bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering of a graphene oxide-based two-dimensional platform for immune activation and modulation
Authors: Despotopoulou Despoina , Stylianou Maria , Arellano Luis Miguel , Kisby Thomas , Lozano Neus , Kostarelos Kostas
Published: August 2023

Nanoscale-based tools for immunomodulation are expected to offer a rich battery of options for more targeted and safer approaches to achieve clinically effective manipulation of the local and systemic immune environment. In this study, we aimed to design nanoscale constructs based on graphene oxide (GO) nanosheets as platform carriers for the TLR7/8 agonist Resiquimod (R848). The non-covalent complexation of R848 molecules on the GO surface resulted in stable complexes by preserving their biological activity. The physicochemical properties, molecular quantification, as well as the overall performance of the complex were systematically investigated. We hypothesized the formation of GO:drug nano-constructs with strong colloidal stability over time, due to the strong π-π interactions between the R848 molecules and the GO surface, and identified that R848 loading efficiency consistently ranged around 75% (of starting molecules), quantified by HPLC and UV-Vis. The 2D morphology of the thin nanosheets was retained after complexation, determined by various (AFM and SEM) microscopic techniques. Based on the surface physicochemical characterization of the complexes by Raman, FTIR, XPS, and XRD, the formation of non-covalent interactions among the GO surface and the R848 molecules was confirmed. Most importantly, GO:R848 complexes did not compromise the biological activity of R848, and effectively activated macrophagesin vitro. Collectively, this study demonstrates that thin GO sheets can act as platforms for the non-covalent association with small TLR7/8 agonist molecules, forming stable and highly reproducible complexes, that could be exploited as effective immunomodulatory agents.
Making Proteomics Accessible: RokaiXplorer for interactive analysis of phospho-proteomic data
Authors: Yılmaz Serhan , Lopes Filipa Blasco Tavares Pereira , Schlatzer Daniela , Ayati Marzieh , Chance Mark R. , Koyutürk Mehmet
Published: August 2023

In this work, we present RokaiXplorer, an intuitive web tool designed to address the scarcity of user-friendly solutions for proteomics and phospho-proteomics data analysis and visualization. RokaiXplorer streamlines data processing, analysis, and visualization through an interactive online interface, making it accessible to researchers without specialized training in proteomics or data science. With its comprehensive suite of modules, RokaiXplorer facilitates the analysis of phosphosites, proteins, kinases, and gene ontology terms. The tool offers functionalities such as data normalization, statistical testing, enrichment analysis, subgroup analysis, report generator, and multiple visualizations, including volcano plots, bar plots, heatmaps, tables, and interactive networks. Additionally, RokaiXplorer allows researchers to effortlessly deploy their own data browsers, fostering the sharing of research data and findings interactively. By providing simplicity, efficiency, and multi-level data analysis within a single application, it is poised to become a valuable resource for the scientific community working with phospho-proteomic data. Access RokaiXplorer at:http://explorer.rokai.io
Sub-membrane actin rings compartmentalize the plasma membrane
Authors: Rentsch Jakob , Bandstra Selle , Sezen Batuhan , Sigrist Philipp Stephan , Bottanelli Francesca , Schmerl Bettina , Shoichet Sarah , Noé Frank , Sadeghi Mohsen , Ewers Helge
Published: August 2023

The compartmentalization of the plasma membrane is a fundamental feature of cells. The diffusivity of membrane proteins in the plane of the membrane is significantly lower in cells than observed in artificial membranes. This seems due to the sub-membranous actin cortex, but tractable assays to prove a direct dependence of membrane protein motion on actin filaments have been elusive. We recently showed that a periodic array of sub-membrane actin filaments that surround neuronal axons in ring-like structures in the axonal initial segment (AIS) confines membrane protein motion between them, but the local enrichment of ion channels may offer an alternative explanation for compartmentalization. Here we show using computational modeling that in contrast to actin rings, the dense array of ion channels in the AIS cannot mediate membrane protein confinement. We go on to show that indeed the actin rings are closely apposed to the plasma membrane, and that they confine membrane protein motion between them in a ∼ 200 nm periodic pattern in progenitor-derived neuronal cells. We find that this compartmentalization is also detectable for inner-leaflet membrane proteins and multi-spanning receptors. Strikingly, several cell types with actin rings in their protrusions, like progenitor-derived astrocytes and oligodendrocytes, also exhibit lateral confinement of membrane proteins in a periodic pattern consistent with actin ring spacing. Actin ring-mediated membrane compartmentalization is thus not unique to neurons. Finally, we show that acute actin disruption in live progenitor-derived neuronal cells leads to a loss of membrane compartmentalization in areas that were compartmentalized before treatment. Taken together, we here develop a much-needed tractable experimental system for the investigation of membrane compartmentalization and show that actin rings compartmentalize the plasma membrane of cells.
Guanidine Production by Plant Homoarginine-6-hydroxylases
Authors: Funck Dietmar , Sinn Malte , Forlani Giuseppe , Hartig Jörg S.
Published: August 2023

Metabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and two pathways for guanidine degradation in bacteria hint at widespread sources of unconjugated guanidine in nature. So far, only three enzymes from a narrow range of bacteria and fungi have been shown to produce guanidine, with the ethylene-forming enzyme (EFE) as the most prominent example. Here, we show that a related class of Fe2+- and 2-oxoglutarate-dependent dioxygenases (2-ODD-C23) highly conserved among plants and algae catalyze the hydroxylation of homoarginine at the C6-position. Spontaneous decay of 6-hydroxyhomoarginine yields guanidine and 2-aminoadipate-6-semialdehyde. The latter can be reduced to pipecolate by pyrroline-5-carboxylate reductase but more likely is oxidized to aminoadipate by aldehyde dehydrogenase ALDH7Bin vivo. Arabidopsis has three 2-ODD-C23 isoforms, among which Din11 is unusual because it also accepted arginine as substrate, which was not the case for the other 2-ODD-C23 isoforms from Arabidopsis or other plants. In contrast to EFE, none of the three Arabidopsis enzymes produced ethylene. Guanidine contents were typically between 10 and 20 nmol*(g fresh weight)-1in Arabidopsis but increased to 100 or 300 nmol*(g fresh weight)-1after homoarginine feeding or treatment with Din11-inducing methyljasmonate, respectively. In 2-ODD-C23 triple mutants, the guanidine content was strongly reduced, whereas it increased in overexpression plants. We discuss the implications of the finding of widespread guanidine-producing enzymes in photosynthetic eukaryotes as a so far underestimated branch of the bio-geochemical nitrogen cycle and propose possible functions of natural guanidine production.
Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans
Authors: Grover Manish , Gang Spencer S. , Troemel Emily R. , Barkoulas Michalis
Published: August 2023

Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF upregulates proteostasis capacity after blockade of the proteasome, and also promotes resistance against bacterial infection in the nematodeC. elegans. SKN-1/NRF has three isoforms, and the SKN-1A/NRF1 isoform in particular regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants inskn-1aand its activating enzymesddi-1andpng-1,show constitutive expression of immune response programmes against natural eukaryotic pathogens ofC. elegans. These programmes are the Oomycete Recognition Response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the Intracellular Pathogen Response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently,skn-1amutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programmes are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner, against natural eukaryotic pathogens of theC. elegansepidermis and intestine.
HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis inin vitroandin vivomodels of amyotrophic lateral sclerosis
Authors: Silvestri Beatrice , Mochi Michela , Mawrie Darilang , de Turris Valeria , Colantoni Alessio , Borhy Beatrice , Medici Margherita , Anderson Eric Nathaniel , Garone Maria Giovanna , Zammerilla Christopher Patrick , Pandey Udai Bhan , Rosa Alessandro
Published: August 2023

