bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional space expansion driven by transitions between energetically advantageous traits in the deep sea
Authors: Bryant S. River D. , McClain Craig R.
Published: November 2022

Climate change is shifting community structure and biodiversity on a global scale, in part due to alterations of chemical and thermal energy availability. These changes may impact ecosystem functioning through their influence on functional diversity. We investigate patterns of functional diversity, functional niches, and functional traits in bivalve communities across the energetic gradient of the deep Atlantic Ocean. We use the functional traits feeding type, tiering, and motility level to define the axes of functional space and the unique combinations of these traits as functional niches. We find that increased energy affords new species, added into functional space through niche expansion rather than niche packing. Underlying this pattern are complex dynamics of gains and losses of individual functional niches, with few adapted to the low- and high-energy extremes, and most occurring at intermediate energy. Adaptive qualities of specific traits are evidenced by those functional niches occurring at energetic extremes. Tradeoffs between these traits within the intermediate energy zone underlie an increased coexistence of functional niches, which in turn drives a unimodal pattern of functional niches and expansion of used functional space. This work suggests that energy-limited communities may be especially vulnerable to continued shifts in food availability through the Anthropocene.
Cryptic diversity impacts model selection and macroevolutionary inferences in diversification analyses
Authors: Utami C. Y. , Sholihah A. , Condamine F. L. , Thébaud C. , Hubert N.
Published: November 2022

Species persist in landscapes through ecological dynamics but proliferate at wider spatial scales through evolutionary mechanisms. Disentangling the contribution of each dynamic is challenging, but the increasing use of dated molecular phylogenies opened new perspectives. First, the increasing use of DNA sequences in biodiversity inventory shed light on a substantial amount of cryptic diversity in species-rich ecosystems. Second, explicit diversification models accounting for various eco-evolutionary models are now available. Integrating both advances, we explored diversification trajectories among 10 lineages of freshwater fishes in Sundaland, for which time-calibrated and taxonomically rich phylogenies are available. By fitting diversification models to dated phylogenies and incorporating DNA-based species delimitation methods, the impact of cryptic diversity on diversification model selection and related inferences is explored. Eight clades display constant speciation rate model as the most likely if cryptic diversity is accounted, but nine display a signature of diversification slowdowns when cryptic diversity is ignored. Cryptic diversification occurs during the last 5 Myr for most groups, and palaeoecological models received little support. Most cryptic lineages display restricted range distribution, supporting geographical isolation across homogeneous landscapes as the main driver of diversification. These patterns question the persistence of cryptic diversity and its role during species proliferation.
The banded colour patterns of sea snakes discourage attack by predatory fishes, enabling Batesian mimicry by harmless species
Authors: Goiran Claire , Shine Terri , Shine Richard
Published: November 2022

The evolution of bright ‘warning’ colours in nontoxic animals often is attributed to mimicry of toxic species, but empirical tests of that hypothesis must overcome the logistical challenge of quantifying differential rates of predation in nature. Populations of a harmless sea snake species (Emydocephalus annulatus) in New Caledonia exhibit colour polymorphism, with around 20% of individuals banded rather than melanic. Stability in that proportion over 20 years has been attributed to Batesian mimicry of deadly snake species by banded morphs of the harmless taxon. This hypothesis requires that banded colours reduce a snake's vulnerability to predation. We tested that idea by pulling flexible snake-shaped models through the water and recording responses by predatory fish. Black and banded lures attracted similar numbers of following fish, but attacks were directed almost exclusively to black lures. Our methods overcome several ambiguities associated with experimental studies on mimicry in terrestrial snakes and support the hypothesis that banded colour patterns reduce a non-venomous marine snake's vulnerability to predation.
Sticky steps and the gender gap: how thoughtful practices could help keep caregivers in science
Authors: Meirmans Stephanie , Lamatsch Dunja K. , Neiman Maurine
Published: November 2022

Many fewer women than men hold senior academic positions, a widely recognized and increasing problem. Our goal is to identify effective and feasible solutions. We begin by providing an in-depth assessment of the drivers of this gender inequity. In our synthesis of existing data, we provide many lines of evidence highlighting caregiving as a primary main factor. This is not a ‘new’ insight per se, but a point worth repeating that we back up by a strong and synthetic body of recent data. We also believe that our analysis provides a step forward in tackling a complex issue. We then develop a more detailed understanding of the challenges academic caregivers face and discuss whether and why it is important to keep caregivers in science. We find that the attrition due to caregiving should not be seen as a factor but rather as a process with multiple ‘sticky steps’ that eventually drive caregivers out of science—which, as we argue, is partly also good news. Indeed, it is here that we believe actions could be taken that would have a real impact: for example, one could effectively increase and expand upon current funding practices that focus on caregiver career advancement.
Quaternary megafauna extinctions altered body size distribution in tortoises
Authors: Joos Julia , Pimiento Catalina , Miles Donald B. , Müller Johannes
Published: November 2022

