bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of external validation and subgroup analysis in artificial-intelligence detecting low ejection fraction from electrocardiograms
Authors: Yagi Ryuichiro , Goto Shinichi , Katsumata Yoshinori , MacRae Calum A , Deo Rahul C
Published: July 2022

Introduction

Asymptomatic left ventricular dysfunction (ALVD) carries an increased risk for overt heart failure and mortality, yet treatable to mitigate disease progression. An artificial intelligence (AI)-enabled 12-lead electrocardiogram (ECG) model demonstrated promise in ALVD screening but an unexpected drop in performance was observed in external validation. We thus sought to train ade novomodel for ALVD detection and investigate its performance across multiple institutions and across a broader set of patient strata.

Methods

ECGs taken within 14 days of an echocardiogram were obtained from 4 academic hospitals from the United States (BWH, MGH and UCSF) and Japan (Keio). Four AI models were trained to detect patients with ejection fraction < 40% using ECG from each of the 4 institutions. All the models were then evaluated on the held-out test dataset from the same intuition and all data from the 3 external institutions. Subgroup analyses stratified by patient characteristics and common overt ECG abnormalities were performed.

Results

A total of 221,846 ECGs were identified from the 4 institutions. While the BWH-trained and Keio-trained model yielded similar accuracy on its internal test data (AUROC 0.913 and 0.914 respectively), external validity was worse for Keio-trained model (AUROC: 0.905-0.915 for BWH-trained and 0.849-0.877 for Keio-trained model). Although ECG abnormalities including atrial fibrillation, left bundle branch block and paced rhythm reduced detection, the models performed robustly across patient characteristics and other ECG features.

Conclusion

Different dataset produces models with different performance highlighting the importance of external validation and extensive stratification analysis.
Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults
Authors: Ferreira-Atuesta Carolina , de Tisi Jane , McEvoy Andrew W. , Miserocchi Anna , Khoury Jean , Yardi Ruta , Vegh Deborah T. , Butler James , Lee Hamin J. , Deli-Peri Victoria , Yao Yi , Wang Feng-Peng , Zhang Xiao-Bin , Shakhatreh Lubna , Siriratnam Pakeeran , Neal Andrew , Sen Arjune , Tristram Maggie , Varghese Elizabeth , Biney Wendy , Gray William P , Peralta Ana Rita , Rainha-Campos Alexandre , Gonçalves-Ferreira António JC. , Pimentel José , Arias Juan Fernando , Terman M Samuel , Terziev Robert , Lamberink Herm J. , Braun Kees P.J. , Otte Willem M , Rugg-Gunn Fergus J. , Gonzalez Walter , Bentes Carla , Hamandi Khalid , O’ Brien Terence J. , Perucca Piero , Yao Chen , Burman Richard J. , Jehi Lara , Duncan John S. , Sander Josemir W , Koepp Matthias , Galovic Marian
Published: July 2022

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models.

We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures (auras) before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than auras, using Cox proportional hazards regression in a derivation cohort (n=231). Independent predictors of seizure recurrence, other than auras, following the start of ASM withdrawal were focal-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n=500). A secondary model predicting recurrence of any seizures (including auras) was developed and validated in a subgroup that did not have auras before withdrawal (n=639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models.

We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients.
DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation
Authors: Jokai Matyas , Torma Ferenc , McGreevy Kristen M. , Koltai Erika , Bori Zoltan , Babszki Gergely , Bakonyi Peter , Gombos Zoltan , Gyorgy Bernadett , Aczel Dora , Toth Laszlo , Osvath Peter , Fridvalszky Marcell , Teglas Timea , Ligeti Balazs , Kalcsevszki Regina , Posa Aniko , Kujach Sylwester , Olek Robert , Kawamura Takuji , Seki Yasuhiro , Suzuki Katsuhiko , Tanisawa Kumpei , Goto Sataro , Boldogh Istvan , Ba Xueqing , Szabo Dora , Davies Kelvin J. A. , Horvath Steve , Radak Zsolt
Published: July 2022

DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm) based biomarkers that reflect the individual aging process. Furthermore, physical fitness is known to relate to the aging process, but its relationship to the gut microbiome has not yet been studied. Here, we examine the relationship among physical fitness, DNAm based biomarkers, and the microbiome in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (ρ=0.2, p=6.4E-4, r=0.19, p=1.2E-3), Jumpmax p=0.11, p=5.5E-2, r=0.13 p= 2.8E-2), Gripmax (=ρ=0.17, p=3.5E-3, r=0.16, p=5.6E-3), and HDL levels (ρ=0.18, p=1.95E-3, r=0.19, p=1.1E-3) are associated with better verbal short term memory. In addition, verbal short term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (ρ: −0.18, p=0.0017). DNAmFitAge is able to distinguish high fitness individuals from low/medium fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high fit males and females (1.5 and 2.0 years younger, respectively). The microbiomal pathways are associated with VO2max, redox balance, and DNAmPhenoAge. PhenoAge Acceleration is influenced by pyruvate producing microbiomal pathways, where higher activity of these pathways lead to suppressed PhenoAge acceleration. Our research shows that regular physical exercise contributes to observable physiological, methylation, and microbiota differences which are beneficial to the aging process. DNAmFitAge emerged as a biological marker of the quality of life.
Part-time or full-time teleworking? A systematic review of the psychosocial risk factors of telework from home
Authors: Antunes Evelise Dias , Bridi Leonardo Rodrigues Thomaz , Santos Marta , Fischer Frida Marina
Published: July 2022

Since the start of the Coronavirus pandemic thousands of people have experienced teleworking and this practice is becoming increasingly commonplace. Systematic reviews can yield evidence and information to help inform the development of policies and regulations, the aim of this study was to highlight the differences in exposure to psychosocial risk factors for health between part-time and full-time teleworking from home. The protocol of the systematic review of the literature was registered on PROSPERO 2020 platform - International Prospective Register of Systematic Reviews (number CRD42020191455), according to the PRISMA statement guidelines. The key words “telework” and frequency (“part-time” or “full-time”), together with their synonyms and variations, were searched. Independent researchers conducted the systematic search of 7 databases: Scopus, SciELO, PePSIC; PsycInfo, PubMed, Applied Social Sciences Index and Abstracts (ASSIA) and Web of Science. Of the 638 articles identified from 2010 to June 2021, 32 were selected for data extraction. The authors evaluated the risk of bias and quality of evidence of the studies included using the Mixed Methods Appraisal Tool. The results were categorized into 7 dimensions of psychosocial risk factors: work intensity and working hours; emotional demands; autonomy; social relationships at work; conflict of values, work insecurity and home/work interface. The results revealed scant practice of full-time teleworking prior to the pandemic. Regarding the psychosocial risk factors found, differences were evident before and during the COVID-19 pandemic. For part-time and full-time telework prior to the pandemic, the dimensions of intensification of work and working hours, social relationships at work, and the home-work interface were the most prominent factors. However, in studies performed during the COVID-19 pandemic where teleworking was mostly performed full-time, there was an increase in focus on emotional demands and the home-work interface, and a reduction in the other dimensions.
High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells
Authors: Phetsouphanh Chansavath , Khoo Weng Hua , Jackson Katherine , Klemm Vera , Howe Annett , Aggarwal Anupriya , Akerman Anouschka , Milogiannakis Vanessa , Stella Alberto Ospina , Rouet Romain , Schofield Peter , Faulks Megan L. , Law Hannah , Danwilai Thidarat , Starr Mitchell , Munier C. Mee Ling , Christ Daniel , Singh Mandeep , Croucher Peter I , Brilot-Turville Fabienne , Turville Stuart , Phan Tri Giang , Dore Gregory J , Darley David , Cunningham Philip , Matthews Gail V , Kelleher Anthony D , Zaunders John J
Published: July 2022

Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)- specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, rather than the effector T- bet+, cytotoxic granzymes+ and perforin+ cells seen in high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, that were absent in individuals with low antibody levels. However, vaccination in low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD- region should be prioritized in booster vaccines.

One Sentence Summary

Individuals with low neutralising antibody titres may be at risk of SARS-CoV-2 re-infection due to a failure to generate a high quality CD4 T cell response specific for receptor binding domain (RBD), including memory CD4 T cells that proliferate in vitro in response to RBD, and which are also therefore an important target for vaccine design.
Decreased ventral tegmental area CB1R signaling reduces sign-tracking and shifts cue-outcome dynamics in rat nucleus accumbens
Authors: Bacharach Sam Z. , Martin David A. , Stapf Cassie A. , Sun Fangmiao , Li Yulong , Cheer Joseph F. , Calu Donna J.
Published: July 2022

Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate-rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTA→NAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases NAc shell, but not core, dopamine levels during reward delivery (US). We also observed a relationship between cue (CS)-evoked NAc dopamine activity and rigidity of behavior between rimonabant treatment sessions. Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc and biases behavioral responding to cues in sign-tracking rats.

