bluuebunny/crossref_metadata_2025 huggingface dataset:
Caudate Volume is Prospectively Associated with Irritability in Toddlerhood
Authors: Dufford Alexander J. , MacNeill Leigha , Nielsen Ashley , Smyser Christopher , Luby Joan L. , Rogers Cynthia E. , Norton Elizabeth , Wakschlag Lauren
Published: June 2023

Irritability refers to the dispositional tendency toward angry emotion with both mood and behavioral elements. The dimensional spectrum of irritability is an RDoC-informed transdiagnostic marker of psychopathology risk, specifically the common and modifiable internalizing and externalizing disorders. Despite substantial interest in this robust developmentally based transdiagnostic indicator of psychopathology risk, its early brain markers are understudied. Here, we present data (n=31) from an imaging sub-study of the When to Worry study, in which we examined prospective associations between volume in three subcortical regions implicated in irritability (the caudate, putamen, and amygdala) around the infants’ first birthday (Baseline) and the dimensional spectrum of observed irritability using the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS) around toddlers’ second birthday (Follow-up). Both left (q<.04, FDR corrected) and right caudate volumes (q<.04, FDR corrected) at Baseline were negatively associated with a measure of irritability measured at Follow-up. We did not find support for associations between putamen and amygdala volumes at Baseline and observed irritability at Follow-up. These findings identify early prospective neuroanatomical correlates of toddler irritability and provide preliminary support for the caudate being an important brain region for understanding the developmental sequalae of irritability.
Visual Motion Detection Thresholds Can Be Reliably Measured During Walking and Standing
Authors: DiBianca Stephen , Jeka John , Reimann Hendrik
Published: June 2023

In upright standing and walking, the motion of the body relative to the environment is estimated from a combination of visual, vestibular and somatosensory cues. Associations between vestibular or somatosensory impairments and balance problems are well established, but less is known about how the ability of the visual system to detect motion affects balance control. Here we asked whether motion detection thresholds can be reliably measured during walking and standing. Typically, motion threshold values have been obtained while sitting, with the head fixated to eliminate self-motion. In this study we 1) tested whether a visual motion detection threshold can be reliably measured during standing and walking in the presence of natural self-motion; and 2) investigated whether visual motion detection thresholds differ during standing and walking.

Methods

Twenty-nine subjects stood on and walked along a self-paced, instrumented treadmill inside a virtual environment displayed on a large dome. Participants performed a 2-alternative forced choice experiment in which they discriminated between a counterclockwise (“left”) and clockwise (“right”) rotation of a visual scene projected on a large dome. A 6-down 1-up adaptive staircase algorithm was implemented to change the amplitude of the rotation. A psychometric fit to the participants’ binary responses provided an estimate for the detection threshold

Results

We found strong correlations between the repeated measurements in both the walking (R = 0.84, p < 0.001) and the standing condition (R = 0.73, p < 0.001) as well as good agreement between the repeated measures with Bland-Altman plots. Average thresholds during walking (mean = 1.04 degrees, SD = 0.43 degrees) were significantly higher than during standing (mean = 0.73 degrees, SD = 0.47 degrees).

Conclusion

Visual motion detection thresholds can be reliably measured during both walking and standing, and thresholds are higher during walking.
Neuronal alterations in AKT isotype expression in schizophrenia
Authors: Devine Emily A. , Joyce Alex W. , Imami Ali S. , Hammoud Abdul-rizaq , Golchin Hasti , Eby Hunter , Shedroff Elizabeth A. , Asah Sophie M. , Walss-Bass Consuelo , O’Donovan Sinead , McCullumsmith Robert E.
Published: June 2023

Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of insulin signaling. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.
Dynamic noise estimation: A generalized method for modeling noise fluctuations in decision-making
Authors: Li Jing-Jing , Shi Chengchun , Li Lexin , Collins Anne G. E.
Published: June 2023

Computational cognitive modeling is an important tool for understanding the processes supporting human and animal decision-making. Choice data in decision-making tasks are inherently noisy, and separating noise from signal can improve the quality of computational modeling. Common approaches to model decision noise often assume constant levels of noise or exploration throughout learning (e.g., theϵ-softmax policy). However, this assumption is not guaranteed to hold – for example, a subject might disengage and lapse into an inattentive phase for a series of trials in the middle of otherwise low-noise performance. Here, we introduce a new, computationally inexpensive method to dynamically infer the levels of noise in choice behavior, under a model assumption that agents can transition between two discrete latent states (e.g., fully engaged and random). Using simulations, we show that modeling noise levels dynamically instead of statically can substantially improve model fit and parameter estimation, especially in the presence of long periods of noisy behavior, such as prolonged attentional lapses. We further demonstrate the empirical benefits of dynamic noise estimation at the individual and group levels by validating it on four published datasets featuring diverse populations, tasks, and models. Based on the theoretical and empirical evaluation of the method reported in the current work, we expect that dynamic noise estimation will improve modeling in many decision-making paradigms over the static noise estimation method currently used in the modeling literature, while keeping additional model complexity and assumptions minimal.
Rats synchronize predictively to metronomes
Authors: Rajendran Vani G. , Tsdaka Yehonadav , Keung Tung Yee , Schnupp Jan W. H. , Nelken Israel
Published: June 2023