The late Quaternary is characterized by the extinction of many terrestrial megafauna, which included tortoises (Family: Testudinidae). However, limited information is available on how extinction shaped the phenotype of surviving taxa. Here, based on a global dataset of straight carapace length, we investigate the temporal variation, spatial distribution and evolution of tortoise body size over the past 23 million years, thereby capturing the effects of Quaternary extinctions in this clade. We found a significant change in body size distribution characterized by a reduction of both mean body size and maximum body size of extant tortoises relative to fossil taxa. This reduction of body size occurred earlier in mainland (Early Pleistocene 2.588–0.781 Ma) than in island tortoises (Late Pleistocene/Holocene 0.126–0 Ma). Despite contrasting body size patterns between fossil and extant taxa on a spatial scale, tortoise body size showed limited variation over time until this decline. Body size is a fundamental functional trait determining many aspects of species ecologies, with large tortoises playing key roles as ecosystem engineers. As such, the transition from larger sized to smaller sized classes indicated by our findings likely resulted in the homogenization of tortoises' ecological functions and diminished the role of tortoises in structuring the vegetation community.
Determinants of Eye Care Service Utilization Among Malawian adults; A Secondary Analysis of the Malawi fifth Integrated Household Survey 2019-2020
Authors: Mzumara Thokozani
Published: November 2022

Purpose

The aim of the study was to assess the self-reported Eye Care Utilization (ECU) and associated demographic factors among Malawians adults.

Methods

This study utilized secondary data from the Malawi Integrated Health Survey (IHS) 5 2019-2020. We entered age, sex, level of education, residency(urban/rural) and having chronic disease into a logistic regression model and used a confusion matrix to predict the accuracy of the model.

Results

The prevalence of ECU was 60.6% (95% CI [60.0,61.2]). The model was statistically significant and correctly classified 72 % of the cases. A logistic regression showed that ECU was positively associated with education compared to none (OR=3.6, 95 % CI [3.104-4.097], p<0.001, (OR =6.6), CI [5.927,7.366], p<0.001), male gender compared to females (OR= 1.2, 95% CI [1.104,1.290], p<0.001), urban residence compared to rural areas (OR= 1.2, 95% CI [1.118,1.375], p<0.001). But It was negatively associated with age compared to young adults, middle age (OR =7.5, 95% CI [6.782,8.476], p<0.001), older age (OR=0.9, 95 % CI [0.866,1.035], p<0.001), and having chronic diseases (OR=0.6, 95 % CI= [0.547,0.708], p<0.001).

Conclusion

Social support, women empowerment, education, and mobile clinics are key strategic areas that would increase Access to eye care in Malawi. Further studies can investigate ECU among the pediatric population.
Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment
Authors: Mouat Julia S. , Li Xueshu , Neier Kari , Zhu Yihui , Mordaunt Charles E. , Merrill Michele A. La , Lehmler Hans-Joachim , Jones Michael P. , Lein Pamela J. , Schmidt Rebecca J. , LaSalle Janine M.
Published: November 2022

Background

Gestational exposure to polychlorinated biphenyls (PCBs) has been associated with elevated risk for neurodevelopmental disorders. The mechanism of risk is unclear but may involve placental epigenetics. Prior studies have associated differential placental DNA methylation with maternal PCB exposure or with increased risk of autism spectrum disorder (ASD). However, sequencing-based placental methylomes have not previously been tested for simultaneous associations with maternal PCB levels and child neurodevelopmental outcomes.

Objectives

We aimed to identify placental DNA methylation patterns associated with maternal PCB levels and child neurodevelopmental outcomes in the high-risk ASD MARBLES cohort.

Methods

We measured 209 PCB congeners in 104 maternal serum samples collected at delivery. We identified networks of DNA methylation from 147 placenta samples using the Comethyl R package, which performs weighted gene correlation network analysis for whole genome bisulfite sequencing data. We tested placental DNA methylation modules for association with maternal serum PCB levels, child neurodevelopment, and other participant traits.

Results

PCBs 153 + 168, 170, 180 + 193, and 187 were detected in over 50% of maternal serum samples and were highly correlated with one another. Consistent with previous findings, maternal age was the strongest predictor of serum PCB levels, alongside year of sample collection, pre-pregnancy BMI, and polyunsaturated fatty acid levels. Twenty seven modules of placental DNA methylation were identified, including five which significantly correlated with one or more PCBs, and four which correlated with child neurodevelopment. Two modules associated with maternal PCB levels as well as child neurodevelopment, and mapped toCSMD1andAUTS2, genes previously implicated in ASD and identified as differentially methylated regions in mouse brain and placenta following gestational PCB exposure.

Conclusions

Placental DNA co-methylation modules were associated with maternal PCBs and child neurodevelopment. Methylation ofCSMD1andAUTS2could potentially be mechanistically involved in ASD risk following maternal PCB exposure.