Early defects at the neuromuscular junction (NMJ) are among the first hallmarks of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). According to the “dying back” hypothesis, disruption of the NMJ not only precedes, but is also a trigger for the subsequent degeneration of the motoneuron in both sporadic and familial ALS, including ALS caused by the severeFUSpathogenic variant P525L. However, the mechanisms linking genetic and environmental factors to NMJ defects remain elusive. By taking advantage of co-cultures of motoneurons and skeletal muscle derived from human induced pluripotent stem cells (iPSCs), we show that the neural RNA binding protein HuD (ELAVL4) may underlie NMJ defects and apoptosis in FUS-ALS. HuD overexpression in motoneurons phenocopies the severe FUSP525Lmutation, while HuD knockdown in FUSP525Lco-cultures produces phenotypic rescue. We validated these findingsin vivoin aDrosophilaFUS-ALS model. Neuronal-restricted overexpression of the HuD-related gene,elav, producesper sea motor phenotype, while neuronal-restrictedelavknockdown significantly rescues motor dysfunction caused by FUS. Finally, we show that HuD levels increase upon oxidative stress in human motoneurons and in sporadic ALS patients with an oxidative stress signature. On these bases, we propose HuD as an important player downstream of FUS mutation in familial ALS, with potential implications for sporadic ALS related to oxidative stress.
The loss-of-function of SOCS2 increases the inflammatory response toStaphylococcus aureusinfection
Authors: Guzylack-Piriou Laurence , Gausseres Blandine , Tasca Christian , Hassel Chervin , Tabouret Guillaume , Foucras Gilles
Published: August 2023

The involvement of suppressor of cytokine signaling (SOCS)2 in anti-infective bacterial immunity remains largely undetermined compared to other members of the SOCS family. We developed a mouse model expressing the loss of function R96C SOCS2 point mutation to characterize the response of macrophages toStaphylococcus aureusand its TLR-ligand derivatives. The model resumes observations of gigantism done in Socs2-/- mice. Stimulation of bone-marrow-derived macrophages with various TLR-2 ligands showed upregulation of the pro-inflammatory cytokines IL-6 and TNF-α production only in cytokine-modulating environments that promote SOCS2 expression. Using this model, we showed that SOCS2 protein reduces STAT-5 phosphorylation in a short time frame upon TLR engagement. When SOCS2 is ablated, neutrophil and F4/80intLy6C+inflammatory macrophage recruitment, as well as IFN-γ and IL-10 concentrations are significantly increased uponS. aureusperitoneal infection. By lowering the pro-inflammatory environment, SOCS2 favors better healing during a systemic infection caused byS. aureus.
Virulence is associated with daily rhythms in the within-host replication of the malaria parasitePlasmodium chabaudi
Authors: Owolabi Alíz T. Y. , Schneider Petra , Reece Sarah E.
Published: August 2023

Asexually replicating stages of most malaria (Plasmodiumspp.) parasite species replicate synchronously within the red blood cells of their vertebrate host. Rhythmicity in this intraerythrocytic developmental cycle (IDC) enables parasites to maximise exploitation of the host and align transmission activities with the time of day that mosquito vectors blood feed. The IDC is also responsible for the major pathologies associated with malaria, and plasticity in the parasite’s rhythm can confer tolerance to antimalarial drugs. Both the severity of infection (virulence) and synchrony of the IDC vary across species and between genotypes ofPlasmodium, yet this variation is poorly understood. Theory predicts that virulence and IDC synchrony are negatively correlated and we tested this hypothesis using two closely related genotypes of the rodent malaria modelPlasmodium chabaudithat differ markedly in virulence. We also test the predictions that in response to perturbations to the timing (phase) of the IDC schedule relative to the phase of host rhythms (misalignment), the virulent parasite genotype recovers the correct phase relationship faster, incurs less fitness loss, and so, hosts benefit less from misalignment of the virulent genotype. Our predictions are partially supported; the virulent parasite genotype was less synchronous in some circumstances and recovered faster from misalignment. While hosts were less anaemic when infected by misaligned parasites, the extent of this benefit did not depend on parasite virulence. Overall, our results suggest that interventions to perturb the alignment between the IDC schedule and host rhythms, and increase synchrony between parasites within each IDC, could alleviate disease symptoms. However, virulent parasites, which are better at withstanding conventional antimalarial treatment, would also be intrinsically better able to tolerate such interventions.
MASH: Mediation Analysis of Survival Outcome and High-dimensional Omics Mediators with Application to Complex Diseases
Authors: Chi Sunyi , Flowers Christopher R , Li Ziyi , Huang Xuelin , Wei Peng
Published: August 2023

