bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryosectioning-enhanced super-resolution microscopy for single-protein imaging across cells and tissues
Authors: Stein Johannes , Ericsson Maria , Nofal Michel , Magni Lorenzo , Aufmkolk Sarah , McMillan Ryan B. , Breimann Laura , Herlihy Conor P. , Lee S. Dean , Willemin Andréa , Wohlmann Jens , Arguedas-Jimenez Laura , Yin Peng , Pombo Ana , Church George M. , Wu Chao-ting
Published: February 2024

DNA-PAINT enables nanoscale imaging with virtually unlimited multiplexing and molecular counting. Here, we address challenges, such as variable imaging performance and target accessibility, that can limit its broader applicability. Specifically, we enhance its capacity for robust single-protein imaging and molecular counting by optimizing the integration of TIRF microscopy with physical sectioning, in particular, Tokuyasu cryosectioning. Our method, tomographic & kinetically enhanced DNA-PAINT (tkPAINT), achieves 3 nm localization precision across diverse samples, enhanced imager binding, and improved cellular integrity. tkPAINT can facilitate molecular counting with DNA-PAINT inside the nucleus, as demonstrated through its quantification of the in situ abundance of RNA Polymerase II in both HeLa cells as well as mouse tissues. Anticipating that tkPAINT could become a versatile tool for the exploration of biomolecular organization and interactions across cells and tissues, we also demonstrate its capacity to support multiplexing, multimodal targeting of proteins and nucleic acids, and 3D imaging.
Voronota-LT: efficient, flexible and solvent-aware tessellation-based analysis of atomic interactions
Authors: Olechnovič Kliment , Grudinin Sergei
Published: February 2024

Motivation

In the fields of structural biology and bioinformatics, understanding molecular interactions is paramount. However, existing advanced geometric methods for describing interatomic contacts considering full structural context have typically demanded substantial computational resources, hindering their practical application. Given the ever-growing volume of structural data, there is an urgent need for more efficient tools for interaction analysis.

Results

We present Voronota-LT, a new efficient method tailored for computing Voronoi tessellation-based atom-atom contacts within the solvent-accessible surface of molecular structures. Voronota-LT constructs every interatomic contact surface directly, without pre-computing the global Voronoi diagram or Delaunay triangulation. This approach results in a method that is not only fast, but also parallelizable and capable of selectively targeting specific interface areas within molecular complexes. While offering high execution speed, Voronota-LT provides a comprehensive description of every interatomic interaction, taking full account of the relevant structural context.

Availability and Implementation

Voronota-LT software is freely available as both a standalone application and a C++ header-only library athttps://kliment-olechnovic.github.io/voronota/expansion_lt/.
Coordinated active repression operates via transcription factor cooperativity and multiple inactive promoter states in a developing organism
Authors: Pimmett Virginia , Douaihy Maria , Maillard Louise , Trullo Antonio , Garcia Idieder Pablo , Costes Melissa , Dufourt Jeremy , Lenden-Hasse Helene , Radulescu Ovidiu , Lagha Mounia
Published: February 2024

Refining transcriptional levels via active repression in an euchromatic context represents a critical regulatory process. While the molecular players of active repression are well described, their dynamics remain obscure. Here, we usedsnailexpression dynamics as a paradigm to uncover how repression, mediated by the Snail (Sna) repressor, can be imposed within a developing tissue. Combining live imaging and mathematical modeling, we show that Sna-mediated repression is cooperative and that cooperativity is primarily mediated by the distal enhancer. Repression shifts transcription bursting dynamics from a two-state ON/OFF regime to a three-state repressed regime with two temporally distinct OFF states. Mutating Sna binding sites suggests that repression introduces the long-lasting inactive state, which is stabilized by cooperativity. Our approach offers quantitative insights into the dynamics of repression and how transcription factor cooperativity coordinates cell fate decisions within a tissue.
PlasmodiumNEK1 coordinates MTOC organisation and kinetochore attachment during rapid mitosis in male gamete formation
Authors: Zeeshan Mohammad , Rashpa Ravish , Ferguson David J. , Mckeown George , Nugmanova Raushan , Subudhi Amit K. , Beyeler Raphael , Pashley Sarah L. , Markus Robert , Brady Declan , Roques Magali , Bottrill Andrew R. , Fry Andrew M. , Pain Arnab , Vaughan Sue , Holder Anthony A. , Tromer Eelco C. , Brochet Mathieu , Tewari Rita
Published: February 2024

Mitosis is an important process in the cell cycle required for cells to divide. Never in mitosis (NIMA)-like kinases (NEKs) are regulators of mitotic functions in diverse organisms.Plasmodium spp, the causative agent of malaria is a divergent unicellular haploid eukaryote with some unusual features in terms of its mitotic and nuclear division cycle that presumably facilitate proliferation in varied environments. For example, during the sexual stage of male gametogenesis that occurs within the mosquito host, an atypical rapid closed endomitosis is observed. Three rounds of genome replication from 1N to 8N and successive cycles of multiple spindle formation and chromosome segregation occur within eight minutes followed by karyokinesis to generate haploid gametes.