GRAPHICAL ABSTRACT
Targeted high throughput mutagenesis of the human spliceosome reveals itsin vivooperating principles
Authors: Beusch Irene , Rao Beiduo , Studer Michael , Luhovska Tetiana , Šukytė Viktorija , Lei Susan , Oses-Prieto Juan , SeGraves Em , Burlingame Alma , Jonas Stefanie , Madhani Hiten D.
Published: November 2022

The spliceosome is a staggeringly complex machine comprising, in humans, 5 snRNAs and >150 proteins. We scaled haploid CRISPR-Cas9 base editing to target the entire human spliceosome and interrogated the mutants using the U2 snRNP/SF3b inhibitor, pladienolide B. Hypersensitive substitutions define functional sites in the U1/U2-containing A-complex but also in components that act as late as the second chemical step after SF3b is dissociated. Viable resistance substitutions map not only to the pladienolide B binding site but also to the G-patch (ATPase activator) domain of SUGP1, which lacks orthologs in yeast. We used these mutants and biochemical approaches to identify the spliceosomal disassemblase DHX15/hPrp43 as the ATPase ligand for SUGP1. These and other data support a model in which SUGP1 promotes splicing fidelity by triggering early spliceosome disassembly in response to kinetic blocks. Our approach provides a template for the analysis of essential cellular machines in humans.
Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma 3D organoids and identify matrix-activated therapeutic targets
Authors: Cruz-Acuña Ricardo , Kariuki Secunda W. , Sugiura Kensuke , Loebel Claudia , Karakasheva Tatiana , Gabre Joel T. , Burdick Jason A. , Rustgi Anil K.
Published: November 2022

Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevantin vitro3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robustin vitrogrowth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted throughin vitroandin vivoenvironments. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic increased matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to inform the development of therapeutics that target ECM stiffness in EAC.
Using Genome Sequence Data to Predict SARS-CoV-2 Detection Cycle Threshold Values
Authors: Duesterwald Lea , Nguyen Marcus , Christensen Paul , Long S. Wesley , Olsen Randall J. , Musser James M. , Davis James J.
Published: November 2022

The continuing emergence of SARS-CoV-2 variants of concern (VOCs) presents a serious public health threat, exacerbating the effects of the COVID19 pandemic. Although millions of genomes have been deposited in public archives since the start of the pandemic, predicting SARS-CoV-2 clinical characteristics from the genome sequence remains challenging. In this study, we used a collection of over 29,000 high quality SARS-CoV-2 genomes to build machine learning models for predicting clinical detection cycle threshold (Ct) values, which correspond with viral load. After evaluating several machine learning methods and parameters, our best model was a random forest regressor that used 10-mer oligonucleotides as features and achieved an R2score of 0.521 ± 0.010 (95% confidence interval over 5 folds) and an RMSE of 5.7 ± 0.034, demonstrating the ability of the models to detect the presence of a signal in the genomic data. In an attempt to predict Ct values for newly emerging variants, we predicted Ct values for Omicron variants using models trained on previous variants. We found that approximately 5% of the data in the model needed to be from the new variant in order to learn its Ct values. Finally, to understand how the model is working, we evaluated the top features and found that the model is using a multitude of k-mers from across the genome to make the predictions. However, when we looked at the top k-mers that occurred most frequently across the set of genomes, we observed a clustering of k-mers that span spike protein regions corresponding with key variations that are hallmarks of the VOCs including G339, K417, L452, N501, and P681, indicating that these sites are informative in the model and may impact the Ct values that are observed in clinical samples.
FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases
Authors: Breeze Charles E. , Haugen Eric , Gutierrez-Arcelus María , Yao Xiaozheng , Teschendorff Andrew , Beck Stephan , Dunham Ian , Stamatoyannopoulos John , Franceschini Nora , Machiela Mitchell J. , Berndt Sonja I.
Published: November 2022

The majority of disease-associated variants identified through genome-wide association studies (GWAS) are located outside of protein-coding regions and are overrepresented in sequences that regulate gene expression. Prioritizing candidate regulatory variants and potential biological mechanisms for further functional experiments, such as genome editing, can be challenging, especially in regions with a high number of variants in strong linkage disequilibrium or multiple proximal gene targets. Improved annotation of the regulatory genome can help identify promising variants and target genes for functional genomics experiments. To advance this area, we developed FORGEdb (https://forge2.altiusinstitute.org/files/forgedb.html), a web-based tool that can rapidly integrate data for individual genetic variants, providing information on associated regulatory elements, transcription factor (TF) binding sites and target genes for over 37 million variants. FORGEdb uses annotations derived from data across a wide range of biological samples to delineate the regulatory context for each variant at the cell type level. Multiple data types, such as Combined Annotation Dependent Depletion (CADD) scores, expression quantitative trait loci (eQTLs), activity-by-contact (ABC) interactions, Contextual Analysis of TF Occupancy (CATO) scores, transcription factor (TF) motifs, DNase I hotspots, histone mark ChIP-seq peaks and chromatin states, are included in FORGEdb and these annotations are integrated into a FORGEdb score to guide assessment of functional importance. In summary, FORGEdb provides an expansive and unique resource of genomic annotations and an integrated score that can be used to accelerate the translation of identified genetic loci into biological insight.
AhR-mediated activation of innate lymphocytes restrains tissue-resident memory-like CD8+ T cell responses during contact hypersensitivity
Authors: Romero-Suárez S. , Correia M.P. , Jeong M. , Ast V. , Platten M. , Sexl V. , Mogler C. , Cerwenka A. , Stojanovic A.
Published: November 2022