Environmental exposures such as cigarette smoking influence health out-comes through intermediate molecular phenotypes, such as the methylome, transcriptome, and metabolome. Mediation analysis is a useful tool for in-vestigating the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposures and health outcomes. However, little work has been done on mediation analysis when the mediators are high-dimensional and the outcome is a survival endpoint, and none of it has provided a robust measure of total mediation effect. To this end, we propose an estimation procedure forMediationAnalysis ofSurvival outcome andHigh-dimensional omics mediators (MASH) based on sure independence screening for putative mediator variable selection and a second-moment-based measure of total mediation effect for survival data analogous to theR2measure in a linear model. Extensive simulations showed good performance of MASH in estimating the total mediation effect and identifying true mediators. By applying MASH to the metabolomics data of 1919 subjects in the Framingham Heart Study, we identified five metabolites as mediators of the effect of cigarette smoking on coronary heart disease risk (total mediation effect, 51.1%) and two metabolites as mediators between smoking and risk of cancer (total mediation effect, 50.7%). Application of MASH to a diffuse large B-cell lymphoma genomics data set identified copy-number variations for eight genes as mediators between the baseline International Prognostic Index score and overall survival.
Interactions between temperature and nutrients determine the population dynamics of primary producers
Authors: Bieg Carling , Vasseur David
Published: August 2023

Global change is rapidly and fundamentally altering many of the processes regulating the flux of energy throughout ecosystems and although researchers now understand the effect of temperature on key rates (such as aquatic primary productivity), the theoretical foundation needed to generate forecasts of biomass dynamics and extinction risk remains underdeveloped. We develop new theory that describes the interconnected effects of nutrients and temperature on phytoplankton populations and show that the thermal response of equilibrium biomass (i.e., carrying capacity) always peaks at a lower temperature than for productivity (i.e., growth rate). This difference results from trade-offs between the thermal responses of growth, death, and per-capita impact on the nutrient pool, making this thermal mismatch highly general and applicable to widely used population models. We further show that non-equilibrium dynamics depend on the pace of environmental change relative to underlying vital rates, and that populations respond to variable environments differently at high vs. low temperatures due to thermal asymmetries.
Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease
Authors: Nuñez-Reza Karen J. , Lozano-Jiménez Isaac , Martínez-Hernández Leslie , Medina-Rivera Alejandra
Published: August 2023

Tolerogenic dendritic cells (tolDC) regulate the immune response, several clinical trials focused on autoimmune diseases use tolDC to promote immune tolerance response and Treg activation. Here we built a logical model for the tolerization cellular process of dendritic cells using IL10. By combining literature knowledge, microarray gene expression, and key tolDC markers, we ensembled a logical model that describes the obtention of tolDC using the IL10 signaling cascade that spawns the most tolerogenic phenotype. The model uses IL10 as input and the signaling cascade that trigger seven transcription factors (TFs), three previously known TFs in the IL10 response (STAT3, NFKB, STAT6), and four were incorporated based on our gene expression analysis (IRF8, TCF7L2, CEBPB, and TFCP2L1). Using our model, we generated mutantsin-silicoand identified that even when IL10 is present the single mutants for TCF7L2, IRF8, TFCP2L1, and STAT3 were not able to reach a tolDC stable state, highlighting the relevance of these TFs in the process. The current model sets a precedent that will help in the development of tolDC for future applications.
Control adjustment costs limit goal flexibility: Empirical evidence and a computational account
Authors: Grahek Ivan , Leng Xiamin , Musslick Sebastian , Shenhav Amitai
Published: August 2023

A cornerstone of human intelligence is the ability to flexibly adjust our cognition and behavior as our goals change. For instance, achieving some goals requires efficiency, while others require caution. Different goals require us to engage different control processes, such as adjusting how attentive and cautious we are. Here, we show that performance incurs control adjustment costs when people adjust control to meet changing goals. Across four experiments, we provide evidence of these costs, and validate a dynamical systems model explaining the source of these costs. Participants performed a single cognitively demanding task under varying performance goals (e.g., being fast or accurate). We modeled control allocation to include a dynamic process of adjusting from one’s current control state to a target state for a given performance goal. By incorporating inertia into this adjustment process, our model accounts for our empirical finding that people under-shoot their target control state more (i.e., exhibit larger adjustment costs) when goals switch rather than remain fixed (Study 1). Further validating our model, we show that the magnitude of this cost is increased when: distances between target states are larger (Study 2), there is less time to adjust to the new goal (Study 3), and goal switches are more frequent (Study 4). Our findings characterize the costs of adjusting control to meet changing goals, and show that these costs emerge directly from cognitive control dynamics. In so doing, they shed new light on the sources of and constraints on flexibility of goal-directed behavior.
Redox-enabled Electronic Interrogation and Feedback Control of Hierarchical and Networked Biological Systems
Authors: Wang Sally , Chen Chen-Yu , Rzasa John R. , Tsao Chen-Yu , Li Jinyang , VanArsdale Eric , Kim Eunkyoung , Zakaria Fauziah Rahma , Payne Gregory F. , Bentley William E.
Published: August 2023