Humans easily and naturally synchronize their motor activity to music, a behavior unparalleled by other species. As a consequence of the mystery surrounding its evolutionary and biological origins, there is rapidly growing interest in exploring the capacity of nonhuman species to synchronize motor activity with auditory rhythms. The hallmark observation in human studies is that synchronization is predictive. Given the highly variable behaviors observed in other animals, it is particularly difficult to distinguish a predictive synchronization behavior from one that perhaps resembles it, but relies on simpler strategies. Here, we introduce a novel modeling approach that quantitatively compares candidate strategies for explaining observed behaviors. Eight rats synchronized to metronomes across a range of tempi (0.5-2 Hz), and immediate water reward was delivered whenever they initiated a lick burst within a short time window around beats. We observed a roughly constant baseline lick probability throughout, with a ∼30% modulation of the lick rate around beats. We fitted to the results six candidate models, ranging from an ‘insensitive’ model assuming that rats lick at random, to predictive models where rats suppress licking between beats for a tempo-dependent duration of time. The predictive model consistently outperformed other models, including a reactive model, demonstrating that rats synchronize predictively to auditory metronomes.
Electrically Conductive DNA-Inspired Coating for Intracortical Neural Microelectrodes
Authors: Sands Ian , Ersöz Alpaslan , Zhang Wuxia , Zhou Libo , Linthicum Will , Santaniello Sabato , Huey Bryan , Han Martin , Chen Yupeng
Published: June 2023

Different from conventional electrodes, intracortical neural microelectrodes are the size of one or several neural cells. Due to the limited space for cell-electrode connections, the bio-integration between each neural cell and the electrode surface is critical. To improve bio-integration and electrode functions, various coating materials (such as conductive polymers (CPs), carbon nanotubes (CNTs), and natural hydrogels) have been developed aiming to provide an enhanced interface for neuron recruitment, bio-anchorage, and electrical function. However, synthetic materials usually have limited biocompatibility and/or relatively high cytotoxicity, while biological materials present poor electrical functions. Therefore, current coatings possess biological, functional or electrochemical limitations that are not optimal for intracortical neural microelectrodes. To overcome this obstacle, we developed an electrically conductive coating based on biological molecules, named Janus base nano-coating (JBNc). JBNc is formed by Janus base nanotubes (JBNts) which are a family of nanotubes assembled from engineered DNA base pair units. Based on the long-distance translocation ability of the π electrons of JBNts, we developed them into an electrically conductive coating on the electrode surface. For the first time, we reported the DNA-inspired JBNc had an electrochemical performance that met and exceeded standard metal electrode surface in cyclic voltammetry, impedance spectroscopy, charge injection capacity tests, and neural recording. Moreover, we demonstrated enhanced bio-anchorage and microelectrode interface integration using SEM and AFM. Importantly, we demonstrated enhanced functional response to JBNc microelectrodes with immunohistochemical staining and RNA sequencing (RNAseq) analysis. Using cell viability assays, we also showed the benefits of DNA-mimicking chemistry of Janus base nanomaterials compared to conventional microelectrode coatings. We anticipate that these results will serve as a foundation for the continued development and study of JBNc to enhance interface dynamics and ultimately the performance and reliability of brain microelectrodes.
Biochemical and chemical biological approaches to mammalian sleep: roles of calcineurin in site-specific dephosphorylation and sleep regulation
Authors: Yu Jianjun , Wang Tao V. , Gao Rui , Li Chenggang , Liu Huijie , Yang Lu , Liu Yuxiang , Cui Yunfeng , Chen Peng R. , Rao Yi
Published: June 2023