Allergic contact dermatitis (ACD) and the mouse model of hapten-induced contact hypersensitivity (CHS) are inflammatory skin responses triggered by the repeated exposure to exogenous allergens and haptens. ACD and CHS effector responses have been extensively studied, but the regulatory mechanisms that control inflammation and determine the kinetics of its resolution are still incompletely understood. In addition, although CHS can be mediated by both innate and adaptive effector cells in a non-redundant manner, leading to distinct skin pathologies, their interplay during the course of inflammation remains so far unaddressed. Here, we show that NKp46+innate lymphoid cells (ILCs) limit the extent of CHS inflammation by modulating the CD8+TRMimmune compartment. This regulatory effect of ILCs depends on the expression of the ligand-induced transcription factor aryl-hydrocarbon receptor (AhR). AhR-deficiency in NKp46+ILCs did not affect the memory response to hapten, but led to spatial propagation and amplification of inflammatory response in the skin. This phenotype correlated with increased numbers ofIfng-producing CD8+TRM-like cells and neutrophilic infiltration in the skin. Our study thereby demonstrates a novel AhR-driven innate-adaptive immune interplay in regulating skin inflammation.
Two-Photon Targeted, Quad Whole-Cell Patch-Clamping Robot
Authors: Vera Gonzalez Gema I , Kgwarae Phatsimo O , Schultz Simon R
Published: November 2022

We present an automated quad-channel patch-clamp technology platform forex vivobrain slice electrophysiology, capable of both blind and two-photon targeted robotically automated patching. The robot scales up the patch-clamp singlecell recording technique to four simultaneous channels, with seal success rates for two-photon targeted and blind modes of 54% and 68% respectively. In 50% of targeted trials (where specific cells were required), at least 2 simultaneous recordings were obtained. For blind mode, most trials yielded dual or triple recordings. This robot, a milestone on the path to a truein vivorobotic multi-patching technology platform, will allow numerous studies into the function and connectivity patterns of both primary and secondary cell types.
Balance-directed protein engineering ofIsPETase enhances both PET hydrolysis activity and thermostability
Authors: Lee Seul Hoo , Seo Hogyun , Hong Hwaseok , Park Jiyoung , Ki Dongwoo , Kim Mijeong , Kim Hyung-Joon , Kim Kyung-Jin
Published: November 2022

A mesophilic PETase fromIdeonella sakaiensis(IsPETase) has been shown to exhibit high PET hydrolysis activity, but its low thermostability limits its industrial applications. We herein developed an engineering strategy forIsPETase to enhance PET hydrolysis activity, thermostability, and protein folding of the enzyme. Balance-directed Z1-PETase variant outperforms the stability-directed Z2-PETase variant under both mesophilic and thermophilic conditions, although Z2-PETase exhibits higher thermostability than Z1-PETase. The Z1-PETase is also superior to Fast-PETase, Dura-PETase, and LC-CICCGin terms of depolymerization rate regardless of temperature conditions we tested. Thus, maintaining a balance between PET hydrolysis activity and thermostability is essential for the development of high-performance PET hydrolases. In a pH-stat bioreactor, Z1-PETase depolymerized >90% of both transparent and colored post-consumer PET powders within 24 and 8 hours at 40°C and 55°C, respectively, demonstrating that the balance-directedIsPETase variant produced herein may be applicable in the bio-recycling of PET.
Anti-oxidant Response of Lipidom Modulates Lipid Metabolism inCaenorhabditis elegansand in OxLDL-Induced Human Macrophages by Tuning Inflammatory Mediators
Authors: Balkrishna Acharya , Gohel Vivek , Pathak Nishit , Singh Rani , Tomer Meenu , Rawat Malini , Dev Rishabh , Varshney Anurag
Published: November 2022

