but were unaffected by OA under low flow. P:R ratios were stable inP. verrucosa. These results suggest that short periods of decreased water flow may modulate OA effects on some coral species, indicating that flow variability is a factor to consider when assessing long-term effects of climate change.
Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny
Authors: Morel Carole , Parise Lyonna F. , Van der Zee Yentl , Issler Orna , Cai Min , Browne Caleb , Blando Anthony , Leclair Katherine , Haynes Sherod , Williams Robert W. , Mulligan Megan K. , Russo Scott J. , Nestler Eric J. , Han Ming-Hu
Published: February 2024

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions—specificallygene x chronic stress—here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J. Utilizing the chronic social defeat stress (CSDS) and chronic variable stress (CVS) paradigms, we first showed sexual dimorphism in the behavioral stress response between the mouse strains. Further, we observed an interaction between genetic background and vulnerability to prolonged exposure to non-social stressors. Finally, we found that DBA/2J and C57BL/6J mice pre-exposed to stress displayed differences in morphine sensitivity. Our results support the hypothesis that genetic variation in predisposition to stress responses influences morphine sensitivity and is likely to modulate the development of drug addiction.
Small molecules targeting the structural dynamics of AR-V7 partially disordered protein using deep learning and physics based models
Authors: Karatzas Pantelis , Brotzakis Z. Faidon , Sarimveis Haralambos
Published: February 2024

Partially disordered proteins can contain both stable and unstable secondary structure segments and are involved in various (mis)functions in the cell. The extensive conformational dynamics of partially disordered proteins scaling with extent of disorder and length of the protein hampers the efficiency of traditional experimental and in-silico structure-based drug discovery approaches. Therefore new efficient paradigms in drug discovery taking into account conformational ensembles of proteins need to emerge. In this study, using as a test case the AR-V7 transcription factor splicing variant related to prostate cancer, we present an automated methodology that can accelerate the screening of small molecule binders targeting partially disordered proteins. By swiftly identifying the conformational ensemble of AR-V7, and reducing the dimension of binding-sites by a factor of 90 by applying appropriate physicochemical filters, we combine physics based molecular docking and multi-objective classification machine learning models that speed up the screening of thousands of compounds targeting AR-V7 multiple binding sites. Our method not only identifies previously known binding sites of AR-V7, but also discovers new ones, as well as increases the multi-binding site hit-rate of small molecules by a factor of 10 compared to naive physics-based molecular docking.
Steeper or Faster? Impacts of Similar-intensity Running Conditions on Heart Rate Variability
Authors: ElDash Vivian MCA , ElDash Ingrid Machado Cusin Ahmed , Marques Fernando Silveira , Natali Jose E S , Chaui-Berlinck Jose Guilherme
Published: February 2024

Increases in speed or slope promote different adjustments in the locomotor system and lead to a higher heart rate (HR). Because heart rate variability (HRV) is known to respond to exercise intensity and to biomechanical stimuli, we aimed to answer whether HRV would be sensitive to changes in speed and/or slope under similar HR. We hypothesize that HRV would depend solely on HR. To test this hypothesis, 6 healthy male runners (age 30 ± 7.5 yrs.) were recruited and a velocity V, with similar HR/HRmax was selected per volunteer. Changes in HR were referred to these particular velocities V, resulting in comparable exercise intensities. HRV was estimated through standard deviation (sdt) and root mean square of successive RR intervals (rmst), normalized per volunteer. Four running conditions were compared. We found that rmst decreased with speed and slope, with significant interaction between the independent variables. The run {0.7 V, 0%} was different from the remaining 3 conditions, which, in turn, were no different from one another. Thus, this estimator did not show a distinct sensitivity to variations in speed or slope. On the other hand, sdt decreased with both speed and slope, with no significant interactions. The runs performed at {0.7 V, 0%} and {0.7 V, 6%} were different from those at {1 V, 0%} and {1 V, 6%}. Therefore, sdt presented different values under similar HR. This finding leads us to conclude that cardiac control operates sensitively due to the mode of the changes imposed on the metabolic demand.
Spatiotemporal dynamics of NF-κB/Dorsal inhibitor IκBα/Cactus inDrosophilablastoderm embryos
Authors: Schloop Allison E. , Hiremath Sharva , Shaikh Razeen , Williams Cranos M. , Reeves Gregory T.
Published: February 2024