Understanding of sleep mechanisms traditionally rely on electrophysiology and genetics but here we have initiated biochemical and chemical biological studies. Sleep was increased in mouse mutants with an alanine replacing threonine at residue 469 (T469A) of the salt inducible kinase 3 (SIK3). We searched for T469 phosphatases by classic purification with HEK293 cells and by a new photo-crosslinking method with mouse brains. Both led to PPP3CA, a catalytic subunit of calcium/calmodulin activated phosphatase (calcineurin). It dephosphorylated T469 and serine (S) 551 but not T221 in SIK3 in vitro. PPP3CA knockdown increased phosphorylation of T469 and S551 but not T221 in mouse brains. Knockdown of its regulatory subunit PPP3R1 significantly reduced daily sleep by more than 5 hours, exceeding other known mouse mutants. Our results have uncovered in vitro and in vivo evidence for site-specific SIK3 dephosphorylation by calcineurin, demonstrated a physiological role for calcineurin in sleep, and suggested sleep control by calcium dependent dephosphorylation.
Visualization of spatial distribution of hemoglobin with various oxygen saturations in small animals using a photoacoustic imaging scanner with a hemispherical detector array
Authors: Asao Yasufumi , Hirano Ryuichiro , Nagae Kenichi , Sekiguchi Hiroyuki , Aiso Sadakazu , Watanabe Shigeaki , Sato Marika , Yagi Takayuki , Kizaka-Kondoh Shinae
Published: June 2023

Abstract

Significance

Photoacoustic (PA) imaging has garnered considerable attention due to its capability to render vascular images in a label-free manner. Specifically, devices employing a hemispherical detector array (HDA) have been heralded for various clinical applications, owing to their potential to yield high reproducibility three-dimensional images. While high-resolution models utilizing high-frequency sensors have been introduced for animal experimentation, their evaluation has been constrained to a single wavelength. In this study, we demonstrate the applicability of in vivo mouse models for visualizing body oxygen saturation distribution using dual wavelengths.

Aim

With the aid of our uniquely developed device and analysis software, our primary objective is to map the spatial distribution of the hemoglobin oxygen saturation coefficient (S-factor) through non-invasive in vivo imaging. Subsequently, we aim to observe the temporal alterations within this distribution, specifically assessing changes in hemoglobin oxygen saturation in both normal and tumor vessels over time.

Approach

High-quality S-factor images were obtained by integrating a newly developed scanning sequence for high contrast with alternate two-wavelength irradiation. Following validation with phantoms, in vivo images were procured in mice. Sequential scanning of the same mouse yielded information about temporal changes. S-factor evaluation was conducted with our photoacoustic image viewer to analyze trends in hemoglobin oxygen saturation.

Results

High-contrast images were achieved by increasing the number of integrations during scanning. S-factor images were acquired using both healthy and tumor-bearing mice. Vessels within the liver and kidneys were distinctly reconstructed, and differences in oxygen saturation discriminated between arteries and veins. Repeated measurements on the same mice, both live and post-euthanasia, provided spatiotemporal information, such as a decrease in oxygen saturation after euthanasia or a precipitous drop in oxygen saturation inside the tumor nine days post-cell line transplantation.

Conclusions

By analyzing S-factor images using a photoacoustic imaging system designed for animal experiments, we succeeded in discerning variations in in vivo oxygen saturation. The custom-built system holds promise as a versatile tool for diverse basic research endeavors, as it can seamlessly interface with human clinical applications.
Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning
Authors: Geminiani A , Casellato C , Boele H-J , Pedrocchi A , De Zeeuw C I , D’Angelo E
Published: June 2023

According to Marr’s motor learning theory, plasticity at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, the discovery of multiple forms of plasticity distributed over different cerebellar circuit synapses prompts to remap the cerebellar learning sites. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding upbound and downbound modules that are subject to multiple plasticity rules. Simulations show that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity in both thepf-PC synapses and in the feedforward inhibitory loop passing through the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both modules contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.
Spatial connectivity and marine disease dispersal: missing links in aquaculture carrying capacity debates
Authors: Schmittmann L. , Busch K. , Kluger L. C.
Published: June 2023

One major societal challenge is meeting the constantly increasing demand for (sea)food in a sustainable way. With marine aquaculture on the rise, it is crucial to define limits to aquaculture growth in order to ensure ocean health. Along these lines, the concept of aquaculture carrying capacity (CC) is increasingly intersected with the principles of the ecosystem approach to aquaculture. Its primary aims are to estimate sustainable production potential and limits of locally defined regions. However, the ocean is a fluid environment, subject to large- and small-scale dynamics, including ocean currents, tidal fluctuations, and human action. These dynamics introduce spatial connectivity between aquaculture sites and more distant ecosystems than considered in current CC estimates. We argue that far-reaching effects of aquaculture on the ocean, such as introduction and spread of invasive species and marine diseases, are thus underestimated when providing recommendations. Marine diseases can impact biodiversity, society, and overall ocean health and it is imperative to guide aquaculture development to reduce the risk of marine disease dispersal. We, therefore, suggest to embrace spatial ocean connectivity into the CC concept by using hydrodynamic modelling and dispersal simulations as high-throughput methods to estimate potential impact areas and provide risk assessments. In this work, we focus on the example of dispersing infectious diseases in bivalve farming and discuss ecological as well as social consequences of spatial connectivity. Both are applicable to a wide range of organisms and marine aquaculture systems internationally.