SIGNIFICANCE STATEMENT

Substance Use Disorder is a chronically relapsing neurobiological disorder that affects a subset of individuals that engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences prior to drug experience that predict addiction and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug motivated behaviors.
Brain-based Lifespan Trajectories of Social Cognition: From Resting-state fMRI Perspective
Authors: Fan Wei , Yan Zhi-Xiong
Published: July 2022

Brain lifespan trajectories of intrinsic functional connectivity (iFC) in social cognition (SC) provide comprehensive insight and effective reference for normal development and clinical intervention. Unfortunately, for a lack of lifespan samples, the neural mechanism underlying SC in a lifespan developmental perspective is largely unknown, though relative behavior evidence has been investigated well. We, based on common functional networks, aim to map out voxel-wise iFC features between the SC networks and the entire cerebral cortex and further chart its corresponding trajectory patterns across the lifespan. Three networks, namely moral cognition, theory of mind (ToM), and empathy, are chosen as representatives of core SC networks. NKI-RS Enhanced (N = 316, ages 8-83 years old) dataset is selected as a lifespan resting-state fMRI dataset to delineate iFC characteristics and construct developmental trajectories. The result shows that the SC networks represent dissociable and network-specific connectivity profiles. Empathy network, as the most age-related susceptible network, shows a linear up trend with dorsal attention network, a linear decrease with ventral attention network, and a quadric-concave with somatomotor and dorsal attention networks. In addition, the sex effect is also discovered in empathy network, which exhibits linear and quadric gender differences with frontoparietal and vision networks respectively. ToM network follows a pronounced quadric-convex (inverted U-shape) trajectory with ventral attention network. No linear and quadric trajectory is found in moral cognition network. These findings indicate that SC networks display a wide range of iFC both with the fundamental networks (e.g., somatomotor, vision) and advanced networks (e.g., attention and control) in specific developmental trajectories, which will provide a better understanding of SC neural mechanism and life-span developmental trajectories also give valuable references for SC abnormal detection and effective therapy.
Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus
Authors: Nagaraj Harshith , Narayanan Rishikesh
Published: July 2022

Motivation and methods

The suprachiasmatic nucleus (SCN) is the master circadian clock of the mammalian brain that sustains a neural code for circadian time through oscillations in the firing rate of constituent neurons. These cell-autonomous oscillations in intrinsic properties are mediated by plasticity in a subset of ion-channels expressed in SCN neurons and are maintained despite widespread neuron-to-neuron variability in ion channel expression profiles. How do SCN neurons undergo stable transitions and maintain precision in intrinsic properties spanning the day-night cycle if several ion channels change concomitantly in a heterogeneous neuronal population? Here, we address this important question using unbiased stochastic searches on the parametric and the plasticity spaces using populations of SCN models, each explored for multiple valid transitions spanning one complete circadian cycle (day-to-night followed by night-to-day transitions).

Results

Our analyses provided three fundamental insights about the impact of heterogeneities on the circadian oscillations of SCN intrinsic properties. First, SCN neurons could achieve signature electrophysiological characteristics (day-like or night-like) despite pronounced heterogeneity in ion channel conductances, with weak pairwise correlations between their conductance values. This ion-channel degeneracy precluded the need to maintain precise ionchannel expression profiles for achieving characteristic electrophysiological signatures of SCN neurons, thus allowing for parametric heterogeneities despite functional precision. Second, it was not essential that specific conductances had to change by precise values for obtaining valid day-to-night or night-to-day transitions. This plasticity degeneracy, the ability of disparate combinations of ion-channel plasticity to yield the same functional transition, confers flexibility on individual neurons to take one of several routes to achieve valid transitions. Finally, we performed nonlinear dimensionality reduction analyses on the valid plasticity spaces and found the manifestation of a low-dimensional plasticity manifold in day-to-night transitions, but not in night-to-day transitions. These observations demonstrated that the concomitant changes in multiple ion channels are not arbitrary, but follow a structured plasticity manifold that provides a substrate for stability in achieving stable circadian oscillations.

Implications

Our analyses unveil an elegant substrate, involving a synthesis of the degeneracy and the plasticity manifold frameworks, to effectuate stable circadian oscillations in a heterogeneous population of SCN neurons. Within this framework, the ability of multiple ion channels to change concomitantly provides robustness and flexibility to effectively achieve precise transitions despite widespread heterogeneities in ion-channel expression and plasticity.
Extracellular matrix sensing via modulation of orientational order of integrins and F-actin in focal adhesions
Authors: Grudtsyna Valeriia , Packirisamy Swathi , Bidone Tamara , Swaminathan Vinay
Published: July 2022