We enable microelectronic devices to interrogate biology’s molecular communication, perform computations, and in real time control biological systems, including at several hierarchical levels: proteins, cells, and cell consortia. A key driver is establishing electronic access to and from biology’s native redox networks. First, redox-mediated electro-biofabrication facilitates facile assembly of biological components onto microelectronic systems, then electrode-actuated redox allows digital programming of enzyme activity, and further, redox-mediated electrogenetics facilitates closed-loop electronic control of cellular function. Specifically, we show algorithm-based feedback control of enzyme activity, cellular genetic circuits (via eCRISPR) and cell consortia behavior, all enabled by electronic data transfer. We further demonstrate electronic switching of cell-cell quorum sensing communication from one autoinducer network to another, creating an electronically controlled “bilingual” cell. We suggest these methodologies will not only help us to better understand biological systems, but design and control those currently unimagined.
An insect’s view of a numerosity illusion: a simple strategy may explain complex numerical performance in bumblebees
Authors: Gatto Elia , Guan Cui , Christian Agrillo , Cutini Simone , Chittka Lars , Petrazzini Maria Elena Miletto
Published: August 2023

Despite some similarities in numerical abilities among vertebrates, animals seem to differ with respect to the perceptual factors underlying numerical estimation. This is particularly evident in the case of numerosity illusions, a type of illusory phenomena elicited by the spatial arrangement of the elements that compose it. We investigated whether an insect experiences the most famous numerosity illusion, the Solitaire Illusion. Bumblebees (Bombus terrestris audax) presented with two mixed arrays containing magenta and yellow dots were trained to select the array containing the larger number of a target colour (either magenta or yellow). In the test phases, bumblebees were presented with sets of stimuli differing in the numerical ratio, including the illusory arrays: in one array, magenta dots were centrally located (yellow dots in the perimeter), whereas in the other one, magenta dots were located in the perimeter (yellow dots in the centre). Bees discriminated up to a ratio of 0.78 (14 vs. 18). Video analyses showed that bumblebees sequentially scanned the stimuli before making a choice. Bumblebees required longer scanning time for patterns with smaller numbers of reinforced colour dots, suggesting that bumblebees spent longer time on searching for more information or finding a reinforced arrangement of spatial dots before making an accurate decision. In the presence of the “illusion arrangement”, bees behaved in a manner consistent with misperception of numerosity, overestimating the number of centrally located dots. The spatial configuration of the stimuli influenced how the patterns were assessed: bees examined the clustered reinforced colour dots longer. Flying paths analysis suggested that bumblebees followed the paths formed by similar colour dots rather than counting each dot to make a numerical discrimination. These results challenge the notion that visual illusions can be inferred simply from evaluating choices of different visual patterns and reinforce the idea that multiple strategies can potentially be used to achieve seemingly similar cognitive outcomes. Detailed analyses of decision-making processes are essential to deduce the cognitive strategies underpinning discrimination tasks, whether they are numerical or other visual tasks.
Plant immunity activated and suppressed by a conserved effector protein family in mirid bugRiptortus pedestris
Authors: Zhou Jiangxuan , Yin Zhiyuan , Shen Danyu , Dong Yumei , Yang Yuxia , Zhang Qingsong , Ma Yurong , Pei Yong , Lu Wangshan , Zhang Yancong , Ai Gan , Yang Donglei , Wang Yuanchao , Dou Daolong , Xia Ai
Published: August 2023