The concept of aquaculture carrying capacity (CC) aims at defining sustainable limits to aquaculture growth in order to ensure ocean health. Usually, estimations are based on locally defined regions and on the farm-scale. However, interactions of aquaculture with the ocean can have far-reaching effects, such as introduction and spread of invasive species and marine diseases. The ocean is a fluid environment, subject to large- and small-scale dynamics that introduce spatial connectivity between aquaculture sites and more distant ecosystems than considered in current CC estimates. We, therefore, suggest to embrace spatial ocean connectivity into the CC concept by using hydrodynamic modelling and dispersal simulations as high-throughput methods to estimate potential impact areas and provide risk assessments. Here, we focus on the example of dispersing infectious diseases in bivalve farming and discuss ecological as well as social consequences of spatial connectivity. Both are applicable to a wide range of organisms and marine aquaculture systems internationally.
Engineered CD47 protects T cells for enhanced antitumor immunity
Authors: Yamada-Hunter Sean A. , Theruvath Johanna , McIntosh Brianna J. , Freitas Katherine A. , Radosevich Molly T. , Leruste Amaury , Dhingra Shaurya , Martinez-Velez Naiara , Xu Peng , Delaidelli Alberto , Desai Moksha H. , Good Zinaida , Labanieh Louai , Mount Christopher W. , Chen Yiyun , Heitzeneder Sabine , Marjon Kristopher D. , Banuelos Allison , Khan Omair , Huang Jing , Wasserman Savannah L. , Spiegel Jay Y. , Fernandez-Pol Sebastian , Sorensen Poul H. , Monje Michelle , Majzner Robbie G. , Weissman Irving L. , Sahaf Bita , Sotillo Elena , Cochran Jennifer R. , Mackall Crystal L.
Published: June 2023

Adoptively transferred T cells and agents designed to block the CD47/SIRPα axis are promising antitumor therapeutics, which activate distinct arms of the immune system. We administered anti-CD47 (αCD47) with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which blunted therapeutic benefit. αCD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPα and provided a “don’t-eat-me” signal that was not blocked by αCD47 antibodies. TCR or CAR T cells expressing 47Ewere resistant to clearance by macrophages following αCD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy resulted in synergistic enhancement in antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests markedly enhanced potency against solid tumors.
Direct observation of autoubiquitination for an integral membrane ubiquitin ligase in ERAD
Authors: Assainar Basila Moochickal , Ragunathan Kaushik , Baldridge Ryan D.
Published: June 2023

The endoplasmic reticulum associated degradation (ERAD) pathway regulates protein quality control at the endoplasmic reticulum. ERAD of lumenal and membrane proteins requires a conserved E3 ubiquitin ligase, called Hrd1. We do not understand the molecular configurations of Hrd1 that enable autoubiquitination and the subsequent retrotranslocation of misfolded protein substrates from the ER to the cytosol. Here, we have established a generalizable, single-molecule platform that enables high-efficiency labeling, stoichiometry determination, and functional assays for any integral membrane protein. Using this approach, we directly count Hrd1 proteins reconstituted into individual proteoliposomes. We found that Hrd1 assembles in different oligomeric configurations with mostly monomers and dimers detected at limiting dilution. By correlating oligomeric states with ubiquitinationin vitro, we determined that Hrd1 monomers were incapable of autoubiquitination while dimers efficiently assembled polyubiquitin chains. Therefore, our results reveal the minimal composition of a Hrd1 oligomer that is capable of autoubiquitination. Our methods are broadly applicable to studying other complex membrane protein functions using reconstituted bilayer systems.
Enhanced real-time mass spectrometry breath analysis for the diagnosis of COVID-19
Authors: Roquencourt Camille , Salvator Hélène , Bardin Emmanuelle , Lamy Elodie , Farfour Eric , Naline Emmanuel , Devillier Philippe , Grassin-Delyle Stanislas
Published: June 2023

Background

Although rapid screening for and diagnosis of COVID-19 are still urgently needed, most current testing methods are either long, costly, and/or poorly specific. The objective of the present study was to determine whether or not artificial-intelligence-enhanced real-time MS breath analysis is a reliable, safe, rapid means of screening ambulatory patients for COVID-19.

Methods

In two prospective, open, interventional studies in a single university hospital, we used real-time, proton transfer reaction time-of-flight mass spectrometry to perform a metabolomic analysis of exhaled breath from adults requiring screening for COVID-19. Artificial intelligence and machine learning techniques were used to build mathematical models based on breath analysis data either alone or combined with patient metadata.