Specificity of cellular responses to distinct cues from the extracellular matrix (ECM) requires precise and sensitive decoding of information from the cell surface. However, how known mechanisms of mechanosensing such as force dependent catch bonds and conformational changes in focal adhesion (FA) proteins can confer this sensitivity is not known. Using a combination of polarization microscopy and computational modeling, here we identify regulation of orientational order or molecular co-alignment of FA proteins as a mechanism able to precisely tune cell sensitivity to the ECM. We find that αV integrins and F-actin in FAs show changes in orientational order in an ECM-mediated integrin activation dependent manner. This magnitude of orientational order is sensitive to changes in ECM density but independent of myosin-II activity though actomyosin contractility can further fine-tune it. A molecular clutch model for integrin binding ECM ligands demonstrates that orientational order of integrin-ECM binding and catch bonds tune cellular sensitivity to ECM density. This mechanism is also able to decouple ECM density changes from changes in ECM stiffness thus also contributing to specificity. Taken together, our results suggest relative geometric organization of FA components as an important regulator of mechanotransduction.
Morphological evaluation of rat cerebellum following administration of nitrogen monoxide precursor and inhibitor
Authors: Chegini Hamidreza , Chegini Azin , Gholamzad Amir , Sadeghi Hadis , Noori Mougahi Seyed Mohammad Hossein
Published: July 2022

In this study, the quantitative and qualitative effects of nitrogen monoxide on cerebellar histopathology, by increasing or decreasing in vivo production of this substance, were investigated. In this study, forty Wistar female rats (RAT) with a weight of about 200 to 250 grams and an average age of eight weeks were used. Rats were divided into five groups of eight, including control groups, normal saline, L-NAME, L-Arginine, L-NAME + L-Arginine. On the third, fourth and fifth days, the injection was performed intraperitoneally and on the eighteenth day, after anesthesia with ether and then craniotomy, the brain and cerebellum of the animals were removed and After quantitative measurements including weight and volume, organs were fixed in 10% formalin and after tissue preparation steps, to prepare the slide, sections with a thickness of 5 to 6 microns were prepared from the samples and by general method such as Hematoxylin-eosin and special techniques like Mason trichrome and toluidine blue were stained and evaluated. The results of this study show that in the case of cerebellum, there is no significant difference in the quantitative weight parameter between the control groups, normal saline, L-Arg, L-NAME and L-NAME + L-Arg groups. Regarding the volume parameter, a significant increase (P <0.01) was observed in L-Arg group compared to L-NAME, L-Arg + L-NAME and normal saline groups. In microscopic qualitative parameters, the most changes in the L-Arg group were seen as follows: The granular and molecular layers of the cerebellum became slightly thickened, some of the nuclei in the granular and molecular layers became severely hyperchromatized, and Purkinje cell accumulation was seen with lymphocytic invasion. In the other groups, there were no significant changes. It is inferred from this study that L-Arginine can cause histopathological changes in cerebellar tissue by increasing NO levels in cerebellum. However, in this study, unlike other similar studies, L-NAME injection did not cause significant histopathological change.
SMITH: Spatially Constrained Stochastic Model for Simulation of Intra-Tumour Heterogeneity
Authors: Streck Adam , Kaufmann Tom , Schwarz Roland F.
Published: July 2022

Motivation

Simulations of cancer evolution and cellular growth have proven highly useful to study, in detail, the various aspects of intra-tumour heterogeneity, including the effect of selection, mutation rates, and spatial constraints. However, most methods are computationally expensive lattice-embedded models which cannot simulate tumours with a realistic number of cells and rely on various simplifications. Alternatively, well-mixed stochastic models, while efficient and scalable, do not typically include spatial constraints and cannot reproduce the rich clonal dynamics observed in real-world tumours.

Results

We present SMITH, a simple, efficient, and explainable model of cancer evolution that combines the advantages of well-mixed stochastic models with a new confinement mechanism which limits the growth of clones based on the overall tumour size. We demonstrate that this confinement mechanism is sufficient to induce the rich clonal dynamics observed in spatial models, while allowing for a clear geometric interpretation and efficient simulation of one billion cells within a few minutes on a desktop PC. We explore the extent of stochasticity and rigorously assess the effects of cell turnover, mutation rate, fitness effects and confinement on the resulting clonal structures.

Availability and Implementation

SMITH is implemented in C# and freely available at bitbucket.org/schwarzlab/smith together with binaries for all major platforms. For rich visualisations of the simulated clonal dynamics we provide an accompanying Python package PyFish at bitbucket.org/schwarzlab/pyfish.

