bluuebunny/crossref_metadata_2025 huggingface dataset:
Practical Bayesian Inference in Neuroscience: Or How I Learned To Stop Worrying and Embrace the Distribution
Authors: Coventry Brandon S , Bartlett Edward L
Published: November 2023

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p-values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies. We first start with an intuitive discussion of Bayes’ rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

Significance Statement

Bayesian inference has received renewed interest as an alternative to null-significance hypothesis testing for its interpretability, ability to incorporate prior knowledge into current inference, and robust model comparison paradigms. Despite this renewed interest, discussions of Bayesian inference are often obfuscated by undue mathematical complexity and misunderstandings underlying the Bayesian inference process. In this article, we aim to empower neuroscientists to adopt Bayesian statistical inference by providing a practical methodological walkthrough using single and multi-unit recordings from the rodent auditory circuit accompanied by a well-documented and user-friendly toolkit containing regression and ANOVA statistical models commonly encountered in neuroscience.
Establishment and comprehensive characterization of a novel dark-reared zebrafish model for myopia studies
Authors: Xie Jiaheng , Goodbourn Patrick T. , Bui Bang V. , Jusuf Patricia R.
Published: November 2023

Purpose

Myopia is predicted to impact approximately 5 billion people by 2050, necessitating mechanistic understanding of its development. Myopia results from dysregulated genetic mechanisms of emmetropization, caused by over-exposure to aberrant visual environments; however, these genetic mechanisms remain unclear. Recent human genome-wide association studies have identified a range of novel myopia-risk genes. To facilitate large-scalein vivomechanistic examination of gene-environment interactions, this study aims to establish a myopia model platform that allows efficient environmental and genetic manipulations.

Methods

We established an environmental zebrafish myopia model by dark-rearing. Ocular biometrics including relative ocular refraction were quantified using optical coherence tomography images. Spatial vision was assessed using optomotor response (OMR). Retinal function was analyzed via electroretinography (ERG). Myopia-associated molecular contents or distributions were examined using RT-qPCR or immunohistochemistry.

Results

Our model produces robust phenotypic changes, showing myopia after 2 weeks of dark-rearing, which were recoverable within 2 weeks after returning animals to normal lighting. 2-week dark-reared zebrafish have reduced spatial-frequency tuning function. ERG showed reduced photoreceptor and bipolar cell function (a- andb-waves) after only 2 days of dark-rearing, which worsened after 2 weeks of dark-rearing. We also found dark-rearing-induced changes to expression of myopia-risk genes, includingegr1, vegfaa, vegfab, rbp3, gjd2aandgjd2b, inner retinal distribution of EFEMP1, TIMP2 and MMP2, as well as transiently reduced PSD95 density in the inner plexiform layer.

Conclusions

Coupled with the gene editing tools available for zebrafish, our environmental myopia model provides an excellent platform for large-scale investigation of gene-environment interactions in myopia development.
The intracellular growth of the vacuolar pathogenLegionella pneumophilais dependent on the acyl chain composition of host membranes
Authors: Wilkins Ashley A. , Schwarz Benjamin , Torres-Escobar Ascencion , Castore Reneau , Landry Layne , Latimer Brian , Bohrnsen Eric , Bosio Catharine M. , Dragoi Ana-Maria , Ivanov Stanimir S.
Published: November 2023

Legionella pneumophilais an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires’ disease. As a prototypical vacuolar pathogenL. pneumophilaestablishes a unique endoplasmic reticulum (ER)-derived organelle within which bacterial replication takes place. Bacteria-derived proteins are deposited in the host cytosol and in the lumen of the pathogen-occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of theLegionella-containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes - such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously fromde novosynthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis andL. pneumophilaintracellular replication. Using saturated fatty acids as well ascis- andtrans- isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidificationL. pneumophilaintracellular replication was significantly reduced. Palmitoleic acid – a C16:1 monounsaturated fatty acid – that promotes membrane disorder when enriched in GPLs significantly increased bacterial replication within human and murine macrophages but not in axenic growth assays. Lipidome analysis of infected macrophages showed that treatment with exogenous palmitoleic acid resulted in membrane acyl chain reprogramming in a manner that promotes membrane disorder and live-cell imaging revealed that the consequences of increasing membrane disorder impinge on several LCV homeostasis parameters. Collectively, we provide experimental evidence thatL. pneumophilareplication within its intracellular niche is a function of the lipid bilayer disorder and hydrophobic thickness.
Global Cluster Analysis and Network Visualization in Chordoma: A Scientometric Mapping
Authors: Zheng Bo-Wen , Zheng Bo-Yv , NIU Hua-Qing , Zou Ming-Xiang , Liu Fu-Sheng
Published: November 2023