Results

We obtained breath samples from 173 participants, of whom 67 had proven COVID-19. After using machine learning algorithms to process breath analysis data and further enhancing the model using patient metadata, our method was able to differentiate between COVID-19-positive and -negative participants with a sensitivity of 98%, a specificity of 74%, a negative predictive value of 98%, a positive predictive value of 72%, and an area under the receiver operating characteristic curve of 0.961. The predictive performance was similar for asymptomatic, weakly symptomatic and symptomatic participants and was not biased by the COVID-19 vaccination status.

Conclusions

Real-time, non-invasive, artificial-intelligence-enhanced mass spectrometry breath analysis might be a reliable, safe, rapid, cost-effective, high-throughput method for COVID-19 screening.
Deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial sections
Authors: Schupp Patrick G. , Shelton Samuel J. , Brody Daniel J. , Eliscu Rebecca , Johnson Brett E. , Mazor Tali , Kelley Kevin W. , Potts Matthew B. , McDermott Michael W. , Huang Eric J. , Lim Daniel A. , Pieper Russell O. , Berger Mitchel S. , Costello Joseph F. , Phillips Joanna J. , Oldham Michael C.
Published: June 2023

Tumors may contain billions of cells including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that is consistently expressed by astrocytoma truncal clones, includingAKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.
Probing the neurophysiology of temporal sensitivity in the somatosensory system using the mismatch negativity (MMN) sensory memory paradigm
Authors: Isenstein Emily L. , Freedman Edward G. , Xu Ashley J. , DeAndrea-Lazarus Ian A. , Foxe John J.
Published: June 2023

Duration is an amodal feature common to all sensory experiences, but current understanding of sensory-perceptual processing of the temporal qualities of somatosensation remains incomplete. The goal here was to better understand how the brain processes the duration of vibrotactile information, which was assessed by parametrically varying the extent of duration deviance in a somatosensory mismatch negativity (sMMN) paradigm while high-density event-related potential (ERP) recordings were acquired. Healthy young adults (N = 20; aged 18-31 years) received stimulation of the right index fingertip with a 100 ms vibro-tactile input on 80% of trials while the other 20% of trials consisted of deviant stimuli with one of the following durations: 115, 130, 145, or 160 ms. Deviant conditions were presented in separate blocks with deviants pseudo-randomly distributed amongst the 100 ms standards. Participants ignored these inputs while watching a silent movie. Robust sMMN responses, with a dipolar field over the left antero-superior parietal cortex, were detected when deviant stimuli were 130, 145, and 160 ms, but not when they were 115 ms. The amplitudes of the sMMN correlated with individuals’ subsequent abilities to detect duration deviants when actively attempting to discriminate their presence. This simple-to-execute sMMN paradigm holds promise for the assessment of tactile processing differences in clinical populations where tactile sensitivities are a common aspect of the phenotype (e.g., Autism, Fragile-X syndrome).
Synthetic Frizzled agonist and LRP antagonist for high-efficiency Wnt/β-catenin signaling manipulation in organoid cultures andin vivo
Authors: Dai Quanhui , Wang Jiawen , Lin Zihuan , Yu Danni , Yang Hui , Zhang Jiting , Li Xiaoyu , Zeng Junwei , Hu Hao , Ni Chao , Zhao Bing
Published: June 2023

Wnt/β-catenin signaling and its dysregulation play critical roles in the fate determination of stem cells and the pathology of various diseases. However, the application of translated Wnt ligand in regenerative medicine is hampered by its hydrophobicity and cross-reactivity with Frizzled (FZD) receptors. Here, we generate an engineered water-soluble, FZD subtype-specific agonist, RRP-pbFn, for high-efficiency Wnt/β-catenin signaling activation. In the absence of direct binding to LRP5/6, RRP-pbFn stimulates Wnt/β-catenin signaling more potently than surrogate Wnt. RRP-pbFn supports the growth of a variety of mouse and human organoids, and induces the expansion of liver and intestine progenitorsin vivo. Meanwhile, we develop a synthetic LRP antagonist, RRP-Dkk1c, which exhibits heightened effectiveness in attenuating Wnt/β-catenin signaling activity compared to Dkk1, thereby abolishing the formation of CT26-derived colon cancer xenograftin vivo. Together, these two paired Wnt/β-catenin signaling manipulators hold great promise for biomedical research and potential therapeutics.
Pesticide-induced resurgence in brown planthopper is mediated by action on a suite of genes that promote juvenile hormone biosynthesis and female fecundity
Authors: Gao Yang , Su Shao-Cong , Xing Ji-Yang , Liu Zhao-Yu , Nassel Dick R. , Bass Chris , Gao Cong-Fen , Wu Shun-Fan
Published: June 2023