Supplementary information

All supplementary figures are in the supplementary document.
FunFun: ITS-based functional annotator of fungal communities
Authors: Krivonos Danil V. , Konanov Dmitry N. , Ilina Elena N.
Published: July 2022

Fungi are inseparable companions of human life, they can be found in both the environment and human organs including skin, respiratory tract and gut. Studies of fungal communities are of great interest to modern biology, partially due to their specific way of life and the presence of unique biochemical pathways they have. Fungi have been shown to be both producers of useful compounds, such as antibiotics and organic acids, and pathogens of various diseases. When considering the selected fungal community, in a number of cases it is rather difficult to evaluate its functional capabilities, which is partially caused by some technical difficulties in the analysis and annotation of whole eukaryotic genomes. In practice, the taxonomic composition of fungal communities is determined using short marker sequences. The most popular fungal taxonomy markers are ITS (internal transcribed spacer) sequences. Here, we present FunFun, the instrument that allows to evaluate the functional content of an individual fungus or mycobiome based on ITS sequencing data.
Wireless Neuromodulation at Submillimeter Precision via a Microwave Split-Ring Resonator
Authors: Marar Carolyn , Jiang Ying , Li Yueming , Lan Lu , Zheng Nan , Yang Chen , Cheng Ji-Xin
Published: July 2022

Microwaves, with wavelengths on the order of millimeters, have centimeter-scale penetration depth and have been shown to reversibly inhibit neuronal activity. Yet, microwaves alone do not provide sufficient spatial precision to modulate target neurons without affecting surrounding tissues. Here, we report an implantable split-ring resonator (SRR) that generates a localized and enhanced microwave field at the gap site with submillimeter spatial precision. The SRR breaks the microwave diffraction limit and greatly enhances the efficiency of microwave inhibition. With the SRR, microwaves at dosages below the safe exposure limit are shown to inhibit neurons within 1 mm from the gap site. Application of the microwave SRR to suppress seizures in an in vivo model of epilepsy is demonstrated.
Transcriptome profiling implicates a role for Wnt signaling during epileptogenesis in a mouse model of temporal lobe epilepsy
Authors: Mardones Muriel D , Gupta Kunal
Published: July 2022

Mesial Temporal lobe epilepsy (mTLE) is a life-threatening condition characterized by recurrent epileptic seizures initiating in the hippocampus. mTLE can develop after exposure to risk factors such as seizure, trauma, and infection. Within the latent period between exposure and onset of recurrent seizures, pathological remodeling events occur which are believed to contribute to epileptogenesis. The molecular mechanisms responsible for epileptogenesis in the seizure network are currently unclear. We used the mouse intrahippocampal kainate model of mTLE to investigate transcriptional dysregulation in the ipsilateral-injected epileptogenic zone (EZ), and contralateral peri-ictal zone (PIZ) in the dentate gyrus (DG) of the hippocampus during the first 14-days after induction of status epilepticus (SE). DG were micro-dissected 3, 7 and 14-days after SE for high-throughput RNA-sequencing. In the EZ, dynamic transcriptional dysregulation was evident over 2-weeks with early expression of genes representing cell signaling, migration and proliferation. In the PIZ, gene dysregulation was most prominent at 3-days in similar domains. Inflammatory gene groups were also prominent over the 2-week epileptogenic period in the EZ and PIZ. We uncovered that the Wnt signaling pathway was dysregulated in the EZ and PIZ at 3-days and we validated these changes via immunohistochemistry. This suggests that critical gene changes occur early after neurological insult and that canonical Wnt signaling may play a role within this latent period. These findings offer new insights into gene expression changes that occur in the hippocampal DG early after SE and may help to identify novel therapeutic targets that could prevent epileptogenesis.

Significance statement

Mesial temporal lobe epilepsy (mTLE) is a severe life-threatening condition that is often medically refractory. While risk factors for the delayed development of mTLE are well-known, there are currently no therapeutic interventions that prevent epileptogenesis. Knowledge of the gene dysregulation events that occur during the latent period between exposure and epilepsy is critical to understanding epileptogenesis and developing new therapies. We utilized a mouse model of adult focal mTLE, the most common form of adult clinical epilepsy, and investigated transcriptional changes in the dentate gyrus during the first 2-weeks after status epilepticus. These data provide new insights into specific gene changes and pathways within different regions of the seizure network that could be targeted to prevent the development of epilepsy.
Event-based vision sensor enables fast and dense single-molecule localization microscopy
Authors: Cabriel Clément , Specht Christian G. , Izeddin Ignacio
Published: July 2022

Single-molecule localization microscopy (SMLM) is often hampered by the fixed frame rate of the acquisition. Here, we present an alternative new approach to data acquisition and processing based on an affordable event-based sensor. This type of sensor reacts to light intensity changes rather than integrating photons during each frame exposure time. This makes it particularly suited to SMLM, where the ability to surpass the diffraction-limited resolution is provided by blinking events. Each pixel works independently and returns a signal only when an intensity change is detected. Since the output is a list containing only useful data rather than a series of frames, the temporal resolution is significantly better than typical scientific cameras. We demonstrate event-based SMLM super-resolution imaging on biological samples with spatial resolution on par with EMCCD or sCMOS performance. Furthermore, taking advantage of its unique properties, we use event-based SMLM to perform very dense single-molecule imaging, where framebased cameras experience significant limitations.
Body-plan reorganization in a sponge correlates with microbiome change
Authors: Vargas Sergio , Leiva Laura , Eitel Michael , Curdt Franziska , Rohde Sven , Arnold Christopher , Nickel Michael , Schupp Peter , Orsi William D. , Adamska Maja , Wörheide Gert
Published: July 2022