Background: A recent scientific and comprehensive examination of the present status and future directions in chordoma research is a subject worth exploring. This study endeavors to investigate and depict the quantitative and qualitative development, research frontiers, and future trends in chordoma using bibliometric approaches. Methods: A total of 2510 publications from the Science Citation Index Expanded of Web of Science Core Collection were obtained from 1991 to 2021 and selected for bibliometric analysis. Bibliometric and knowledge-map analysis were performed using visualized approaches such as VOS viewer and CiteSpace, along with Origin 8.0 and GraphPad prism 8 tools.Results: The top five countries with the highest number of publications are the United States, China, Japan, Italy, and Germany. The most impactful journal is World Neurosurgery, while the most cited journal is Journal of Neurosurgery. The five most common research fields are neuroscience neurology, surgery, oncology, pathology, and radiology nuclear medicine medical imaging. Harvard University has the highest number of publications among institutions, and Gokaslan, Ziya L. has published the most papers and has the highest total link strength. The article "Chordoma: incidence and survival patterns in the United States, 1973-1995" has the most citations. The co-occurrence analysis includes 744 keywords that were categorized into five clusters: radiotherapy study, basic and clinical trill research, diagnostic study, surgical approach research, and prognostic study. CiteSpace identified 12 clusters of keywords, with clusters 0-5, 7, and 12 being former hotspots, clusters 6 and 11 being mid-period hotspots, and cluster 8 being the current research hotspot. Conclusions: This bibliometric analysis and visualized study of chordoma's global research field in the past 30 years is the first of its kind. The findings may help academic researchers comprehend chordoma's dynamic evolution and research trends.
Crossmodal Hierarchical Predictive Coding for Audiovisual Sequences in Human Brain
Authors: Huang Yiyuan Teresa , Wu Chien-Te , Fang Yi-Xin Miranda , Fu Chin-Kun , Koike Shinsuke , Chao Zenas C.
Published: November 2023

Predictive-coding theory proposes that the brain actively predicts sensory inputs based on prior knowledge. While this theory has been extensively researched within individual sensory modalities, there is a crucial need for empirical evidence supporting hierarchical predictive processing across different modalities to further generalize the theory. Here, we examine how crossmodal knowledge is represented and learned in the brain by identifying the hierarchical networks underlying crossmodal predictions when information of one sensory modality leads to a prediction in another modality. We record electroencephalogram (EEG) in humans during a crossmodal audiovisual local-global oddball paradigm, in which the predictability of transitions between tones and images are manipulated at two hierarchical levels: stimulus-to-stimulus transition (local level) and multi-stimulus sequence structure (global level). With a model-fitting approach, we decompose the EEG data using three distinct predictive-coding models: one with no audiovisual integration, one with audiovisual integration at the global level, and one with audiovisual integration at both the local and global levels. The best-fitting model demonstrates that audiovisual integration occurs at both levels. This highlights a convergence of auditory and visual information to construct crossmodal predictions, even in the more basic interactions that occur between individual stimuli. Furthermore, we reveal the spatio-spectro-temporal signatures of prediction-error signals across hierarchies and modalities, and show that auditory and visual prediction-error signals are progressively redirected to the central-parietal area of the brain as learning progresses. Our findings unveil a crossmodal predictive coding mechanism, where the unimodal framework is implemented through more distributed brain networks to process hierarchical crossmodal knowledge.
Male germ cell-associated kinase (MAK) is required for axoneme formation during ciliogenesis in zebrafish photoreceptors
Authors: Chiang Hung-Ju , Nishiwaki Yuko , Chiang Wei-Chieh , Masai Ichiro
Published: November 2023

Vertebrate photoreceptors are highly specialized retinal neurons that have cilium-derived membrane organelles called outer segments (OS), which function as platforms for phototransduction. Male germ cell-associated kinase (MAK) is a cilium-associated serine/threonine kinase, and its genetic mutation causes photoreceptor degeneration in mice and retinitis pigmentosa in humans. However, the role of MAK in photoreceptors is not fully understood. Here, we report that zebrafishmakmutants show rapid photoreceptor degeneration during embryonic development. Inmakmutants, both cone and rod photoreceptors completely lack OSs and undergo apoptosis. Interestingly, zebrafishmakmutants fail to generate axonemes during photoreceptor ciliogenesis, whereas basal bodies are specified. These data suggest that MAK contributes to axoneme development in zebrafish, in contrast to mouseMakmutants, which have elongated photoreceptor axonemes. Furthermore, the kinase activity of MAK is critical in ciliary axoneme development and photoreceptor survival. Thus, MAK is required for ciliogenesis and OS formation in zebrafish photoreceptors to ensure intracellular protein transport and photoreceptor survival.