Pesticide-induced resurgence, increases in pest insect populations following pesticide application, is a serious threat to the sustainable control of many highly damaging crop pests. Resurgence can result from pesticide-enhanced pest reproduction, however, the molecular mechanisms mediating this process remain unresolved. Here we show that brown planthopper (BPH) resurgence following emamectin benzoate (EB) exposure results from the coordinated action of a diverse suite of actors that regulate juvenile hormone (JH) levels, resulting in increased JH titer in adult females and enhanced fecundity. Following reports of BPH resurgence in rice crops when this species is exposed to EB, we demonstrate that EB treatment results in profound changes in female BPH fitness including enhanced ovarian development and elevated egg production. This enhanced reproductive fitness results from the EB-mediated upregulation of key genes involved in the regulation of JH, including JHAMT, Met and Kr-h1 and the downregulation of allatostatin (AstA) and allatostatin receptor (AstAR) expression. The remodulation of gene expression following EB exposure is dependent on the action of this insecticide on its molecular target the glutamate-gated chloride channel (GluCl) receptor. Collectively, these results provide mechanistic insights into the regulation of negative pesticide-induced responses in insects and reveal the key actors involved in the JH-signaling pathway that underpin pesticide resurgence.
Spatial and temporal distribution of ribosomes in single cells reveals aging differences between old and new daughters ofEscherichia coli
Authors: Chao Lin , Chan Chun Kuen , Shi Chao , Rang Camilla U.
Published: June 2023

Lineages of rod-shaped bacteria such asEscherichia coliexhibit a temporal decline in elongation rate in a manner comparable to cellular or biological aging. The effect results from the production of asymmetrical daughters, one with a lower elongation rate, by the division of a mother cell. The slower daughter compared to the faster daughter, denoted respectively as the old and new daughters, has more aggregates of damaged proteins and fewer expressed gene products. We have examined further the degree of asymmetry by measuring the density of ribosomes between old and new daughters and between their poles. We found that ribosomes were denser in the new daughter and also in the new pole of the daughters. These ribosome patterns match the ones we previously found for expressed gene products. This outcome suggests that the asymmetry is not likely to result from properties unique to the gene expressed in our previous study, but rather from a more fundamental upstream process affecting distribution of ribosomal abundance. Because damage aggregates and ribosomes are both more abundant at the poles ofE. colicells, we suggest that competition for space between the two could explain the reduced ribosomal density in old daughters. Using published values for aggregate sizes and the relationship between ribosomal number and elongation rates, we show that the aggregate volumes could in principle displace quantitatively the amount of ribosomes needed to reduce the elongation rate of the old daughters.

IMPORTANCE

Bacteria exhibit a growth decline in a manner comparable to cellular or biological aging. When a mother bacterium reproduces by binary fission it allocates more damage to one of the two daughters. The extra damage correlates with a slower growth. Thus, a lineage of daughters successively acquiring more damage over generations ages, sometimes even to death under stressful conditions. Aging lineages also have lower levels of expressed gene products. Here we show that the aging process also correlates with lower cellular levels of ribosomes. The identification of a ribosomal effect shows that the aging process is acting at a much more fundamental upstream level. While decreased gene products could have resulted from local regulation of specific genes, a lower ribosomal density affects the entirety of cellular metabolism. Understanding bacterial aging is important because biological aging may have originated in single-celled organisms such asE. coli.
Storm: Incorporating transient stochastic dynamics to infer the RNA velocity with metabolic labeling information
Authors: Peng Qiangwei , Qiu Xiaojie , Li Tiejun
Published: June 2023

Abstract

The time-resolved scRNA-seq (tscRNA-seq) provides the possibility to infer physically meaningful kinetic parameters, e.g., the transcription, splicing or RNA degradation rate constants with correct magnitudes, and RNA velocities by incorporating temporal information. Previous approaches utilizing the deterministic dynamics and steady-state assumption on gene expression states are insufficient to achieve favorable results for the data involving transient process. We present a dynamical approach, Storm (Stochastic models of RNA metabolic-labeling), to overcome these limitations by solving stochastic differential equations of gene expression dynamics. The derivation reveals that the new mRNA sequencing data obeys different types of cell-specific Poisson distributions when jointly considering both biological and cell-specific technical noise. Storm deals with measured counts data directly and extends the RNA velocity methodology based on metabolic labeling scRNA-seq data to transient stochastic systems. Furthermore, we relax the constant parameter assumption over genes/cells to obtain gene-cell-specific transcription/splicing rates and gene-specific degradation rates, thus revealing time-dependent and cell-state specific transcriptional regulations. Storm will facilitate the study of the statistical properties of tscRNA-seq data, eventually advancing our understanding of the dynamic transcription regulation during development and disease.
Tradeoffs in Modeling Context Dependency in Complex Trait Genetics
Authors: Weine Eric , Smith Samuel Pattillo , Knowlton Rebecca Kathryn , Harpak Arbel
Published: June 2023