Riptortus pedestris(Fabricius) a major soybean pest migrates into soybean fields during pod filling stage resulting in a leaf and stem staygreen while pods without beans syndrome. Given the agricultural importance of this species and the lack of characterized HAMP from piercing-sucking insects we performed a large scale of screening by expression of 87R. pedestrissalivary proteins with signal peptides inNicotiana benthamianaobtaining a candidate HAMP RPH1. RPH1 activated a series of PTI responses including ROS burst upregulation of defense marker genes such as PR1 WRKY7 WRKY8 Acre31 and CYP71D20 MAPK activation and biosynthesis of phytohormones in plants. RPH1 significantly enhances soybean resistance againstR. pedestrisfeeding. PRR coreceptors BAK1 and SOBIR1 were required for RPH1-induced PTI responses. Remarkably RPH1 homologs were widely distributed in herbivorous insects and majority of homologs from selected species induced cell death or ROS. Thus our results demonstrated that RPH1 is a conserved HAMP within chewing and piercing-sucking insects. We also discovered thatR. pedestrisevolved four paralogs to overcome the plant immunity triggered by RPH1. This study filled a major gap of HAMP identification from piercing-sucking insect and also deciphered a novel evasion strategy of plant immunity exploited by herbivorous insects.

One sentence summary

Riptortus pedestrisRPH1, a conserved HAMP in herbivores, activates a variety of PTI responses in plants. To couterdefense,R. pedestrisevolved four paralogs to suppress RPH1-induced PTI responses.

The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Ai Xia (xia@njau.edu.edu).
Connecting Thiamine Availability to the Microbial Community Composition in Chinook Salmon Spawning Habitats of the Sacramento River Basin
Authors: Suffridge Christopher P. , Shannon Kelly C. , Matthews H. , Johnson R. , Jeffres C. , Mantua N. , Ward Abigail E. , Holmes E. , Kindopp J. , Aidoo M. , Colwell F.
Published: August 2023

Thiamine Deficiency Complex (TDC) is a major emerging threat to global populations of culturally and economically important populations of salmonids. Salmonid eggs and embryos can assimilate exogenous thiamine, and evidence suggests that microbial communities in benthic environments can produce substantial amounts of thiamine. We therefore hypothesize that microbially produced thiamine in both riverine surface water and hyporheic zones could serve to rescue early life stages of salmonids suffering from TDC. The distributions of thiamine and its metabolically related compounds (dTRCs) have never been determined in freshwater systems. Similarly, the microbial cycling of these compounds has never been investigated. Here we determine that all dTRCs are present in femto-picomolar concentrations across diverse salmon spawning habitats in California’s Sacramento River system. We observed that thiamine concentrations in the Sacramento River are orders of magnitude lower than marine environments, indicating substantial differences in thiamine cycling between these two environments. Our data suggest that the hyporheic zone is likely the source of thiamine to the overlying surface water. Temporal variations in dTRC concentration were observed where highest concentrations were seen when Chinook salmon were actively spawning. Significant correlations were identified between the richness of differentially abundant ASVs and dTRC concentrations. The influence of these ASVs on dTRC concentrations provide evidence of dTRC cycling by microbes in the hyporheic zone, which would influence the conditions where embryonic salmon incubate. Together, these results indicate a connection between microbial communities in freshwater habitats and the availability of thiamine to spawning TDC-impacted California Central Valley Chinook salmon.
A Continuous Extension of Gene Set Enrichment Analysis using the Likelihood Ratio Test Statistics Identifies VEGF as a Candidate Pathway for Alzheimer’s disease
Authors: Mahzarnia Ali , Lutz Michael W. , Badea Alexandra
Published: August 2023

Background

Alzheimer’s disease involves brain pathologies such as amyloid plaque depositions and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand the disease etiology and devise therapies.

Objective

Our objective was to identify molecular pathways associated with AD biomarkers (Amyloid-β and tau) and cognitive status (MMSE) accounting for variables such as age, sex, education, and APOE genotype.

Methods

We introduce a novel pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (Amyloid-β, tau, cognition), using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved a large sample size with data available for all three phenotypes, allowing for the identification of common pathways.

Results

We identified 14 pathways significantly associated with Amyloid-β, 5 associated with tau, and 174 associated with MMSE. Surprisingly, the MMSE outcome showed a larger number of significant pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited significant associations with all three phenotypes.