Summary statement

Male germ cell-associated kinase (MAK) is a cilium-associated serine/threonine kinase that promotes axoneme development during ciliogenesis in zebrafish photoreceptors to ensure intracellular protein transport and photoreceptor survival.
Speedy and satisfying: Real-time Location System increases Emergency Department efficiency and decreases frustration with finding medical equipment
Authors: LoGalbo Sandhya , Trojanowski Sophia , Slusser Alexandria , Iyeke Lisa , Jordan Lindsay , Richman Mark
Published: November 2023

INTRODUCTION

We evaluated the impact of a real-time locating system on emergency department efficiency and frustration locating mobile otoscope/ophthalmoscope carts.

DATA AND METHODS

Thirty ED providers were selected on-shift, each serving as their own control. Investigators hid two mobile otoscope/ophthalmoscopes carts (with and without the RTLS device) equidistant from the center of a provider’s work area. Providers were timed finding both devices and were queried regarding feelings about the search experience.

RESULTS

RTLS was associated with statistically-significantly less time locating equipment (average of 25 vs. 92 seconds) and percent of providers requiring 30, 60, 90, and 120 seconds to find the device. Providers felt finding the mobile cart with RTLS was easier; all rated finding the RTLS-tagged cart as easy. Without RTLS, two-thirds of subjects reported either frustration or extreme frustration vs. 3% with RTLS. All differences in comparisons of subjective experience were statistically-significant. Annual time and cost saving with RTLS would be 116.4 hours ($9,135.66).

CONCLUSION

RTLS in EDs can decrease time and frustration associated with finding equipment and is cost-effective. Frustration is a common driver behind burnout in Emergency Medicine. Use of RTLS technology might improve the provider experience and, thereby, reduce burnout levels.
Understanding healthcare workers’ experiences of face mask and RPE use in healthcare settings: an interview study
Authors: Carter Holly , Sharp Ashley , Davidson Louise , Foster Clare , McGuire Emma , Brown Colin , Weston Dale
Published: November 2023

Whilst healthcare workers (HCWs) are at high risk of contracting COVID-19, measures can be put in place to reduce the spread of COVID-19 and other respiratory infections in healthcare settings. These currently include the use of masks: fluid-resistant surgical masks and respiratory protective equipment. However, for mask policies to be effective, compliance with their use must be high. This study interviewed 12 HCWs from a variety of backgrounds to understand their experiences of mask use. We explored factors associated with compliance with mask use and potential impacts on HCW wellbeing. Overall, participants reported good understanding of the benefits of masks and high compliance levels with policy. However, factors that reduced their compliance with mask policy and impacted their ability to carry out their role were highlighted. These included wearing masks for longer durations, policy being perceived as out of proportion with risk, communication challenges, and discomfort. This study highlights the importance of clear communication of guidance, particularly when it has changed, ensuring staff are familiar with up-to-date research on efficacy of masks, and ensuring guidance aligns with risk. Furthermore, this study highlights the importance of masks being required for an appropriate duration (based on risk).
Management and outcomes of fractures over cranial venous sinuses: A scoping review protocol
Authors: Takoutsing Berjo D. , Njineck Ubraine Wunde , Wah Praise Senyuy , Sebopelo Lorraine , Tchoffo Josiane Ngouanfo , Bah Ella Shiynyuy , Esene Ignatius
Published: November 2023

Introduction

Fractures over venous sinuses (FOVS) are associated with difficulties in diagnosis, and treatment resulting in a high level of morbidity, and mortality. Despite its importance, there is limited aggregate data to guide the management of these fractures ultimately inflicting a major challenge to neurosurgeons. This protocol describes the methodology of a scoping review that aims to synthesise contemporary evidence on the management and outcomes of FOVS.

Methods and analysis

The proposed study will be conducted in accordance with the Arksey and O’Malley’s framework for scoping reviews. The research question, eligibility criteria and search strategy were developed based on the Population, Intervention, Comparator, Outcome strategy. The following electronic bibliographic databases will be searched without restrictions on language, and date of publication: PubMed, WHO Global Index Medicus, African Journals Online, SCOPUS, Embase. All peer-reviewed studies of primary data reporting on the management and outcomes of FOVS will be included. The data extracted from included articles will be presented through descriptive statistics, pooled statistics, and a narrative description.