Atherosclerosis is the main pathological process of most cardiovascular diseases. It can begin early in life and may remain latent and asymptomatic for an extended period before its clinical manifestation. Lipidom, an ayurvedic prescription medicine, contains five herbal constituents with reported anti-inflammatory, anti-oxidant and lipid lowering properties. The present study is aimed to characterize the pharmacological potentials of Lipidom. The phytochemical analysis of Lipidom was performed on high performance liquid chromatography (HPLC) platform. Lipidom was evaluated for cytosafety, NF-κB activity, IL-1β and MCP-1 levels, modulation of NLRP3 pathway, ROS generation, lipid accumulation and gene expression in oxidized LDL stimulated THP1 macrophages. Furthermore, assessment of Lipidom was also done in the in-vivoCaenorhabditis elegansmodel. Analysis of brood size, % adult, lipid accumulation, triglyceride levels, MDA formation, SOD-3 levels and gene expression was performed inC. elegans. Lipidom treatment significantly reduced the inflammatory markers, lipid accumulation, oxidative stress and normalized genes involved in atherosclerosis development in THP1 macrophages. Lipidom treatedC. elegansshowed a significant decline in the lipid accumulation and oxidative stress. Lipidom showed a multifaceted approach in modulating the mediators responsible for development and progression of atherosclerosis.
Systematic Review of Genetic Polymorphisms Associated with Acute Pain and Relevant Acute Toxicities Induced by Radiotherapy for Head and Neck Cancer
Authors: Salama Vivian , Geng Yimin , Rigert Jillian , Fuller Clifton D. , Moreno Amy C. , Shete Sanjay , Reyes-Gibby Cielito C.
Published: November 2022

Background/objective

Pain is the most common acute toxicity following radiation therapy (RT) for head and neck cancer (HNC). The multifactorial origin of radiotherapy-induced pain makes it highly challenging to manage in HNC patients. Multiple studies have been conducted to identify different germline genetic variants associated with cancer pain, however few of them focused on RT-induced acute pain. In this systematic review, we summarize potential mechanisms of acute pain after radiotherapy in HNC focusing on oral cavity/oropharyngeal cancer and identify genetic variants associated with radiotherapy-induced acute pain and other relevant acute toxicities.

Methods

A comprehensive search of Ovid Medline, EMBASE and Web of Science databases using concepts and terms including “Variants”, “Polymorphisms”, “Radiotherapy”, “Acute pain”, “Acute toxicity” published up to February 28, 2022 was performed by two reviewers. Review articles and citations were reviewed manually. The reported SNPs associated with RT-induced acute pain and toxicities were reported, and the molecular function of the associated genes and pathways were described based on genetic annotation using The Human Gene Database; GeneCards.

Results

A total of 386 articles were identified electronically and an additional 8 articles were included after manual search. 39 articles were finally included. 51 variants were associated with 40 genes, of which 30 % had function in DNA damage response and repair, 25% in inflammatory and immune response, 17.5 % in cell death or cell cycle, and were associated with RT-inflammatory pain and acute mucositis or dermatitis. 4 variants in 4 genes were associated with neuropathy and neuropathic pain. 13 variants in 10 genes and were associated with RT-induced mixed types of post-RT-pain.

Conclusion

Different types of pain develop after RT, including inflammatory pain (acute mucositis and acute skin reaction); neuropathic pain; nociceptive pain; and mixed oral pain. Genetic variants involved in DNA damage response and repair, cell death, inflammation and neuropathic pathways may affect pain presentation post-RT. These variants could be used for acute pain prediction and personalized pain management in HNC patients receiving RT.
Ethical reporting of research on violence against women and children during COVID-19: Analysis of 75 studies and recommendations for future guidelines
Authors: Peterman Amber , Devries Karen , Guedes Alessandra , Chandan Joht Singh , Minhas Sonica , Hui Lim Rachel Qian , Gennari Floriza , Bhatia Amiya
Published: November 2022

Changes in research practice during the COVID-19 pandemic necessitates renewed attention to ethical protocols and reporting for data collection on sensitive topics. We systematically searched journal publications from the start of the pandemic to November 2021, identifying 75 studies that collected primary data on violence against women and children. We assess the transparency of ethics reporting and adherence to relevant guidelines against a 14-item checklist of best practices. Studies reported adhering to best practices on 31% of scored items with highest reporting for ethical clearance (87%) and informed consent/assent (84/83%) and lowest reporting for facilitating referrals for minors and soliciting participant feedback (both 0%). Violence studies of primary data collected during COVID-19 report on few ethical standards, obscuring stakeholder ability to enforce a ‘do no harm’ approach and to assess the reliability of findings. We offer recommendations and guidelines to improve future reporting and implementation of ethics within violence studies.
Alpha closed-loop auditory stimulation modulates waking alpha oscillations and sleep onset dynamics in a phase-dependent manner in humans
Authors: Hebron Henry , Lugli Beatrice , Dimitrova Radost , Jaramillo Valeria , Rhodes Edward , Grossman Nir , Dijk Derk-Jan , Violante Ines R.
Published: November 2022