Mounting evidence suggests that animals and their associated bacteria interact via intricate molecular mechanisms, and it is hypothesized that disturbances to the microbiome can influence animal development. Sponges diverged from other animals more than 750 MYA and represent one of the earliest branching animal phyla that exhibit symbiotic relationships with diverse bacteria. Over 41 microbial phyla have been found in association with sponges, forming a holobiont that is integral to aquatic ecosystems worldwide. Sponge-associated microbes contain an enriched set of proteins bearing eukaryotic-like domains, and their metabolism supports the host with nutrients. This indicates strong physiological interconnections in the holobiont, which are thought to be modulated by sponge immunity and pattern-recognition proteins. Despite the hypothesized tight physiological integration and ancient origin of the sponge holobiont, the effect of changes in the symbiotic community on the sponge metabolism and morphogenesis remains poorly understood. Here, we show that the loss of a key microbial sponge symbiont correlates with a stark body plan reorganization of the sponge host. This reorganization is coupled with broad transcriptomic changes and includes the modulation of signaling pathways known to be involved in morphogenesis and innate immune response in sponges and other animals. This study provides a combined genetic, physiological, and morphological assessment of the effect of changes in the microbiome on sponge post-embryonic development and homeostasis. The drastic microbiome reorganization and the correlated response observed in the sponge host provide evidence for a coupling between sponge transcriptomic state and the state of its microbiome. Our results suggest that sponges use molecular mechanisms to respond to changes in their microbiome and that the ability to sense and respond to microbiome perturbations has deep evolutionary origins among animals.
Disaggregation as an interaction mechanism among intestinal bacteria
Authors: Sundarraman Deepika , Smith T. Jarrod , Kast Jade V. Z. , Guillemin Karen , Parthasarathy Raghuveer
Published: July 2022

The gut microbiome contains hundreds of interacting species that together influence host health and development. The mechanisms by which intestinal microbes can interact, however, remain poorly mapped and are often modeled as spatially unstructured competitions for chemical resources. Recent imaging studies examining the zebrafish gut have shown that patterns of aggregation are central to bacterial population dynamics. In this study, we focus on bacterial species of genera Aeromonas and Enterobacter. Two zebrafish gut derived isolates, Aeromonas ZOR0001 (AE) and Enterobacter ZOR0014 (EN), when mono-associated with the host, are highly aggregated and located primarily in the intestinal midgut. An Aeromonas isolate derived from the commensal strain, Aeromonas-MB4 (AE-MB4), differs from the parental strain in that it is composed mostly of planktonic cells localized to the anterior gut. When challenged by AE-MB4, clusters of EN rapidly fragment into non-motile, slow-growing, dispersed individual cells with overall abundance two orders of magnitude lower than the mono-association value. In the presence of a certain set of additional gut bacterial species, these effects on EN are dampened. In particular, if AE-MB4 invades an already established multi-species community, EN persists in the form of large aggregates. These observations reveal an unanticipated competition mechanism based on manipulation of bacterial spatial organization, namely dissolution of aggregates, and provide evidence that multi-species communities may facilitate stable intestinal co-existence.

Significance

The diverse microbial communities inhabiting vertebrate intestines influence many aspects of their hosts’ health and development. The rules governing community assembly and even the types of interactions that are possible among gut microbes remain poorly understood, however, with the role of spatial aggregation in interspecies dynamics being especially unclear. To address this, we performed live imaging studies of the larval zebrafish gut, focusing on two spatially distinct bacterial species that exhibit strong competition, discovering that the latter can induce a striking, rapid disintegration of aggregates of the former. This competition is attenuated in the presence of a particular set of additional bacterial species. Our findings reveal an unanticipated interaction mechanism and highlight that diverse communities may stabilize the gut microbiome.
Metabolic functional redundancy of the CYP9A subfamily members leads to P450-mediated lambda-cyhalothrin resistance in Cydia pomonella
Authors: Li Pei-Rong , Shi Yu , Liu Yu-Xi , Wang Wei , Ju Di , He Ying-Shi , Zhang Yu-Yun , Yang Xue-Qing
Published: July 2022

BACKGROUND

The evolution of insect resistance to pesticides poses a continuing threat to sustainable pest management. While much is known about the molecular mechanisms that confer resistance in model insects and few agricultural pests, far less is known about fruit pests.