Ethics and dissemination

Because this study did not directly involve human individuals, ethical approval was not necessary. Dissemination strategies will include publication in a peer-reviewed journal, oral and poster presentations at local, regional, national and international conferences and promotion over social media.

ARTICLE SUMMARY

Strengths and limitations of this study

To our knowledge this is the first scoping review focusing on the management and outcomes of fractures over the venous sinuses

This protocol will ensure transparency in the methodology of the proposed review, thus will reduce the likelihood of reviewing bias.

The search strategy will be conducted in five electronic databases commonly used across both high- and low-income countries.

There will be no restrictions on language, location, or publication date during the screening process.

Unpublished studies will not be sought.

There will be no formal assessment on the quality of the included studies.
Increased Severity of New-onset Type 1 Diabetes in Children and Adolescents during the COVID-19 Pandemic: Experience from a Tertiary Care Center in Serbia
Authors: Jovanovic Damjan , Blagojevic Jelena , Stanisavljevic Dejana , Jesic Maja
Published: November 2023

Background and objectives

Public health measures, parental fear of infection, and redeployment of medical resources in response to the COVID-19 pandemic might have led to a decrease in pediatric healthcare access. As a result, a delay in type 1 diabetes diagnosis might have occurred, leading to the worsening of its clinical presentation in the pediatric population. This study aimed to examine the clinical and biochemical features of new-onset DM1 in children and adolescents during the COVID-19 pandemic, comparing it to the pre-pandemic period.

Materials and methods

The clinical and biochemical features of diabetes observed during the COVID-19 period from April 1, 2020, until December 31, 2022, were compared with the period from April 1, 2017, until December 31, 2019. In the COVID-19 pandemic group, the clinical and biochemical features were compared between children with and without SARS-CoV-2 infection at diagnosis or before the diagnosis of DM1.

Results

During the COVID-19 pandemic, observed frequencies of DKA and severe DKA at diagnosis were 47.6% and 20.7%, both significantly higher than during the pre-pandemic period (an absolute increase of 15% and 11.3%, respectively). In the COVID-19 group, blood pH levels were significantly lower than in the pre-pandemic group, while HbA1c levels were higher. Clinical and biochemical features of diabetes in children with SARS-CoV-2 infection at or before the diagnosis were not significantly different compared to children without an infection.

Conclusion

We report a significant worsening of the clinical presentation of new-onset type 1 diabetes and an increase in the frequency of DKA and severe DKA at diagnosis during the COVID-19 pandemic. Further studies are necessary to gain quantitative insight into pediatric healthcare availability in Serbia.
Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins
Authors: Bahrami Flora , Psikuta Agnes , Rossi René Michel , Dommann Alex , Defraeye Thijs
Published: November 2023

Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl’s transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes anin-silicoskin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3% higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18% lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8% from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5% and 33.3%, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy out-come variability. This holds promise as a potentially useful tool for physicians.

Graphical Abstract

(Created withBioRender.comandwww.flaticon.com)
Estimating the optimal age for infant measles vaccination
Authors: Goult Elizabeth , Barrero Guevara Laura Andrea , Briga Michael , Domenech de Cellès Matthieu
Published: November 2023

The persistence of measles in many regions demonstrates large immunity gaps, resulting from incomplete or ineffective immunization with measles-containing vaccines (MCVs). A key factor affecting MCV impact is age, with infants receiving dose 1 (MCV1) at older ages having a reduced risk of vaccine failure, but also an increased risk of contracting infection before vaccination. Here, we designed a new method—based on a transmission model incorporating realistic vaccination delays and age variations in MCV1 effectiveness—to capture this risk trade-off and estimate the optimal age for recommending MCV1. We predict a large heterogeneity in the optimal ages (range: 6–20 months), contrasting the homogeneity of observed recommendations worldwide. Furthermore, we show that the optimal age depends on the local epidemiology of measles, with a lower optimal age predicted in populations suffering higher transmission. Overall, our results suggest the scope for public health authorities to tailor the recommended schedule for better measles control.
Quality of systematic reviews on physiotherapy interventions for musculoskeletal disorders is critically low: a meta-epidemiological study
Authors: Ferri Nicola , Ravizzotti Elisa , Bracci Alessandro , Carreras Giulia , Pillastrini Paolo , Di Bari Mauro
Published: November 2023

Question

How good is the quality of systematic reviews on the effectiveness of physiotherapy for musculoskeletal conditions? Are there any factors associated with quality?

Design

This is a meta-epidemiological study on systematic reviews with meta-analysis (SR-MA) of randomised controlled trials (RCT).