Alpha oscillations play a vital role in managing the brain’s resources, inhibiting neural activity as a function of their phase and amplitude, and are changed in many brain disorders. Developing minimally invasive tools to modulate alpha activity and identifying the parameters that determine its response to exogenous modulators, is essential for the implementation of focussed interventions. We introduce Alpha Closed-Loop Auditory Stimulation (αCLAS) as an EEG-based method to augment and investigate these brain rhythms in humans with specificity and selectivity, using targeted auditory stimulation. Across three independent studies, we demonstrate thatαCLASalters alpha power, frequency, and connectivity in a phase, amplitude and topography-dependent manner. Using a single-pulse-αCLASevoked potentials approach we show that the effects of auditory stimuli on alpha oscillations and resulting evoked potentials can be explained within the theoretical framework of oscillator theory and a phase-reset mechanism. Finally, we demonstrate the functional relevance of our approach by showing thatαCLASmodulates sleep onset dynamics in an alpha phase-dependent manner.
A programmable reaction-diffusion system for spatiotemporal cell signaling circuit design
Authors: Rajasekaran Rohith , Chang Chih-Chia , Weix Elliott W. Z. , Galateo Thomas M. , Coyle Scott M.
Published: November 2022

Cells self-organize molecules in space and time to generate complex behaviors, but we lack synthetic strategies for engineering spatiotemporal signaling. We present a programmable reaction-diffusion platform for designing protein oscillations, patterns, and circuits in mammalian cells using two bacterial proteins, MinD and MinE (MinDE). MinDE circuits act like “single-cell radios”, emitting frequency-barcoded fluorescence signals that can be spectrally isolated and analyzed using digital signal processing tools. We define how to genetically program these signals and modulate their dynamics using engineerable protein-protein interactions. By connecting MinDE to endogenous cellular pathways, we built circuits that broadcast frequency-barcoded single-cell kinase activity or that synthetically pattern actin polymerization. Our work establishes a new paradigm for probing and engineering cellular activities at length and timescales critical for biological function.
Aim18p and Aim46p are CHI-domain-containing mitochondrial hemoproteins inSaccharomyces cerevisiae
Authors: Schmitz Jonathan M. , Wolters John F. , Murray Nathan H. , Guerra Rachel M. , Bingman Craig A. , Hittinger Chris Todd , Pagliarini David J.
Published: November 2022

Chalcone isomerases (CHIs) have well-established roles in the biosynthesis of plant flavonoid metabolites.Saccharomyces cerevisiaepossesses two predicted CHI-like proteins, Aim18p (encoded by YHR198C) and Aim46p (YHR199C), but it lacks other enzymes of the flavonoid pathway, suggesting that Aim18p and Aim46p employ the CHI fold for distinct purposes. Here, we demonstrate that Aim18p and Aim46p reside on the mitochondrial inner membrane and adopt CHI folds, but they lack select active site residues and possess an extra fungal-specific loop. Consistent with these differences, Aim18p and Aim46p lack chalcone isomerase activity and also the fatty acid-binding capabilities of other CHI-like proteins, but instead bind heme. We further show that diverse fungal homologs also bind heme and that Aim18p and Aim46p possess structural homology to a bacterial hemoprotein. Collectively, our work reveals a distinct function and cellular localization for two CHI-like proteins, introduces a new variation of a hemoprotein fold, and suggests that ancestral CHI-like proteins were hemoproteins.
Exploring the properties of the left angular gyrus using TMS-evoked potentials
Authors: Sulcova Dominika , Salman Yasmine , Ivanoiu Adrian , Mouraux André
Published: November 2022

The angular gyrus (AG) is involved in multiple cognitive processes and its structural alterations are commonly observed in many neuropsychiatric syndromes. Since changes in excitability may precede structural changes and clinical symptoms, there is a need for diagnostic tools assessing the functional state of hub brain regions like the AG. The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) can provide such functional readouts by probing the brain response to direct stimulation.

This study aimed to characterize TMS-evoked potentials (TEP) elicited by AG stimulation, determine optimal stimulation parameters, and identify TEP biomarkers of AG function. We recorded AG-TEPs in 19 subjects using four TMS orientations and three intensities and compared TEP spatiotemporal features using topographic dissimilarity and microstate analyses. Additionally, we explored the relationship between AG-TEP topography and TMS-evoked muscular activity.

Our results showed topographic variability in AG-TEP components P25, N45, and N75. The P25 topography was sensitive to TMS orientation, while the topography of N45 and N75 was highly dependent on both coil orientation and intensity. Interestingly, we found that TMS-evoked muscular activity was also dependent on both these parameters and strongly related to the occurrence of a specific topographic pattern, which therefore possibly corresponds to the somatosensory brain response to muscle contraction.