The NF-κB signaling pathway is a key regulatory network in mammals that controls many cellular processes, including immunity and inflammation. Of particular note is the relationship between NF-κB and its inhibitor IκBα, which sequesters NF-κB to the cytoplasm of cells until needed. It is also known that IκBα can enter nuclei, disrupt NF-κB binding to DNA, and shuttle it out to again sequester NF-κB in the cytoplasm. InDrosophila melanogaster, a homologous system between the proteins Dorsal (homologous to NF-κB) and Cactus (homologous to IκBα) is important in embryo development, specifically in establishment of the Dorsal nuclear concentration gradient. Previous work suggests Cactus also enters the nucleus; mathematical models of the Dorsal gradient fail to accurately predict the normal range of the gradient without nuclear Cactus. However, direct,in vivovisualization of Cactus spatiotemporal dynamics, including its localization to the nuclei, has been difficult to gather. Previously, imaging Cactus in live embryos was complicated by rapid protein turnover, preventing fluorescent protein fusions from fully maturing. To address this, we used the CRISPR/Cas9 system to tag Cactus with the recently developed “LlamaTag” (LT), a genetically encodable nanobody from llamas that dynamically binds to GFPin vivo. We then employed standard confocal imaging, as well as advanced optical techniques such as raster image correlation spectroscopy (RICS) and fluorescent recovery after photobleaching (FRAP) to investigate the spatiotemporal distribution of Cactus-LlamaTag inDrosophilaembryos at the blastoderm stage. Our results demonstrate that Cactus can be found in the nuclei of early embryos, consistent with its role as a transcription factor regulator. Moreover, by using the data from FRAP and RICS, we were able to estimate biophysical parameters of Cactus dynamicsin vivo, including its nuclear transport rate constants and fraction bound to GFP. These data were further used to constrain a mathematical model that allowed us to infer experimentally inaccessible biophysical parameters, such as the concentration of Cact protein and the dissociation constant of LT and GFP. Our study provides new insights into the regulation of the NF-κB pathway in earlyDrosophilaembryos and highlights the power of advanced optical techniques for investigating complex biological dynamics.
The lipidome of posttraumatic stress disorder
Authors: Bhargava Aditi , Knapp Johannes D. , Fiehn Oliver , Neylan Thomas C. , Inslicht Sabra S.
Published: February 2024

Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 individuals with PTSD and 40 trauma-exposed non-PTSD individuals. Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ∼ 90 measures were collected, on sleep, mental and physical health indices. Sleep quality worsened as PTSD severity increased in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 classes of lipids. After adjusting for sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The triglycerides and ceramide metabolites that were most highly increased were correlated with cholesterol metabolites and systolic blood pressure in men but not always in women with PTSD. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher weight may have contributed to changes in the lipidome found in PTSD.
Object motion representation in the macaque ventral stream – a gateway to understanding the brain’s intuitive physics engine
Authors: Ramezanpour Hamidreza , Ilic Filip , Wildes Richard P. , Kar Kohitij
Published: February 2024

Effective interaction with moving objects and the ability to infer and predict their motion (a core component of “intuitive physics”) is essential for survival in the dynamic world. How does the primate visual system process such stimuli, enabling predictive capabilities for dynamic stimuli statistics like motion velocity and expected trajectories? In this study, we probed brain areas in the ventral visual pathway of rhesus macaques implicated in object recognition (areas V4 and inferior temporal, IT, cortex) to evaluate how they represent object motion speed and direction. We assessed the relationship between the distributed population activity in the ventral stream and two distinct object motion-based behaviors—one reliant on information directly available in videos (speed discrimination) and the other predicated on predictive motion estimates from videos (future event predictions). Further, employing microstimulation strategies, we confirm the causal, functional role of the IT cortex in these behaviors. Our results underscore the need to re-examine the traditional functional segregation of the primate visual cortices into “what” and “where” pathways and provide empirical constraints to model their interaction for a better circuit-level understanding of visual motion and intuitive physics.