Methods

MEDLINE, Cochrane Database of Systematic Reviews (CDSR), CINAHL, and PEDro were searched for SR-MA of RCT on physiotherapy in musculoskeletal disorders in the last ten years. Two independent researchers screened and extracted the records and analysed the full-texts. The quality of SR-MA was quantified with AMSTAR-2 tool on a sample of 100 studies, randomly selected from the records retrieved. Disagreements were solved by consensus.

Results

The number of eligible publications increased over the past ten years. However, the methodological quality was critically low in as many as 90% of the studies retrieved and did not increase with time. The last author’s H-index was the only quality predictor among the variables analysed.

Conclusion

The methodological quality of the SR-MA of RCT is unacceptably low. Given the frequent application of physiotherapy in musculoskeletal disorders, there is an urgent need to improve secondary research by adopting more rigorous methods.

Registration

Open Science Framework (https://osf.io/bc8zw/)
Deep Learning Approach to Measure Alveolar Bone Loss After COVID-19
Authors: Lee Sang Won , Huz Kateryna , Gorelick Kayla , Bina Thomas , Matsumura Satoko , Yin Noah , Zhang Nicholas , Naa Ardua Anang Yvonne , Li Jackie , Servin-DeMarrais Helena I. , McMahon Donald J , Yin Michael T. , Wadhwa Sunil , Lu Helen H.
Published: November 2023

Severity of periodontal disease may be determined by measurement of alveolar crestal height (ACH) on dental bitewing radiographs; however, the prevailing method of assessment is through visualization which is time consuming and not a direct measure. The primary objective of this manuscript is to create and validate a deep learning technique for precise evaluation of alveolar bone loss in bitewing radiographs. Additionally, surveys were conducted with dental professionals to determine accuracy of visualized measures of ACH for severe periodontal disease versus the deep learning program and to determine the acceptability of utility of the program among diverse dental professionals. Lastly, the deep learning program was utilized in research to evaluate the role of COVID on periodontal disease through longitudinal measures of bitewing radiograph ACH from patients during the: "pre-pandemic" (Feb 2017 - Feb 2020) and "post-pandemic" (Feb 2020 - Feb 2023) periods. The pre-pandemic group had a mean percentage loss of ACH of -1.74 + 16.5%, representing a gain in alveolar bone. In contrast, the post-pandemic group had a gain in ACH of 2.46 + 14.6%, representing a loss in alveolar bone. There remained a trend for greater annualized percent change in ACH in the post-pandemic vs pre-pandemic group (1.33 + 11.9% vs -0.94 + 12.5%, p=0.07), after accounting for differences in duration between xrays. Overall, this study demonstrates the successful training and validation of a deep learning program for ACH measurement as well as its utility and acceptability among dental professionals for clinical and research.
High radiosensitivity in Norway spruce (Picea abies) is rendered by less comprehensive mobilisation of protection, repair and stress responses compared to the radiotolerantArabidopsis thaliana
Authors: Bhattacharjee Payel , Blagojevic Dajana , Lee YeonKyeong , Gillard Gareth B , Grønvold Lars , Hvidsten Torgeir Rhoden , Sandve Simen Rød , Lind Ole Christian , Salbu Brit , Brede Dag Anders , Olsen Jorunn E.
Published: November 2023

Risk assessment and protection of plant communities in contaminated ecosystems require in-depth understanding of differential sensitivity to chronic ionising radiation in plants. However, the contributing molecular factors are poorly understood.

We compared early molecular events associated with protection, repair, and stress responses, by analysing growth, organelle and DNA damage, and the dynamics of transcriptome and DNA damage repair (DDR) gene expression in gamma-irradiated seedlings of the radiosensitive conifer Norway spruce (Picea abies) and the radiotolerantArabidopsis thaliana.

Norway spruce showed reduced growth at 290 mGy h-1and severe organelle damage, especially in mitochondria, at ≥ 1 mGy h-1whereasA. thalianashowed unaffected development, minor organelle damage at ≥ 100 mGy h-1and significantly less DNA damage, after 48-h of gamma exposure. Comparative transcriptomics revealed thatA. thalianashowed massive activation of genes related to DDR, antioxidants, and other stress responses at ≥ 1 mGy h-1while Norway spruce mobilized transcription of such pathways only at ≥ 40 mGy h-1.