Our previousPlasmodium bergheikinome screen identified fourNekgenes, of which two, NEK2 and NEK4, are required for meiosis. NEK1 is likely to be essential for mitosis in asexual blood stage schizogony in the vertebrate host, but its function during male gametogenesis is unknown. Here, we study NEK1 location and function, using live cell imaging, ultrastructure expansion microscopy (U-ExM) and electron microscopy, together with conditional gene knockdown and proteomic approaches. We report spatiotemporal NEK1 location in real-time, coordinated with microtubule organising centre (MTOC) dynamics during the unusual mitoses at various stages of thePlasmodium spp.life cycle. Knockdown studies reveal NEK1 to be an essential component of the MTOC in male cell differentiation, associated with rapid mitosis, spindle formation and kinetochore attachment. These data suggest thatPlasmodium bergheiNEK1 kinase is an important component of MTOC organisation and essential regulator of chromosome segregation during male gamete formation.
Circadian rhythmicity and photobiological mechanisms of light sensitivity and discomfort glare in humans
Authors: Daguet I , Raverot V , Gronfier C
Published: February 2024

Discomfort glare is a common visual sensation, which is generally reported when being exposed to a brighter lit environment. In certain clinical conditions, this sensation is abnormally amplified, and is commonly named photophobia. Despite the frequent appearance of this sensation in everyday life or in pathological conditions, the underlying mechanisms remain poorly understood. We show here, in highly controlled laboratory constant routine conditions, that light-induced discomfort glare is rhythmic over the 24-hour day. We reveal a strong circadian drive, with a sinusoidal rhythmicity, with maximal discomfort glare in the middle of the night and minimal in the afternoon. We also find a modest sleep-related homeostatic drive of visual discomfort, with a linear increase in discomfort glare over 34 hours of prolonged wakefulness. Our study reveals that discomfort glare is primarily driven by the ipRGC pathway, and that mid and/or long wavelengths cones are involved as well. The 6.5-hour phase lag between the rhythms of photoreceptors’ sensitivity, assessed through pupillary light reflex, and of glare discomfort, suggests two independent underlying mechanisms. In conclusion, our findings highlight the need to take time-of-day and biological rhythmicity into account in the evaluation of light-induced discomfort glare. Apprehending these mechanisms may help understand photophobia in clinical populations, such as in migraine patients, and should be taken into account to optimize light quality at home and at the workplace, both for day and night work.
MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures
Authors: Sit Timothy PH , Feord Rachael C , Dunn Alexander WE , Chabros Jeremi , Oluigbo David , Smith Hugo H , Burn Lance , Chang Elise , Boschi Alessio , Yuan Yin , Gibbons George M , Khayat-Khoei Mahsa , De Angelis Francesco , Hemberg Erik , Hemberg Martin , Lancaster Madeline A , Lakatos Andras , Eglen Stephen J , Paulsen Ole , Mierau Susanna B
Published: February 2024

Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology, and network dynamics—patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing microscale functional brain networks from MEA recordings. Here, we present a MATLAB MEA network analysis pipeline (MEA-NAP) for raw voltage time-series acquired from single- or multi-well MEAs. Applications to 3D human cerebral organoids or 2D human-derived or murine cultures reveal differences in network development, including topology, node cartography, and dimensionality. MEA-NAP incorporates multi-unit template-based spike detection, probabilistic thresholding for determining significant functional connections, and normalization techniques for comparing networks. MEA-NAP can identify network-level effects of pharmacologic perturbation and/or disease-causing mutations and, thus, can provide a translational platform for revealing mechanistic insights and screening new therapeutic approaches.
Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1
Authors: Griffith Sarah , Muir Luke , Suchanek Ondrej , Hope Joshua , Pade Corinna , Gibbons Joseph M , Tuong Zewen Kelvin , Fung Audrey , Touizer Emma , Rees-Spear Chloe , Nans Andrea , Roustan Chloe , Alguel Yilmaz , Fink Douglas , Orkin Chloe , Deayton Jane , Anderson Jane , Gupta Ravindra K , Doores Katie J , Cherepanov Peter , McKnight Áine , Clatworthy Menna , McCoy Laura E
Published: February 2024

Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface. ELC07 binds the closed state of the viral glycoprotein causing considerable perturbations to the gp41 trimer core structure. Phenotypic analysis of memory B cell subsets from the ELC07 bnAb donor revealed a lack of expected HIV-1-associated dysfunction, specifically no increase in CD21-/CD27-cells was observed whilst the resting memory (CD21+/CD27+) population appeared preserved despite uncontrolled HIV-1 viraemia. Moreover, single cell transcriptomes of memory B cells from this bnAb donor showed a resting memory phenotype irrespective of the epitope they targeted or their ability to neutralise diverse strains of HIV-1. Strikingly, single memory B cells from the ELC07 bnAb donor were transcriptionally similar to memory B cells from HIV-negative individuals. Our results demonstrate that potent bnAbs can arise without the HIV-1-induced dysregulation of the memory B cell compartment and suggest that sufficient levels of antigenic stimulation with a strategically designed immunogen could be effective in HIV-negative vaccine recipients.
Kappa Opioid Receptors Negatively Regulate Real Time Spontaneous Dopamine Signals by Reducing Release and Increasing Uptake
Authors: Wallace Conner W , Holleran Katherine M , Slinkard Clare Y , Centanni Samuel W , Jones Sara R
Published: February 2024

Abstract

The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations and increases DA transporter (DAT) activity and trafficking to the membrane. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6 mice. First, we established that the rise and fall of spontaneous DA signals were due to DA release and reuptake, respectively. Then mice were systemically administered the KOR agonist U50,488H (U50), with or without pretreatment with the KOR antagonist aticaprant (ATIC). U50 reduced both the amplitude and width of spontaneous signals in males, but only reduced width in females. Further, the slope of the correlation between amplitude and width was increased in both sexes, suggesting that DA uptake rates were increased. U50 also reduced the frequency of signals in both males and females. All effects of KOR activation were stronger in males. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DAT-mediated uptake, and reducing the frequency of signals.
WildPose: A Long-Range 3D Wildlife Motion Capture System
Authors: Muramatsu Naoya , Shin Sangyun , Deng Qianyi , Markham Andrew , Patel Amir
Published: February 2024

Understanding and monitoring wildlife behavior is crucial in ecology and biomechanics, yet challenging due to the limitations of current methods. To address this issue, we introduce WildPose, a novel long-range motion capture system specifically tailored for free-ranging wildlife observation. This system combines an electronically controllable zoom-lens camera with a LiDAR to capture both 2D videos and 3D point cloud data, thereby allowing researchers to observe high-fidelity animal morphometrics, behavior and interactions in a completely remote manner. Field trials conducted in Kgalagadi Transfrontier Park have successfully demonstrated WildPose’s ability to quantify morphological features of different species, accurately track the 3D movements of a springbok herd over time, and observe the respiratory patterns of a distant lion. By facilitating non-intrusive, long-range 3D data collection, WildPose marks a significant complementary technique in ecological and biomechanical studies, offering new possibilities for conservation efforts and animal welfare, and enriching the prospects for interdisciplinary research.
Translational activation by a synthetic PPR protein elucidates control ofpsbAtranslation in Arabidopsis chloroplasts
Authors: Rojas Margarita , Chotewutmontri Prakitchai , Barkan Alice
Published: February 2024

Translation initiation onpsbAmRNA in plant chloroplasts scales with light intensity, providing its gene product, D1, to replace photodamaged D1 in Photosystem II. ThepsbAtranslational activator HCF173 has been hypothesized to mediate this regulation. HCF173 belongs to the short-chain dehydrogenase/reductase superfamily, associates with thepsbA5’-untranslated region (5’-UTR), and has been hypothesized to enhance translation by binding an RNA segment that would otherwise pair with and mask the ribosome binding region. To test these hypotheses, we examined whether a synthetic pentatricopeptide repeat (sPPR) protein can substitute for HCF173 when bound to the HCF173 binding site. We show that an sPPR designed to bind HCF173’s footprint in thepsbA5’-UTR bound the intended sitein vivoand partially substituted for HCF173 to activatepsbAtranslation. However, sPPR-activated translation did not respond to light. These results imply that HCF173 activates translation, at least in part, by sequestering the RNA it binds to maintain an accessible ribosome binding region, and that HCF173 is also required to regulatepsbAtranslation in response to light. Translational activation can be added to the functions that can be programmed with sPPR proteins for synthetic biology applications in chloroplasts.

One sentence summary

A synthetic PPR protein substitutes for HCF173, a non-PPR translational activator in chloroplasts, elucidating HCF173 functions and demonstrating the ability of synthetic PPRs to activate translation.
Fine-scale tracking reveals visual field use for predator detection and escape in collective foraging of pigeon flocks
Authors: Delacoux Mathilde , Kano Fumihiro
Published: February 2024