We conclude that the early AG-TEP component P25 likely reflects neural processes triggered by direct AG activation and could provide an index of local excitability. Later components N45 and N75 must be interpreted with caution as they may primarily reflect peripherally evoked activity.
CRISPR-based tools for genetic manipulation in pathogenicSporothrixspecies
Authors: Hatinguais Remi , Leaves Ian , Brown Gordon D. , Brown Alistair J. P. , Brock Matthias , da Silva Roberta Peres
Published: November 2022

Sporothrix brasiliensisis an emerging fungal pathogen frequently associated with zoonotic transmission of sporotrichosis. Although certain virulence factors have been proposed as potential sporotrichosis determinants, the scarcity of molecular tools for reverse genetics studies onSporothrixhas significantly impeded the dissection of mechanisms underlying the disease. Here, we demonstrate that PEG-mediated protoplast transformation is a powerful method for heterologous expression inS. brasiliensis, S. schenckiiandS. chilensis. Combined with CRISPR/Cas9 gene editing, this transformation protocol allowed the deletion of the putative DHN-melanin synthase genepks1, which is a proposed virulence factor ofSporothrixspecies. To improve in locus integration of deletion constructs, we deleted the KU80homologue that is critical for non-homologous end-joining DNA repair. The use ofS. brasiliensisΔku80strains enhanced homologous-directed repair during transformation resulting in increased targeted gene deletion. In conclusion, our CRISPR/Cas9-based transformation protocol provides an efficient tool for targeted gene manipulation inSporothrixspecies.
It’s not easy seeing green: the veridical perception of small spots
Authors: Vanston John Erik , Boehm Alexandra E. , Tuten William S. , Roorda Austin
Published: November 2022

When single cones are stimulated with spots of 543-nm light presented against a white background, subjects report percepts that vary between predominately red, white, and green. However, light of the same spectral composition viewed over a large field under normal viewing conditions looks invariably green and highly saturated. It remains unknown what stimulus parameters are most important for governing the color appearance in the transition between these two extreme cases. The current study varied the size, intensity and retinal motion of stimuli presented in an adaptive optics scanning laser ophthalmoscope. Stimuli were either stabilized on target locations or allowed to drift across the retina with the eye’s natural motion. Increasing both stimulus size and intensity led to higher likelihoods that monochromatic spots of light were perceived as green, while only higher intensities led to increases in perceived saturation. The data also show an interaction between size and intensity, suggesting that the balance between magnocellular and parvocellular activation may be critical factors for color perception.

Surprisingly, under the range of conditions tested, color appearance did not depend on whether stimuli were stabilized or not. Sequential activation of many cones does not appear to drive hue and saturation perception as effectively as simultaneous activation of many cones.
Minimal models of the inspiratory and sigh breathing rhythms of the preBötzinger complex
Authors: Borrus Daniel S. , Grover Cameron J. , Del Negro Christopher A. , Conradi Smith Gregory D.
Published: November 2022

The preBötzinger complex of the lower brainstem generates two breathing-related rhythms: one for inspiration on a timescale of seconds, and another that produces larger amplitude sighs on the order of minutes. We hypothesize that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to the inspiratory rhythm while a calcium oscillator generates sighs; distinct neuronal populations are not required. We present several mathematical models that instantiate our working hypothesis including: (1) an activity (firing rate) model and (2) a minimal spiking network model. Both modeling frameworks corroborate the single-population rhythmogenic hypothesis.
Understanding Lesion Progression in a Chronic Model of Cerebral Cavernous Malformations through Combined MRI and Histology
Authors: Fisher Delaney G. , Sharifi Khadijeh A. , Ulutas E. Zeynep , Kumar Jeyan S. , Kalani M. Yashar S. , Miller G. Wilson , Price Richard J. , Tvrdik Petr
Published: November 2022

Cerebral cavernous malformations (CCM), also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurologic deficits, while others have no symptoms. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. To address this problem, we have established a chronic mouse model of CCM, induced by postnatal ablation ofKrit1withPdgfb-CreERT. These mice develop CCM lesions gradually over 4-6 months of age throughout of the brain. We examined lesion progression in these mice with T2-weighted 7T MRI protocols. Precise volumetric analysis of individual lesions revealed non-monotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and accelerated after about 3 months. Next, we established a modified protocol for dynamic contrast enhanced (DCE) MR imaging and produced quantitative maps of gadolinium tracer MultiHance in the lesions, indicating a high degree of heterogeneity in lesional permeability. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial cells, astrocytes, and microglia revealed that increased cell density surrounding lesions correlates with stability, while increased vasculature within and surrounding lesions may correlate with instability. Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive pre-clinical platform for testing new drug and gene therapies for controlling CCM.
Viewpoint-Dependence and Scene Context Effects Generalize to Depth Rotated 3D Objects
Authors: Kallmayer Aylin , Võ Melissa L.-H. , Draschkow Dejan
Published: November 2022