The transcriptional activation of repair and protection responses at higher gamma dose-rates only and its absence in lower dose-rates, corelates with high radiosensitivity of Norway spruce, compared to the massive transcriptional activation from low dose-rates in the radiotolerantA. thaliana.
Mass lysis of bacterial predators drives the enrichment of antibiotic resistance in soil microbial communities
Authors: Saha Saheli , Kalathera Jyotsna , Sumi Thoniparambil Sunil , Mane Vishwadeep , Zimmermann Sina , Waschina Silvio , Pande Samay
Published: November 2023

While studies on anthropogenic activities and antibiotic resistance are numerous, the impact of microbial interactions on resistance in complex communities remains uncertain. Here we demonstrate a correlation between the presence ofMyxococcus xanthusin natural soil communities and the abundance of antibiotic-resistant bacteria. Further, introducingM. xanthusisolates also enriches antibiotic resistance. This is due to the mass lysis ofM. xanthuscells, which results in a toxic environment that fosters the proliferation of pre-existing resistant bacteria rather than de novo resistance evolution. Metagenomic analysis revealed that this enrichment is not limited to the tested antibiotics in culture-based methods, indicating its broader relevance. Crucially, these findings go beyond laboratory settings, showingM. xanthusintroduction enriches resistant isolates in natural soil communities. Finally, we demonstrate that the mass lysis ofM. xanthuscells during starvation-induced development—key aspect of the lifecycle ofM. xanthus—also results in the enrichment of antibiotic resistance in soil communities. Together, we demonstrate how life-history traits in bacterial predators, likeM. xanthus, significantly impact antibiotic resistomes in nature. This study also highlights the complex dynamics at play in the evolution and maintenance of antibiotic resistance, emphasizing the role of interspecies interactions in shaping antibiotic resistance profiles.
Statistical Methods for Microrheology of Airway Mucus with Extreme Heterogeneity
Authors: Caughman Neall , Papanikolas Micah , Markovetz Matthew , Freeman Ronit , Hill David B. , Forest M. Gregory , Lysy Martin
Published: November 2023

The mucus lining of the human airway epithelium contains two gel-forming mucins, MUC5B and MUC5AC. During progression of cystic fibrosis (CF), mucus hyper-concentrates as its mucin ratio changes, coinciding with formation of insoluble, dense mucus flakes. We explore rheological heterogeneity of this pathology with reconstituted mucus matching three stages of CF progression and particle-tracking of 200 nm and 1 micron diameter beads. We introduce statistical data analysis methods specific to low signal-to-noise data within flakes. Each bead time series is decomposed into: (i) a fractional Brownian motion (fBm)classifier of the pure time-series signal; (ii) high-frequency static and dynamic noise; and (iii) low-frequency deterministic drift. Subsequent analysis focuses on the denoised fBm classifier ensemble from each mucus sample and bead diameter. Every ensemble fails a homogeneity test, compelling clustering methods to assess levels of heterogeneity. The first binary level detects beads within vs. outside flakes. A second binary level detects within-flake bead signals that can vs. cannot be disentangled from the experimental noise floor. We show all denoised ensembles, within- and outside-flakes, fail a homogeneity test, compelling additional clustering; next, all clusters with sufficient data fail a homogeneity test. These levels of heterogeneity are consistent with outcomes from a stochastic phase-separation process, and dictate applying the generalized Stokes-Einstein relation to each bead per cluster per sample, then frequency-domain averaging to assess rheological heterogeneity. Flakes exhibit a spectrum of gel-like and sol-like domains, outside-flake solutions a spectrum of sol-like domains, painting a rheological signature of the phase-separation process underlying flake-burdened mucus.
RNA sequencing demonstratesex vivoneocortical transcriptomic changes induced by epileptiform activity in male and female mice
Authors: Vaughan Alec J. , McMeekin Laura J. , Hine Kutter , Stubbs Isaac W. , Codadu Neela K. , Cockell Simon , Hill Jonathon T. , Cowell Rita , Trevelyan Andrew J , Parrish R. Ryley
Published: November 2023

Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile are likely to alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterie how gene expression is changed by seizure activity. To this end, we developed a simplifiedex vivotechnique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue that had up to 3 hours of epileptiform activity induced by 4-aminopyridine (4AP), relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signalling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile to be complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes.