During collective vigilance, it is commonly assumed that individual animals compromise their feeding time to be vigilant against predators, benefiting the entire group. One notable issue with this assumption concerns the unclear nature of predator “detection”, particularly in terms of vision. It remains uncertain how a vigilant individual utilizes its high-acuity vision (such as the fovea) to detect a predator cue and subsequently guide individual and collective escape responses. Using fine-scale motion capture technologies, we tracked the head and body orientations of pigeons (hence reconstructed their visual fields and foveal projections) foraging in a flock during simulated predator attacks. Pigeons used their fovea to inspect predator cues. Earlier foveation on a predator cue was linked to preceding behaviors related to vigilance and feeding, such as head-up or down positions, head-scanning, and food-pecking. Moreover, earlier foveation predicted earlier evasion flights at both the individual and collective levels. However, we also found that relatively long delay between their foveation and escape responses in individuals obscured the relationship between these two responses. While our results largely support the existing assumptions about vigilance, they also underscore the importance of considering vision and addressing the disparity between detection and escape responses in future research.
Second Boost of Omicron SARS-CoV-2 S1 Subunit Vaccine Induced Broad Humoral Immune Responses in Elderly Mice
Authors: Kim Eun , Khan Muhammad S. , Ferrari Alessandro , Huang Shaohua , Kenniston Thomas W. , Cassaniti Irene , Baldanti Fausto , Gambotto Andrea
Published: February 2024

Currently approved COVID-19 vaccines prevent symptomatic infection, hospitalization, and death from the disease. However, repeated homologous boosters, while considered a solution for severe forms of the disease caused by new SARS-CoV-2 variants in elderly individuals and immunocompromised patients, cannot provide complete protection against breakthrough infections. This highlights the need for alternative platforms for booster vaccines. In our previous study, we assessed the boost effect of the SARS-CoV-2 Beta S1 recombinant protein subunit vaccine (rS1Beta) in aged mice primed with an adenovirus-based vaccine expressing SARS-CoV-2-S1 (Ad5.S1) via subcutaneous injection or intranasal delivery, which induced robust humoral immune responses (1). In this follow-up study, we demonstrated that a second booster dose of a non-adjuvanted recombinant Omicron (BA.1) S1 subunit vaccine with Toll-like receptor 4 (TLR4) agonist RS09 (rS1RS09OM) was effective in stimulating strong S1-specific immune responses and inducing significantly high neutralizing antibodies against the Wuhan, Delta, and Omicron variants in 100-week-old mice. Importantly, the second booster dose elicits cross-reactive antibody responses, resulting in ACE2 binding inhibition against the spike protein of SARS-CoV-2 variants, including Omicron (BA.1) and its subvariants. Interestingly, the levels of IgG and neutralizing antibodies correlated with the level of ACE2 inhibition in the booster serum samples, although Omicron S1-specific IgG level showed a weaker correlation compared to Wuhan S1-specific IgG level. Furthermore, we compared the immunogenic properties of the rS1 subunit vaccine in young, middle-aged, and elderly mice, resulting in reduced immunogenicity with age, especially an impaired Th1-biased immune response in aged mice. Our findings demonstrate that the new variant of concern (VOC) rS1 subunit vaccine as a second booster has the potential to offer cross-neutralization against a broad range of variants and to improve vaccine effectiveness against newly emerging breakthrough SARS-CoV-2 variants in elderly individuals who were previously primed with the authorized vaccines.
PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis
Authors: Liu Gang , Hou Yunxuan , Jin Xin , Zhang Yixue , Sun Chaoyue , Huang Chengquan , Ren Yujie , Gao Jianmin , Wang Xiuli , Jiang Xiumei
Published: February 2024

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+ HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.
A comprehensive examination of Chelicerate genomes reveals no evidence for a whole genome duplication among spiders and scorpions
Authors: Thomas Gregg W.C. , McKibben Michael T.W. , Hahn Matthew W. , Barker Michael S.
Published: February 2024

Whole genome duplications (WGDs) can be a key event in evolution, playing a role in both adaptation and speciation. While WGDs are common throughout the history of plants, only a few examples have been proposed in metazoans. Among these, recent proposals of WGD events in Chelicerates, the group of Arthropods that includes horseshoe crabs, ticks, scorpions, and spiders, include several rounds in the history of horseshoe crabs, with an additional WGD proposed in the ancestor of spiders and scorpions. However, many of these inferences are based on evidence from only a small portion of the genome (in particular, theHoxgene cluster); therefore, genome-wide inferences with broader species sampling may give a clearer picture of WGDs in this clade. Here, we investigate signals of WGD in Chelicerates using whole genomes from 17 species. We employ multiple methods to look for these signals, including gene tree analysis of thousands of gene families, comparisons of synteny, and signals of divergence among within-species paralogs. We test several scenarios of WGD in Chelicerates using multiple species trees as a backbone for all hypotheses. While we do find support for at least one WGD in the ancestral horseshoe crab lineage, we find no evidence for a WGD in the history of spiders and scorpions using any genome-scale method. This study not only sheds light on genome evolution and phylogenetics within Chelicerates, but also demonstrates how a combination of comparative methods can be used to investigate signals of ancient WGDs.
Corticospinal excitability at rest outside of a task does not differ from task intertrial intervals in healthy adults
Authors: Bakken Kate , Horton Chris , Fisher Mitchell , Wadsley Corey G. , Greenhouse Ian
Published: February 2024