Viewpoint effects on object recognition interact with object-scene consistency effects. While recognition of objects seen from “accidental” viewpoints (e.g., a cup from below) is typically impeded compared to processing of objects seen from canonical viewpoints (e.g., the string-side of a guitar), this effect is reduced by meaningful scene context information. In the present study we investigated if these findings established by using photographic images, generalise to 3D models of objects. Using 3D models further allowed us to probe a broad range of viewpoints and empirically establish accidental and canonical viewpoints. In Experiment 1, we presented 3D models of objects from six different viewpoints (0°, 60°, 120°, 180° 240°, 300°) in colour (1a) and grayscaled (1b) in a sequential matching task. Viewpoint had a significant effect on accuracy and response times. Based on the performance in Experiments 1a and 1b, we determined canonical (0°-rotation) and non-canonical (120°-rotation) viewpoints for the stimuli. In Experiment 2, participants again performed a sequential matching task, however now the objects were paired with scene backgrounds which could be either consistent (e.g., a cup in the kitchen) or inconsistent (e.g., a guitar in the bathroom) to the object. Viewpoint interacted significantly with scene consistency in that object recognition was less affected by viewpoint when consistent scene information was provided, compared to inconsistent information. Our results show that viewpoint-dependence and scene context effects generalize to depth rotated 3D objects. This supports the important role object-scene processing plays for object constancy.
Development of the digital economy, transformation of the economic structure and leaping of the middle-income trap
Authors: Qi Yudong , Chu Xi
Published: November 2022

Purpose

Currently, China’s economy is in the critical phase of transforming economic development patterns and replacing old growth drivers with new ones. Whether it can successfully overcome the “middle-income trap” has become a significant issue attracting wide attention.

Design/methodology/approach

Driven by underlying digital technologies such as artificial intelligence, blockchain, cloud computing and big data, the fourth industrial revolution featuring the booming digital economy has provided significant opportunities for China’s economy to “overtake” and overcome the “middle-income trap”. The transformation of economic development pattern, the optimization of industrial structure, and the change of growth drivers, brought by the deep integration of digital and real economies are the keys to leaping over the “middle-income trap”.

Findings

From the supply side, the digital economy can improve the quality and efficiency of the supply side and promote the supply-side structural reform and economic growth from the following three aspects: First, promote the quality, efficiency and diversification of the supply system; second, promote networking, opening-up and synergy in the innovation system and third, promote the socialization, modularization and flexibility of production pattern. From the demand side, the digital economy can boost the new drivers of the “troika” of economic growth consisting of consumption, exports and investment by changing the market investment direction, promoting consumption upgrade and fostering export strengths. However, once these two attributes interact with each other, especially when data is combined with capital, the most adhesive factor in the market economy, a series of new social relations will then be produced based on the technical attribute, resulting in significant adjustments in social relations, involving both positive and negative externalities.

Originality/value

To overcome the “middle-income trap”, it is necessary to adapt to the laws of economic evolution and promote a fundamental change in economic growth drivers; boost the high-quality development of the digital economy by strengthening the support role of data in the digital economy; and accelerate digital industrialization and industrial digitalization to realize the integration of digital and real economies.
Moving toward a circular economy in manufacturing organizations: the role of circular stakeholder engagement practices
Authors: Fobbe Lea , Hilletofth Per
Published: November 2022

Purpose

The circular economy (CE) approach has been acknowledged as key for manufacturing organizations wishing to overcome sustainability challenges. However, the transition has been slow. Stakeholder engagement is a driver of the transition, but there is limited knowledge on stakeholder engagement practices in a CE context. The purpose of this paper is thus to explore with whom, on what and how organizations engage with stakeholders to implement CE as part of sustainability efforts.

Design/methodology/approach

This study is situated at the intersection of CE, stakeholder theory and supply chain literature. A case study with three Swedish manufacturing organizations was conducted to explore stakeholder engagement practices that facilitate the implementation of CE in organizational practice and the supply chain, considering conceptual differences between stakeholder engagement for sustainability and CE.

Findings

This study provides empirical evidence on how manufacturing organizations engage stakeholders to implement CE as part of organizations' sustainability efforts. The study highlights that manufacturing organizations have to move not only from linear to circular resource flows, but also from linear to circular stakeholder engagement. Such engagement can be achieved by extending with whom, expanding on what and leveling up how stakeholders are engaged.

Originality/value

This study provides an enhanced conceptual understanding of stakeholder engagement in the CE context and discusses differences regarding stakeholder engagement based on linear thinking. The study emphasizes the role of circular stakeholder engagement practices for the transition toward CE in manufacturing organizations.
The role of website features in the branding of higher education institutions
Authors: Ghorbanzadeh Davood
Published: November 2022

Purpose

This study investigates the effect of university website features and value co-creation behaviors of students on promoting brand image and brand reputation at Islamic Azad University in Iran.

Design/methodology/approach

The study is quantitative. Using convenience sampling techniques, a responsive group of 384 students was chosen from the Islamic Azad University of Tehran in Iran. Survey methods were used for data collection. Partial least squares-structural equation modeling was used to test the derived hypotheses.

Findings

The present research findings indicated that website features have a positive effect on fostering value co-creation behaviors (participation and citizenship behavior), and participation behavior, in turn, improves university's brand image and reputation. At the same time, among value co-creation behaviors, citizenship behavior has no impact on the university's brand image. Finally, the brand image formed through website features and participation behavior positively affects brand reputation.

Originality/value

These findings contribute to the marketing literature by empirically validating the three elements in the website features construct, providing intelligence on how website features can drive value co-creation behaviors, brand image and reputation.