Significance Statement

It is well-established that strong neuronal activation results in large-scale transcriptomic changes. Understanding this process is of particular importance in epilepsy, which is characterized by paroxysmal pathological discharges. The complexity ofin vivoactivity patterns, however, present many difficulties for interpretation of the transcriptional changes. In contrast,ex vivoseizure models provide better experimental control and quantification of activity patterns, with lower welfare impact. Importantly, we now show that these models also replicate the transcriptional patterns previously reported in chronic human and animal epilepsy, thus validating their use in these kinds of study.
Unravelling the molecular mechanisms of fish salinity adaptation in the face of multiple stressors: A comparative multi-tissue transcriptomic study in the Llobregat River, Barcelona, Spain
Authors: Escobar-Sierra Camilo , Cañedo-Argüelles Miguel , Vinyoles Dolors , Lampert Kathrin P.
Published: November 2023

Freshwater salinization poses a growing global environmental concern, introducing complex chemical cocktails and jeopardizing freshwater biodiversity, particularly fish populations. This research aimed to elucidate the molecular foundations of salinity adaptation in a non-native minnow species (Phoxinus septimaniaexP. dragarum) exposed to saline effluents from potash mines in the Llobregat River, Barcelona, Spain. Employing high-throughput mRNA sequencing and differential gene expression analyses, we examined brain, gills, and liver tissues collected from fish at two stations (upstream and downstream of saline effluent discharge). Salinization markedly influenced global gene expression profiles, with the brain exhibiting the most differentially expressed genes, emphasizing its unique sensitivity to salinity fluctuations. Pathway analyses revealed the expected enrichment of ion transport and osmoregulation pathways across all tissues. Furthermore, tissue-specific pathways associated with stress, reproduction, growth, immune responses, methylation, and neurological development were identified in the context of salinization. Rigorous validation of RNA-seq data through quantitative PCR (qPCR) underscored the robustness and consistency of our findings across platforms. This investigation unveils intricate molecular mechanisms steering salinity adaptation in non-native minnows confronting diverse environmental stressors. Advancing our comprehension of genomic responses to salinity changes, our study provides crucial insights into the adaptive strategies of aquatic organisms grappling with freshwater salinization. This comprehensive analysis sheds light on the underlying genetic and physiological mechanisms governing fish adaptation in salinity-stressed environments, offering essential knowledge for the conservation and management of freshwater ecosystems facing escalating salinization pressures.
Neural correlates of modality-specific and modality-invariant object recognition in the perirhinal cortex
Authors: Lim Heung-Yeol , Lee Inah
Published: November 2023

The perirhinal cortex (PER) supports multimodal object recognition, but how multimodal information of objects is integrated within the PER remains unknown. Here, we recorded single units within the PER while rats performed a PER-dependent multimodal object-recognition task. In this task, audiovisual cues were simultaneously (multimodally) or separately (unimodally) presented. We identified two types of object-selective neurons in the PER: crossmodal cells, showing constant firing patterns for an object irrespective of its modality, and unimodal cells, showing a preference for a specific modality. Unimodal cells further dissociated unimodal and multimodal versions of the object by modulating their firing rates according to the modality condition. A population-decoding analysis confirmed that the PER could perform both modality-invariant and modality-specific object decoding – the former for recognizing an object as the same in various conditions and the latter for remembering modality-specific experiences of the same object.
Phenotypic memory in quorum sensing
Authors: Ostovar Ghazaleh , Boedicker James Q.
Published: November 2023

Quorum sensing (QS) is a regulatory mechanism used by bacteria to coordinate group behavior in response to high cell densities. During QS, cells monitor the concentration of external signals, known as autoinducers, as a proxy for cell density. QS often involves positive feedback loops, leading to the upregulation of genes associated with QS signal production and detection. This results in distinct steady-state concentrations of QS-related molecules in QS-ON and QS-OFF states. Due to the slow decay rates of biomolecules such as proteins, even after removal of the initial stimuli, cells can retain elevated levels of QS-associated biomolecules for extended periods of time. This persistence of biomolecules after the removal of initial stimuli has the potential to impact the response to future stimuli, denoting a memory of past exposure. This phenomenon, which is a consequence of the carry-over of biomolecules rather than genetic inheritance, is known as “phenotypic” memory.

This theoretical study aims to investigate the presence of phenotypic memory in QS and the conditions that influence this memory. Numerical simulations based on ordinary differential equations and analytical modeling were used to study gene expression in response to sudden changes in cell density and extracellular signal concentrations. The model examined the effect of various cellular parameters on the strength of QS memory and the impact on gene regulatory dynamics. The findings revealed that QS memory has a transient effect on the expression of QS-responsive genes. These consequences of QS memory depend strongly on how cell density was perturbed, as well as various cellular parameters, including the Fold Change in the expression of QS-regulated genes, the autoinducer synthesis rate, the autoinducer threshold required for activation, and the cell growth rate.