Human corticospinal excitability modulates during movement, when muscles are active, but also at rest, when muscles are not active. These changes in resting motor system excitability can be transient or longer lasting. Evidence from transcranial magnetic stimulation (TMS) studies suggests even relatively short periods of motor learning on the order of minutes can have lasting effects on resting corticospinal excitability. Whether individuals are able to return corticospinal excitability to out-of-task resting levels during the intertrial intervals of behavioral tasks that do not include an intended motor learning component is an important question. Here, in twenty-six healthy young adults, we used single-pulse TMS and electromyography (EMG) to measure motor evoked potentials (MEPs) during two different resting contexts: 1) intertrial intervals of a choice-reaction time task, and 2) outside the task. In both contexts, five TMS intensities were used to evaluate possible differences in recruitment of corticospinal output. We hypothesized resting state excitability would be greater during intertrial intervals than out-of-task rest, reflected in larger MEP amplitudes. Contrary to our hypothesis, we observed no significant difference in MEP amplitudes between out-of-task rest and in-task intertrial intervals, and instead found evidence of equivalence, indicating that humans are able to return to a stable motor resting state within seconds after a response. These data support the interpretation that rest is a uniform motor state in the healthy nervous system. In the future, our data may be a useful reference for motor disorder populations with an impaired ability to return to rest.
Model-Agnostic Neural Mean Field With The Refractory SoftPlus Transfer Function
Authors: Spaeth Alex , Haussler David , Teodorescu Mircea
Published: February 2024

Due to the complexity of neuronal networks and the nonlinear dynamics of individual neurons, it is challenging to develop a systems-level model which is accurate enough to be useful yet tractable enough to apply. Mean-field models which extrapolate from single-neuron descriptions to large-scale models can be derived from the neuron’s transfer function, which gives its firing rate as a function of its synaptic input. However, analytically derived transfer functions are applicable only to the neurons and noise models from which they were originally derived. In recent work, approximate transfer functions have been empirically derived by fitting a sigmoidal curve, which imposes a maximum firing rate and applies only in the diffusion limit, restricting applications. In this paper, we propose an approximate transfer function called Refractory SoftPlus, which is simple yet applicable to a broad variety of neuron types. Refractory SoftPlus activation functions allow the derivation of simple empirically approximated mean-field models using simulation results, which enables prediction of the response of a network of randomly connected neurons to a time-varying external stimulus with a high degree of accuracy. These models also support an accurate approximate bifurcation analysis as a function of the level of recurrent input. Finally, the model works without assuming large presynaptic rates or small postsynaptic potential size, allowing mean-field models to be developed even for populations with large interaction terms.

Author Summary

As one of the most complex systems known to science, modeling brain behavior and function is both fascinating and extremely difficult. Empirical data is increasingly available fromex vivohuman brain organoids and surgical samples, as well asin vivoanimal models, so the problem of modeling the behavior of large-scale neuronal systems is more relevant than ever. The statistical physics concept of a mean-field model offers a tractable approach by modeling the behavior of a single representative neuron and extending this to the population. However, most mean-field models work only in the limit of weak interactions between neurons, where synaptic input behaves more like a diffusion process than the sum of discrete synaptic events. This paper introduces a data-driven mean-field model, estimated by curve-fitting a simple transfer function, which works with larger interaction strengths. The resulting model can predict population firing rates and bifurcations of equilibria, as well as providing a simple dynamical model that can be the basis for further analysis.
Use of large language models as a scalable approach to understanding public health discourse
Authors: Espinosa Laura , Salathé Marcel
Published: February 2024

Online public health discourse is becoming more and more important in shaping public health dynamics. Large Language Models (LLMs) offer a scalable solution for analysing the vast amounts of unstructured text found on online platforms. Here, we explore the effectiveness of Large Language Models (LLMs), including GPT models and open-source alternatives, for extracting public stances towards vaccination from social media posts. Using an expert-annotated dataset of social media posts related to vaccination, we applied various LLMs and a rule-based sentiment analysis tool to classify the stance towards vaccination. We assessed the accuracy of these methods through comparisons with expert annotations and annotations obtained through crowdsourcing. Our results demonstrate that few-shot prompting of best-in-class LLMs are the best performing methods, and that all alternatives have significant risks of substantial misclassification. The study highlights the potential of LLMs as a scalable tool for public health professionals to quickly gauge public opinion on health policies and interventions, offering an efficient alternative to traditional data analysis methods. With the continuous advancement in LLM development, the integration of these models into public health surveillance systems could substantially improve our ability to monitor and respond to changing public health attitudes.