Genetic effects on complex traits may depend on context, such as age, sex, environmental exposures or social settings. However, it is often unclear if the extent of context dependency, or Gene-by-Environment interaction (GxE), merits more involved models than the additive model typically used to analyze data from genome-wide association studies (GWAS). Here, we suggest considering the utility of GxE models in GWAS as a tradeoff between bias and variance parameters. In particular, We derive a decision rule for choosing between competing models for the estimation of allelic effects. The rule weighs the increased estimation noise when context is considered against the potential bias when context dependency is ignored. In the empirical example of GxSex in human physiology, the increased noise of context-specific estimation often outweighs the bias reduction, rendering GxE models less useful when variants are considered independently. However, we argue that for complex traits, the joint consideration of context dependency across many variants mitigates both noise and bias. As a result, polygenic GxE models can improve both estimation and trait prediction. Finally, we exemplify (using GxDiet effects on longevity in fruit flies) how analyses based on independently ascertained ``top hits'' alone can be misleading, and that considering polygenic patterns of GxE can improve interpretation.
Uncovering novel endolysins against methicillin-resistantStaphylococcus aureususing microbial single-cell genome sequencing
Authors: Yoda Takuya , Matsuhashi Ayumi , Matsushita Ai , Shibagaki Shohei , Sasakura Yukie , Aoki Kazuteru , Hosokawa Masahito , Tsuda Soichiro
Published: June 2023

Endolysins, peptidoglycan hydrolases derived from bacteriophages (phages), are being developed as a promising alternative to conventional antibiotics. To obtain highly active endolysins, a diverse library of endolysins is vital. We here propose microbial single-cell genome sequencing as an efficient tool to discover dozens of previously unknown endolysins, owing to its culture-independent sequencing method. As a proof-of-concept, we analyzed and recovered endolysin genes within prophage regions ofStaphylococcussingle-amplified genomes (SAGs) in human skin microbiome samples. We constructed a library of chimeric endolysins by shuffling domains of the natural endolysins and performed high-throughput screening againstStaphylococcus aureus. One of the lead endolysins, bbst1027, exhibited desirable antimicrobial properties such as rapid bactericidal activity, no detectable resistance development, andin vivoefficacy. We foresee that this endolysin discovery pipeline is in principle applicable to any bacterial target, and boost the development of novel antimicrobial agents.
Purine nucleotide limitation undermines antibiotic action in clinicalEscherichia coli
Authors: Lubrano Paul , Schramm Thorben , Lorenz Elisabeth , Alvarado Alejandra , Eigenmann Seraina Carmen , Stadelmann Amelie , Thavapalan Sevvalli , Waffenschmidt Nils , Glatter Timo , Peter Silke , Drescher Knut , Link Hannes
Published: June 2023

Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics1–4and promote evolution of antimicrobial resistance (AMR)5,6. However, little is known about which metabolic pathways contribute to AMR, and the underlying mechanisms. Here, we measured antibiotic resistance of 15,120Escherichia colimutants, each with a single amino acid change in one of 346 essential proteins. Most of the mutant strains that showed resistance to either of the two tested antibiotics carried mutations in metabolic genes. Resistance mutations against a β-lactam antibiotic (carbenicillin) were associated with purine nucleotide biosynthesis and limited the supply of ATP. We show that ATP limitation confers both resistance and tolerance against β-lactam antibiotics by upregulating the purine nucleoside transporter PunC. These results are clinically relevant, because anE. colistrain isolated from a clinical specimen had a purine nucleotide limitation, which reduced its susceptibility to antibiotics.
Flagellar switch inverted repeat impacts flagellar invertibility and variesClostridioides difficileRT027/MLST1 virulence
Authors: Nhu Nguyen T. Q. , Lin Huaiying , Pigli Ying , Sia Jonathan K. , Kuhn Pola , Snitkin Evan S. , Young Vincent , Kamboj Mini , Pamer Eric G. , Rice Phoebe A. , Shen Aimee , Dong Qiwen
Published: June 2023