Author summary

Bacteria use a mechanism known as quorum sensing (QS) to collaborate when their numbers are high. Cells produce and detect signals that trigger the production of certain proteins and changes in cell behavior. Interestingly, the molecules produced during this process can linger even after the initial signal is gone. The persistence of these molecules is a form of “memory”, as cells are temporarily changed by events in the recent past. Our theoretical study focuses on exploring this memory and the factors that influence it. To do this, we used simulations and models to examine how history of exposure to signals can affect the future response of cells. We found that the prior exposure to signals can influence how bacteria respond in the future, but this memory only has consequences under specific conditions. This research contributes to our understanding of quorum sensing and how bacteria adapt to environmental changes.
The HtrA chaperone monitors sortase-assembled pilus biogenesis inEnterococcus faecalis
Authors: Yong Adeline M.H. , Winter Cristina Colomer , Chong Kelvin K. L. , Gao Iris Hanxing , Matysik Artur , Chen Swaine L. , Kline Kimberly A.
Published: November 2023

Sortase-assembled pili contribute to virulence in many Gram-positive bacteria. InEnterococcus faecalis, the endocarditis and biofilm-associated pilus (Ebp) is polymerized on the membrane by sortase C (SrtC) and attached to the cell wall by sortase A (SrtA). In the absence of SrtA, polymerized pili remain anchored to the membrane (i.e. off-pathway). Here we show that the high temperature requirement A (HtrA) bifunctional chaperone/protease ofE. faecalisis a quality control system that clears aberrant off-pathway pili from the cell membrane. In the absence of HtrA and SrtA, accumulation of membrane-bound pili leads to cell envelope stress and partially induces the regulon of the ceftriaxone resistance-associated CroRS two-component system, which in turn causes hyper-piliation and cell morphology alterations. Inactivation ofcroRin the ΔsrtAΔhtrAbackground partially restores the observed defects of the ΔsrtAΔhtrAstrain, supporting a role for CroRS in the response to membrane perturbations. Moreover, absence of SrtA and HtrA decreases basal tolerance ofE. faecalisagainst cephalosporins and daptomycin. The link between HtrA, pilus biogenesis and the CroRS two-component system provides new insights into theE. faecalisresponse to endogenous membrane perturbations.

Author summary

To explore the role of the HtrA chaperone/protease inE. faecalisoff-pathway pilus clearance, we deletedhtrAin anE. faecalisOG1RF ΔsrtAstrain known to retain polymerized pili on the cell membrane. Cells in the ΔsrtAΔhtrAbackground are hyper-piliated, possess altered morphology, and are more susceptible to cell envelope-targeting antibiotics as compared to the parent OG1RF strain. RNA sequencing of the ΔsrtAΔhtrAstrain revealed transcriptional changes reminiscent of a membrane stress response. This response was pilus-dependent and contained several members of the CroR regulon. Inactivation of the response regulator CroR in the ΔsrtAΔhtrAbackground restored (at least partially) piliation and cell morphology but not antibiotic susceptibility, linking CroR for the first time to pilus biogenesis and endogenous cell envelope stress.
The nematode (Ascaris suum) intestine is a location of synergistic anthelmintic effects of Cry5B and levamisole
Authors: Williams Paul D. E. , Brewer Matthew T. , Aroian Raffi , Robertson Alan P. , Martin Richard J.
Published: November 2023

A novel group of biocidal compounds are the Crystal 3D (Cry) and Cytolytic (Cyt) proteins produced byBacillus thuringiensis(Bt). Some Bt Cry proteins have a selective nematocidal activity, with Cry5B being the most studied. Cry5B kills nematode parasites by binding selectively to membrane glycosphingolipids, then forming pores in the cell membranes of the intestine leading to damage. Cry5B selectively targets multiple species of nematodes from different clades and has no effect against mammalian hosts. Levamisole is a cholinomimetic anthelmintic that acts by selectively opening L-subtype nicotinic acetylcholine receptor ion-channels (L-AChRs) that have been found on muscles of nematodes. A synergistic nematocidal interaction between levamisole and Cry5B has been described previously, but the location, mechanism and time-course of this synergism is not known. In this study we follow the timeline of the effects of levamisole and Cry5B on the Ca2+levels in enterocyte cells from the intestine ofAscaris suumusing fluorescence imaging. The peak Ca2+responses to levamisole were observed after approximately 10 minutes while the peak responses to activated Cry5B were observed after approximately 80 minutes. When levamisole and Cry5B were applied simultaneously, we observed that the responses to Cry5B were bigger and occurred sooner than when it was applied by itself. It is proposed that there is an irreversible cytoplasmic Ca2+overload that leads to necrotic cell-death in the enterocyte that is induced by levamisole opening Ca2+permeable L-subtype nAChRs and the development of Ca2+permeable Cry5B toxin pores in enterocyte plasma membranes. The effects of levamisole potentiate and speed the actions of Cry5B.