Authors summary

We examined how Large Language Models (LLMs), including GPT models and open-source versions, can analyse online discussions about vaccination from social media. Using a dataset with expert-checked posts, we tested various LLMs and a sentiment analysis tool to identify public stance towards vaccination. Our findings suggest that using LLMs, and prompting them with labelled examples, is the most effective approach. The results show that LLMs are a valuable resource for public health experts to quickly understand the dynamics of public attitudes towards health policies and interventions, providing a faster and efficient option compared to traditional methods. As LLMs continue to improve, incorporating these models into digital public health monitoring could greatly improve how we observe and react to dynamics in public health discussions.
symptomcheckR: an R package for analyzing and visualizing symptom checker performance
Authors: Kopka Marvin , Feufel Markus A.
Published: February 2024

Background

A major stream of research on symptom checkers aims at evaluating the technology’spredictive accuracy, but apart from general trends, the results are marked by high variability. Several authors suggest that this variability might in part be due to different assessment methods and a lack of standardization. To improve the reliability of symptom checker evaluation studies, several approaches have been suggested, including standardizing input procedures, the generation of test vignettes, and the assignment of gold standard solutions for these vignettes. Recently, we suggested a third approach––test-theoretic metrics for standardized performance reporting–– to allow systematic and comprehensive comparisons of symptom checker performance. However, calculating these metrics is time-consuming and error prone, which could hamper the use and effectiveness of these metrics.

Results

We developed the R package symptomcheckR as an open-source software to assist researchers in calculating standard metrics to evaluate symptom checker performance individually and comparatively and produce publicationready figures. These metrics include accuracy (by triage level), safety of advice (i.e., rate of correct or overtriage), comprehensiveness (i.e., how many cases could be entered or were assessed), inclination to overtriage (i.e., how risk-averse a symptom checker is) and a capability comparison score (i.e., a score correcting for case difficulty and comprehensiveness that enables a fair and reliable comparison of different symptom checkers). Each metric can be obtained using a single command and visualized with another command. For the analysis of individual or the comparison of multiple symptom checkers, single commands can be used to produce a comprehensive performance profile that complements the standard focus on accuracy with additional metrics that reveal strengths and weaknesses of symptom checkers.

Conclusions

Our package supports ongoing efforts to improve the quality of vignette-based symptom checker evaluation studies by means of standardized methods. Specifically, with our package, adhering to reporting standards and metrics becomes easier, simple, and time efficient. Ultimately, this may help users gain a more systematic understanding of the strengths and limitations of symptom checkers for different use cases (e.g., all-purpose symptom checkers for general medicine versus symptom checkers that aim at improving triage in emergency departments), which can improve patient safety and resource allocation.
A single-cell 3D spatiotemporal multi-omics atlas fromDrosophilaembryogenesis to metamorphosis
Authors: Wang Mingyue , Hu Qinan , Tu Zhencheng , Kong Lingshi , Yao Jiajun , Xiang Rong , Chen Zhan , Zhao Yan , Zhou Yanfei , Yu Tengxiang , Wang Yuetian , Jia Zihan , Ouyang Kang , Wang Xianzhe , Bai Yinqi , Lian Mingwei , Yang Zhenyu , Yang Tao , Chen Jing , Huang Yunting , Yin Ni , Mo Wenyuan , Liang Wenfu , Liu Chang , Lin Xiumei , Liu Chuanyu , Gu Ying , Chen Wei , Liu Longqi , Xu Xun , Hu Yuhui
Published: February 2024

The development of a multicellular organism is a highly intricate process tightly regulated by numerous genes and pathways in both spatial and temporal manners. Here, we present Flysta3D, a comprehensive multi-omics atlas of the model organismDrosophila, spanning its developmental lifespan from embryo to pupa. Our datasets encompass 3D single-cell spatial transcriptomic, single-cell transcriptomic, and single-cell chromatin accessibility information. By integrating these multi-dimensional data, we constructed cell state trajectories that uncover the detailed profiles of tissue development. With a focus on the central nervous system (CNS) and midgut, we dissected the spatiotemporal dynamics of gene regulatory networks, cell type diversity, and morphological changes from a multi-omics perspective. This extensive atlas provides an unprecedentedly rich resource and serves as a systematic platform for studyingDrosophiladevelopment with integrated single-cell data at an ultra-high spatiotemporal resolution.
QOT: Efficient Computation of Sample Level Distance Matrix from Single-Cell Omics Data through Quantized Optimal Transport
Authors: Wang Zexuan , Zhan Qipeng , Yang Shu , Mu Shizhuo , Chen Jiong , Garai Sumita , Orzechowski Patryk , Wagenaar Joost , Shen Li
Published: February 2024