Conclusions

The study’s findings highlight the importance of the VEGF signaling pathway in aging in AD. The complex interactions within the VEGF signaling family offer valuable insights for future therapeutic interventions.
Employing Machine Learning Techniques to Detect Protein-Protein Interaction: A Survey, Experimental, and Comparative Evaluations
Authors: Taha Kamal
Published: August 2023

This survey paper provides an in-depth analysis of various machine learning techniques and algorithms that are utilized in the detection of PPI (Protein-Protein Interactions). For every technique examined, the paper evaluates its efficiency, shortcomings, possibilities for enhancement, and outlook for the future. A major challenge in current survey papers focusing on machine learning algorithms for PPI identification is the successful categorization of these algorithms. To overcome this challenge, the paper introduces a novel hierarchical taxonomy that organizes algorithms into more intricate categories and distinct techniques. The proposed taxonomy is constructed on a four-tier structure, beginning with the broad methodology category, and ending with specific sub-techniques. This structure facilitates a more systematic and exhaustive categorization of algorithms, aiding researchers in grasping the connections between different algorithms and techniques. Included in the paper are both empirical and experimental assessments to classify the various techniques. The empirical assessment judges the techniques according to four standards. The experimental evaluations carry out the following rankings: (1) the algorithms that employ the same specific sub-technique, (2) the different sub-techniques that employ the same technique, (3) the different techniques that employ the same methodology sub-category, and (4) the different methodology sub-categories within the same methodology category. By merging the new methodological taxonomy, empirical analyses, and experimental evaluations, the paper provides a multifaceted and thorough comprehension of the machine learning methods and algorithms for PPI detection. This synthesis helps researchers make well-informed decisions. In its conclusion, the paper furnishes crucial insights into the future possibilities of machine learning techniques for PPI identification, underscoring potential advancements and areas ripe for continued exploration and development.
PreventingE. colibiofilm formation with antimicrobial peptide surface coatings: recognizing the dependence on the bacterial binding mode using live-cell microscopy
Authors: Hansson Adam , Karlsen Eskil André , Stensen Wenche , Svendsen John-Sigurd , Berglin Mattias , Lundgren Anders
Published: August 2023

Antimicrobial peptides (AMPs) can kill bacteria by destabilizing their membranes, yet, to translate these molecules’ properties into a covalently attached coating is challenging. Standard microbiology methods do not work well for grafted AMPs, particularly it is difficult to distinguish the AMPs’ bactericidal potency from factors relating to bacteria’s binding behavior, e.g., which type of and how persistent bacteria-surface contacts that is necessary. Here we present a method combining live-cell microscopy and microfluidics to study the response ofE. colichallenged by the same small AMP either in solution or grafted to the surface through click chemistry. The AMP coating initially suppressed bacterial growth as strongly as AMPs in solution. While AMPs in solution eventually killed theE. colibacteria, those binding to the AMP coating changed contact mode one hour after binding and then became insensitive to it. The transition depended on binding-induced expression of Type 1 fimbriae, which limits contact between the AMPs and theE. coliouter membrane. By quantifying several different factors contributing to the antibacterial efficacy, these measurements provide a holistic understanding of how antibacterial surface coatings function. We therefore expect this tool to be important for the design of elaborate antibacterial coatings that can reduce the need for antibiotics and thus contribute to slower spreading of antibiotic resistance genes.
Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice
Authors: Martino Michael R. , Habibi Mohammad , Ferguson Daniel , Brookheart Rita T. , Thyfault John P. , Meyer Gretchen A. , Lantier Louise , Hughey Curtis C. , Finck Brian N.
Published: August 2023

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.
Long-term history dependence of growth rates ofE. coliafter nutrient shifts
Authors: Christodoulou Dimitris , Mukherjee Avik , Wegmann Rebekka , Pagano Adriano , Sharma Varun , Linker Stephanie Maria , Chang Yu-Fang , Palme Julius Sebastian , Sauer Uwe , Basan Markus
Published: August 2023

According to a widely accepted paradigm of microbiology, steady-state growth rates are determined solely by current growth conditions1–3and adaptations between growth states are rapid, as recently recapitulated by simple resource allocation models4. However, even in microbes overlapping regulatory networks can yield multi-stability or long-term cellular memory. Species likeListeria monocytogenes5andBacillus subtilis“distinguish” distinct histories for the commitment to sporulation6, but it is unclear if these states can persist over many generations. Remarkably, studying carbon co-utilization ofEscherichia coli, we found that growth rates on combinations of carbon sources can depend critically on the previous growth condition. Growing in identical conditions, we observed differences in growth rates of up to 25% and we did not observe convergence of growth rates over 15 generations. We observed this phenomenon occurs across combinations of different phosphotransferase (PTS) substrates with various gluconeogenic carbon sources and found it to depend on the transcription factor Mlc.
The genome of a globally invasive passerine, the common myna (Acridotheres tristis)
Authors: Stuart Katarina C. , Johnson Rebecca N. , Major Richard , Atsawawaranunt Kamolphat , Ewart Kyle M. , Rollins Lee A. , Santure Anna W. , Whibley Annabel
Published: August 2023