RESULTS

Here we found that functional redundancy and preference of metabolism by cytochrome P450 monooxygenases (P450s) genes in the CYP9A subfamily confer resistance to lambda-cyhalothrin in Cydia pomonella, a major invasive pest of pome fruit. A total of four CYP9A genes, including CYP9A61, CYP9A120, CYP9A121, and CYP9A122, were identified from C. pomonella. Among these, CYP9A120, CYP9A121, and CYP9A122 were predominantly expressed in the midgut of larvae. The expression levels of these P450 genes were significantly induced by LD10 of lambda-cyhalothrin and were overexpressed in a field-evolved lambda-cyhalothrin resistant population. Knockdown of CYP9A120 and CYP9A121 by RNA-mediated interference (RNAi) increased the susceptibility of larvae to lambda-cyhalothrin. In vitro assays demonstrated that recombinant P450s expressed in Sf9 cells can metabolize lambda-cyhalothrin, but with functional redundancy and divergence through regioselectivity of metabolism. CYP9A121 preferred to convert lambda-cyhalothrin to 2′-hydroxy-lambda-cyhalothrin, whereas CYP9A122 only generated 4′-hydroxy metabolite of lambda-cyhalothrin. Although possesses a relatively low metabolic capability, CYP9A120 balanced catalytic competence to generate both 2′- and 4′-metabolites.

CONCLUSION

Collectively, these results reveal that metabolic functional redundancy of three members of the CYP9A subfamily leads to P450-mediated lambda-cyhalothrin resistance in C. pomonella, thus representing a potential adaptive evolutionary strategy during its worldwide expansion.
Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance
Authors: Jiang Kuan , Lim Su Bin , Xiao Jingwei , Jokhun Doorgesh Sharma , Shang Menglin , Song Xiao , Zhang Pan , Liang Lanfeng , Low Boon Chuan , Shivashankar G.V. , Lim Chwee Teck
Published: July 2022

Cancer cells derived from secondary tumors can form new distant metastases more efficiently as compared to their primary tumor counterparts. This is partially due to the unfavorable microenvironments encountered by metastasizing cancer cells that result in the survival of a more metastatic phenotype from the original population. However, it is unclear how cancer cells may acquire such metastatic competency after overcoming deleterious mechanical stresses. Here, by forcing cancer cells to flow through small capillary-sized constrictions, we demonstrate that mechanical deformation can select a tumor cell subpopulation that exhibits resilience to mechanical squeezing-induced cell death. Transcriptomic profiling reveals up-regulated proliferation and DNA damage response pathways in this subpopulation, which are further translated into a more proliferative and chemotherapy-resistant phenotype. Our results highlight a potential link between the microenvironmental physical barriers and the enhanced malignancy of metastasizing cancer cells which may potentially be utilized for novel therapeutic strategies in preventing the metastatic spread of cancer cells.
Viability Discrimination of Bacterial Microbiomes in Home Kitchen Dish Sponges via Propidium Monoazide Treatment
Authors: Carstens Christina K. , Salazar Joelle K. , Sharma Shreela , Chan Wenyaw , Darkoh Charles
Published: July 2022

Dish sponges are known to support the survival and growth of human bacterial pathogens yet are commonly used by consumers to wash dishes and clean kitchen surfaces. Exposure to foodborne pathogens via sponge use may lead to foodborne illness, which is of particular concern among susceptible populations. Limitations associated with culture-independent or - dependent methods for bacterial community characterization have challenged the complete assessment of foodborne pathogen exposure risk presented by sponges. In this study, the bacterial microbiomes of five dish sponges were characterized to evaluate the presence of viable bacterial foodborne pathogens using propidium monoazide treatment, which is a novel approach in this medium. Total and viable sponge microbiomes were subsequently metataxonomically evaluated via targeted 16S rRNA sequencing. Select pathogen viability was confirmed using targeted selective enrichment. The comparison of total and viable sponge microbiome beta diversity indicated that sponge taxonomic abundance profiles did not vary significantly according to PMA treatment. The numbers of unique bacterial species (p-value = 0.0465) and unique bacterial foodborne pathogens (p-value = 0.0102) identified were significantly lower after PMA-treatment. A total of 20 unique bacterial foodborne pathogens were detected among sponge microbiomes regardless of PMA treatment. Three to six unique viable foodborne pathogens were identified in each sponge.Escherichia coliandStaphylococcus aureuswere identified in all five viable sponge microbiomes evaluated. ViableE. coliwere recovered from two of five sponges via targeted selective enrichment. These findings suggest that most sponge-associated bacterial communities may be viable and contain multiple viable bacterial foodborne pathogens.