Abstract

Single-cell technologies have emerged as a transformative technology enabling high-dimensional characterization of cell populations at an unprecedented scale. The data’s innate complexity and voluminous nature pose significant computational and analytical challenges, especially in comparative studies delineating cellular architectures across various biological conditions (i.e., generation of sample level distance matrices). Optimal Transport (OT) is a mathematical tool that captures the intrinsic structure of data geometrically and has been applied to many bioinformatics tasks. In this paper, we propose QOT (Quantized Optimal Transport), a new method enables efficient computation of sample level distance matrix from large-scale single-cell omics data through a quantization step. We apply our algorithm to real-world single-cell genomics and pathomics datasets, aiming to extrapolate cell-level insights to inform sample level categorizations. Our empirical study shows that QOT outperforms OT-based algorithms in terms of accuracy and robustness when obtaining a distance matrix at the sample level from high throughput single-cell measures. Moreover, the sample level distance matrix could be used in downstream analysis (i.e. uncover the trajectory of disease progression), highlighting its usage in biomedical informatics and data science.
Unveiling Multi-level and Multi-modal Semantic Representations in the Human Brain using Large Language Models
Authors: Nakagi Yuko , Matsuyama Takuya , Koide-Majima Naoko , Yamaguchi Hiroto Q. , Kubo Rieko , Nishimoto Shinji , Takagi Yu
Published: February 2024

In recent studies, researchers have used large language models (LLMs) to explore semantic representations in the brain; however, they have typically assessed different levels of semantic content, such as speech, objects, and stories, separately. In this study, we recorded brain activity using functional magnetic resonance imaging (fMRI) while participants viewed 8.3 hours of dramas and movies. We annotated these stimuli at multiple semantic levels, which enabled us to extract latent representations of LLMs for this content. Our findings demonstrate that LLMs predict human brain activity more accurately than traditional language models, particularly for complex background stories. Furthermore, we identify distinct brain regions associated with different semantic representations, including multi-modal vision-semantic representations, which highlights the importance of modeling multi-level and multi-modal semantic representations simultaneously. We will make our fMRI dataset publicly available to facilitate further research on aligning LLMs with human brain function. Please check out our webpage athttps://sites.google.com/view/llm-and-brain/.
Brain and grammar: revealing electrophysiological basic structures with competing statistical models
Authors: Cometa Andrea , Battaglini Chiara , Artoni Fiorenzo , Greco Matteo , Frank Robert , Repetto Claudia , Bottoni Franco , Cappa Stefano F , Micera Silvestro , Ricciardi Emiliano , Moro Andrea
Published: February 2024

Acoustic, lexical and syntactic information is simultaneously processed in the brain. Therefore, distinguishing the electrophysiological activity pertaining to these components requires complex and indirect strategies. Capitalizing on previous works which factor out acoustic information, we could concentrate on the lexical and syntactic contribution to language processing by testing competing statistical models. We exploited EEG recordings and compared different surprisal models selectively involving lexical information, part of speech or syntactic structures in various combinations. EEG responses were recorded in 32 participants during listening to affirmative active declarative sentences and compared the activation corresponding to basic syntactic structures, such as noun phrases vs verb phrases. Lexical and syntactic processing activates different frequency bands, different time windows and different networks. Moreover, surprisal models based on part of speech inventory only do not explain well the electrophysiological data, while those including syntactic information do. Finally, we confirm previous measures obtained with intracortical recordings independently supporting the original hypothesis addressed here in a robust way.
Proactive selective attention across competition contexts
Authors: Aguado-López Blanca , Palenciano Ana F. , Peñalver José M.G. , Díaz-Gutiérrez Paloma , López-García David , Avancini Chiara , Ciria Luis F. , Ruz María
Published: February 2024

Selective attention is a cognitive function that helps filter out unwanted information. Theories such as the biased competition model (Desimone & Duncan, 1995) explain how attentional templates bias processing towards targets in contexts where multiple stimuli compete for resources. However, it is unclear how the anticipation of different levels of competition influences the nature of attentional templates, in a proactive fashion. In this study, we used EEG to investigate how the anticipated demands of attentional selection (either high or low stimuli competition contexts) modulate target-specific preparatory brain activity and its relationship with task performance. To do so, participants performed a sex judgement task in a cue-target paradigm where, depending on the block, target and distractor stimuli appeared simultaneously (high competition) or sequentially (low competition). Multivariate Pattern Analysis (MVPA) showed that, in both competition contexts, there was a preactivation of the target category to select with a ramping-up profile at the end of the preparatory interval. However, cross-classification showed no generalization across competition conditions, suggesting different preparatory formats. Notably, time-frequency analyses showed differences between anticipated competition demands, reflecting higher theta band power for high than low competition, which mediated the impact of subsequent stimuli competition on behavioral performance. Overall, our results show that, whereas preactivation of the internal templates associated with the category to select are engaged in advance in both competition contexts, their underlying neural patterns differ. In addition, these codes could not be associated with theta power, suggesting different preparatory processes. The implications of these findings are crucial to increase our understanding of the nature of top-down processes across different contexts.
Protein-protein interactions with G3BPs drive stress granule condensation and gene expression changes under cellular stress
Authors: Liboy-Lugo José M. , Espinoza Carla A. , Sheu-Gruttadauria Jessica , Park Jesslyn E. , Xu Albert , Jowhar Ziad , Gao Angela L. , Carmona-Negrón José A. , Wittmann Torsten , Jura Natalia , Floor Stephen N.
Published: February 2024