Clostridioides difficileRT027 strains cause infections that vary in severity from asymptomatic to lethal, but the molecular basis for this variability is poorly understood. Through comparative analyses of RT027 clinical isolates, we determined that isolates that exhibit greater variability in their flagellar gene expression exhibit greater virulencein vivo.C. difficileflagellar genes are phase-variably expressed due to the site-specific inversion of theflgB5’UTR region, which reversibly generates ON vs. OFF orientations for the flagellar switch. We found that longer inverted repeat (IR) sequences in this switch region correlate with greater disease severity, with RT027 strains carrying 6A/6T IR sequences exhibiting greater phenotypic heterogeneity in flagellar gene expression (60%-75% ON) and causing more severe disease than those with shorter IRs (> 99% ON or OFF). Taken together, our results reveal that phenotypic heterogeneity in flagellar gene expression may contribute to the variable disease severity observed inC. difficilepatients.
Auditors' sensemaking of other comprehensive income through metaphors
Authors: Durocher Sylvain , Picard Claire-France , Dugal Léa
Published: June 2023

Purpose

This paper aims to examine how auditors make sense of the ill-theorized and contentious notion of other comprehensive income (OCI), specifically by uncovering their use of metaphors to make OCI plausible and intelligible.

Design/methodology/approach

This interpretative paper draws on a collection of 21 interviews with experienced auditors. The analysis first uncovers metaphors that naturally surface within the talk and sensemaking of auditors about OCI (elicited metaphors). The authors then encapsulate these elicited metaphors into second-order constructs (projected metaphors) to synthesize and further explain auditors’ practical sensemaking.

Findings

Auditors conceive OCI as a “safety” that ensures the well-functioning of fair value accounting, metaphorically qualifying this notion as a “necessary evil”, a “passage obligé”, and a “parking lot” resolving fair value-related issues and aberrations. Auditors also metaphorize OCI as a “purifier” that allows “polluted”, “noisy”, and “unloved” items to be “parked” outside net income.

Practical implications

The study’s findings further the understanding of auditors’ tendency to remain uncritical throughout their sensemaking process. Making sense of professional standards of practice through metaphors indubitably involves shadowing and silencing other worldviews.

Originality/value

This paper extends knowledge of auditors’ sensemaking, specifically showing how auditors easily make sense of complex notions even in the absence of conceptual grounds. This study also highlights that metaphors are a powerful sensemaking device that auditors mobilize to render complex notions intelligible and mitigate IFRS inconsistencies.
Impact of e-servicescape on hotel booking intention: examining the moderating role of COVID-19
Authors: Srivastava Praveen , Srivastava Shelly , Mishra Niraj
Published: June 2023

Purpose

The paper aims to illuminate the relationship between attitude toward the hotel’s website (e-servicescape) and purchase intention. It proposes modeling the dimension of the hotel’s website, its impact on building attitude toward the website and the relations with purchase intention. Further, the role of social risk arising from COVID-19 on the relationship between attitude and purchase intention is explored.

Design/methodology/approach

The authors conducted empirical research using an online questionnaire based on a comprehensive evaluation of prior literature. The online questionnaire has 15 questions, and data is gathered from guests who have visited the hotel’s website in the preceding year. SmartPLS was used to analyze the data. Attitude toward the website has been identified as a higher-order factor, and a two-stage embedding technique was adopted for analysis.

Findings

The paper gives empirical evidence about how different dimensions of a hotel’s website influence one’s attitude. The finding indicates that the ambience factor, i.e. how effectively a website provides a pleasant and interesting atmosphere for online visitors, is the most critical component for attitude development. Additionally, the finding reveals the negative moderating effect of social risk on the relationship between attitude and purchase intention.

Research limitations/implications

Since demographic factors play a significant role in the social-risk component, the study findings may lack generalizability. As a result, scholars are urged to do more study on the offered ideas.

Practical implications

The paper includes implications for the development of a better e-servicescape, which should incorporate the dimensions discussed in the study to entice the customers for hotel booking and can remove the fear of social risk.

Originality/value

This paper addresses an established need by examining how social risk affects the relationship between attitude toward a website and purchase intention.
Does corporate governance matter in the cleanup of reported oil spills? Evidence from Nigeria
Authors: Abdul-Baki Zayyad , Haniffa Roszaini , Diab Ahmed
Published: June 2023

Purpose

This study aims to examine whether corporate governance mechanisms – board size, board independence and CEO duality – influence the actions of oil companies operating in Nigeria to clean up oil spills from their facilities.

Design/methodology/approach

Both binary logistic regression (linear) and random-effects logistic regression models were used to test three hypotheses using a unique data set of 1,262 oil spill events involving 24 oil companies from 2017 to 2019.

Findings

The study found that board size and board independence are positively related to oil spill cleanup.

Practical implications

Private oil companies in Nigeria should encourage larger and more independent boards in their corporate governance (CG) structures, as these boards may be more effective in serving the interests of stakeholders by bringing diverse knowledge and experience to the boards. Similarly, regulators should extend the enforcement of CG codes to private firms.

Originality/value

To the best of the authors’ knowledge, this is the first study that investigates the influence of CG attributes on oil spill cleanup.