Importance

Bacterial pathogens may exist in the domestic kitchen environment, threatening both sanitation levels and the health of residents. Dish sponges are commonly used kitchen tools that can harbor foodborne pathogens as they present adequate conditions for the survival and growth of bacteria. Using a contaminated sponge may lead to foodborne illness through direct contact with pathogens or via cross-contamination with food or other surfaces. Although bacterial foodborne pathogens have been identified in sponges, previous limitations in methodology have prevented the complete understanding of sponge microbiomes. This study used a novel application of a chemical reagent coupled with targeted amplicon sequencing to identify sponge communities and differentiate between viable and non-viable bacteria. Insights into dish sponge microbiomes and potential risks of bacterial foodborne pathogen exposure can inform food safety education programs to aid in the prevention of home-acquired foodborne illness and cross-contamination events.
Evaluation of Seropositivity after Standard Doses of Vaccination against SARS-CoV-2 in Early Breast Cancer Patients Receiving Adjuvant Treatment
Authors: Kim Jinyong , Chang Euijin , Park Song Yi , Lee Dae-Won , Kang Chang Kyung , Choe Pyoeng Gyun , Kim Nam Joong , Oh Myoung-don , Park Wan Beom , Lee Kyung-Hun , Im Seock-Ah
Published: July 2022

Background

Coronavirus disease 2019 (COVID-19) pandemic affected millions of individuals and patients with cancer are known to be more susceptible. Vaccines against SARS-CoV-2 have been developed and used for patients with cancer, but scarce data is available on their efficacy in patients under active anti-cancer therapies.

Materials and Methods

In this study, we semi-quantitatively measured the titers of the immunoglobulin G against the anti-spike protein subunit 1 of SARS-CoV-2 after vaccination in early breast cancer patients with concurrent chemotherapy, endocrinal or targeted non-cytotoxic treatments, and no treatments.

Results

Standard doses of COVID-19 vaccines provided sufficient immune responses in patients with early breast cancer, regardless of the type of anticancer therapies. However, the post-vaccination serum anti-spike antibody titers were significantly lower in the patients under cytotoxic chemotherapy.

Conclusion

Our study emphasizes the importance of the personalized risk stratification and consideration for booster doses in more vulnerable populations.

Implications for Practice

In this article, we present rare data on the homogeneous population of patients with early breast cancer under active anti-cancer treatments. The patients showed adequate serologic responses against SARS-CoV-2 virus after standard doses of vaccination without serious adverse events in concurrence with active adjuvant anti-cancer therapy. The patients receiving concurrent cytotoxic chemotherapy, however, have significantly lower serum anti-spike antibody titers than those under non-cytotoxic anti-cancer treatments or without treatments. Selection of the COVID-19 vaccines should be based on personalized risk stratification considering the use of concurrent cytotoxic chemotherapy and the patient’s medical circumstances. Booster doses of vaccination could be considered for the vulnerable population, such as elderly with comorbidities and the single standard dose of vaccination.
SGLT2 inhibition mitigates perturbations in nephron segment-specific metabolic transcripts and mTOR pathway activity in kidneys of young persons with type 2 diabetes
Authors: Schaub Jennifer A. , AlAkwaa Fadhl M. , McCown Phillip J. , Naik Abhijit S. , Nair Viji , Eddy Sean , Menon Rajasree , Otto Edgar A. , Hartman John , Fermin Damian , O’Connor Christopher , Bitzer Markus , Harned Roger , Ladd Patricia , Pyle Laura , Hodgin Jeffrey B. , Brosius Frank C. , Nelson Robert G. , Kretzler Matthias , Bjornstad Petter
Published: July 2022

The molecular mechanisms of SGLT2 inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometrics data were collected from research kidney biopsies donated by participants with youth onset type 2 diabetes (T2D), aged 12-21 years of age, and healthy controls (HC) to study the effects of SGLT2i on kidney transcriptomics. Participants with T2D were more obese, had higher glomerular filtration rate, mesangial and glomerular volumes than HC. There were no clinically significant differences between participants prescribed SGLT2i (T2Di(+), n=10) and other T2D (T2Di(-), n=6). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster. Transcriptional alterations in T2Di(+) compared to T2Di(-) were seen across most nephron segments, most prominently in the distal nephron. SGLT2i treatment was associated with suppression of genes in the glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways in PT, but enhanced expression in thick ascending limb. The energy sensitive mTOR signaling pathway transcripts were suppressed towards HC level in all nephron segments in T2Di(+). These transcriptional changes were confirmed in a diabetes mouse model treated with SGLT2i. Therefore, the beneficial effects of SGLT2i treatment to the kidneys might be from mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling across nephron segments, including those not expressing SGLT2.