Stress granules (SGs) are macromolecular assemblies that form under cellular stress. Formation of these condensates is driven by the condensation of RNA and RNA-binding proteins such as G3BPs. G3BPs condense into SGs following stress-induced translational arrest. Three G3BP paralogs (G3BP1, G3BP2A, and G3BP2B) have been identified in vertebrates. However, the contribution of different G3BP paralogs to stress granule formation and stress-induced gene expression changes is incompletely understood. Here, we identified key residues for G3BP condensation such as V11. This conserved amino acid is required for formation of the G3BP-Caprin-1 complex, hence promoting SG assembly. Total RNA sequencing and ribosome profiling revealed that disruption of G3BP condensation corresponds to changes in mRNA levels and ribosome engagement during the integrated stress response (ISR). Moreover, we found that G3BP2B preferentially condenses and promotes changes in mRNA expression under endoplasmic reticulum (ER) stress. Together, this work suggests that stress granule assembly promotes changes in gene expression under cellular stress, which is differentially regulated by G3BP paralogs.
mTORC1 activity oscillates throughout the cell cycle promoting mitotic entry and differentially influencing autophagy induction
Authors: Joshi Jay N. , Lerner Ariel D. , Scallo Frank , Grumet Alexandra N. , Matteson Paul , Millonig James H. , Valvezan Alexander J.
Published: February 2024

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that stimulates anabolic cell growth while suppressing catabolic processes such as autophagy. mTORC1 is active in most, if not all, proliferating eukaryotic cells. However, it remains unclear whether and how mTORC1 activity changes from one cell cycle phase to another. Here we tracked mTORC1 activity through the complete cell cycle and uncover oscillations in its activity. We find that mTORC1 activity peaks in S and G2, and is lowest in mitosis and G1. We further demonstrate that multiple mechanisms are involved in controlling this oscillation. The interphase oscillation is mediated through the TSC complex, an upstream negative regulator of mTORC1, but is independent of major known regulatory inputs to the TSC complex, including Akt, Mek/Erk, and CDK4/6 signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex, and instead involves CDK1-dependent control of the subcellular localization of mTORC1 itself. Functionally, we find that in addition to its well-established role in promoting progression through G1, mTORC1 also promotes progression through S and G2, and is important for satisfying the Wee1- and Chk1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific functional consequences in proliferating cells.
Performance investigation of conduction-cooled cryogenic permanent magnet undulator at high beam currents
Authors: Huang Jui-Che , Kitamura Hideo , Yang Chih-Shen , Yang Ching-Kang , Chen Chih-Wei , Chuang Yu-Chun
Published: February 2024

A conduction-cooled cryogenic permanent magnet undulator, CU15, with a period length of 15 mm and 133 periods has been successfully developed. This undulator has been operated at the Taiwan Photon Source (TPS) storage ring at a beam current of 500 mA for more than 3 years. In CU15, two cryocoolers are used to cool the PrFeB magnets to 80 K. The effective magnetic field measures 1.33 Tesla for a magnet gap of 4.2 mm, maintaining an rms phase error below 2.6°. The bunch length of the electron beam in TPS is as short as 16 psec, leading to a serious issue with high beam-induced heating in CU15. This report addresses the above issues and provides detailed adaptations of CU15 to operate at a beam current of 500 mA.

Published by the American Physical Society
2024
Manipulating spectral topology and exceptional points by nonlinearity in non-Hermitian polariton systems
Authors: Wingenbach Jan , Schumacher Stefan , Ma Xuekai
Published: February 2024

Exceptional points (EPs), with their intriguing spectral topology, have attracted considerable attention in a broad range of physical systems, with potential sensing applications driving much of the present research in this field. Here, we investigate spectral topology and EPs in systems with significant nonlinearity, exemplified by a nonequilibrium exciton-polariton condensate. With the possibility to control loss and gain and nonlinearity by optical means, this system allows for a comprehensive analysis of the interplay of nonlinearities (Kerr type and saturable gain) and non-Hermiticity. Not only do we find that EPs can be intentionally shifted in parameter space by the saturable gain, but we also observe intriguing rotations and intersections of Riemann surfaces and find nonlinearity-enhanced sensing capabilities. With this, our results illustrate the potential of tailoring spectral topology and related phenomena in non-Hermitian systems by nonlinearity.

Published by the American Physical Society
2024