In an era of global climate change and massive environmental disturbance, biodiversity conservation is receiving increased attention. Conservation efforts are being greatly aided by genetic tools and approaches, which seek to understand patterns of genetic diversity and how they impact species health and ability to persist under future climate regimes. Invasive species offer vital model systems in which to investigate questions around adaptive potential, with a particular focus on how changes in genetic diversity and effective population size interact with the novel selection regime of the invaded range to drive rapid evolution. The common myna (Acridotheres tristis) is a globally invasive passerine, which has undergone multiple concurrent and sequential bottlenecks across its globally invasive range, and yet has established itself across a diverse array of ecological conditions. It is therefore an excellent model species for research both into the persistence of low-diversity populations and the mechanics of biological invasion. To underpin research on the invasion genetics of this species, we present the genome assembly of the common myna, assembled using a backbone of Oxford Nanopore Technologies long reads, alongside an RNA-seq based transcriptome and genome annotation. To provide genomic context for future studies, we describe the genomic landscape of this species, including genome wide allelic diversity, methylation, repeats, and recombination rate, as well as an examination of gene family expansions and contractions. Finally, we use demographic analysis to identify that some native regions underwent a dramatic population increase between the two most recent periods of glaciation, but also reveal artefactual impacts of genetic bottlenecks on demographic analysis.
Evaluating single-cell variability in proteasomal decay
Authors: Das Sukanya , Singh Abhyudai , Shah Premal
Published: August 2023

Gene expression is a stochastic process that leads to variability in mRNA and protein abundances even within an isogenic population of cells grown in the same environment. This variation, often called gene-expression noise, has typically been attributed to transcriptional and translational processes while ignoring the contributions of protein decay variability across cells. Here we estimate the single-cell protein decay rates of two degron GFPs inSaccharomyces cerevisiaeusing time-lapse microscopy. We find substantial cell-to-cell variability in the decay rates of the degron GFPs. We evaluate cellular features that explain the variability in the proteasomal decay and find that the amount of 20s catalytic beta subunit of the proteasome marginally explains the observed variability in the degron GFP half-lives. We propose alternate hypotheses that might explain the observed variability in the decay of the two degron GFPs. Overall, our study highlights the importance of studying the kinetics of the decay process at single-cell resolution and that decay rates vary at the single-cell level, and that the decay process is stochastic. A complex model of decay dynamics must be included when modeling stochastic gene expression to estimate gene expression noise.
The resting and ligand-bound states of the membrane-embedded human T-cell receptor–CD3 complex
Authors: Notti Ryan Q. , Yi Fei , Heissel Søren , Bush Martin W. , Molvi Zaki , Das Pujita , Molina Henrik , Klebanoff Christopher A. , Walz Thomas
Published: August 2023

The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain(1–4). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR–CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the “open and extended” conformation seen in detergent(5–8), the unliganded TCR–CD3 in nanodiscs adopts two related “closed and compacted” conformations that represent its physiologic resting statein vivo. By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. Together, these results reveal allosteric conformational change during TCR activation and highlight the importance of native-like lipid environments for membrane protein structure determination.
Spectral decomposition unlocks ascidian morphogenesis
Authors: Dokmegang Joel , Faure Emmanuel , Lemaire Patrick , Munro Ed , Mani Madhav
Published: August 2023

Describing morphogenesis generally consists in aggregating the multiple high resolution spatiotemporal processes involved into reproducible low dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks, as they can be time consuming, hence unfit for scale, and often lack standardisation and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardised framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain-rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.
Pharmaceutical pollution alters the cost of bacterial infection and its relationship to pathogen load
Authors: Aulsebrook Lucinda C. , Wong Bob B.M. , Hall Matthew D.
Published: August 2023

The relationship between pathogen proliferation and the cost of infection experienced by a host drives the ecology and evolution of host-pathogen dynamics. While environmental factors can shape this relationship, there is currently limited knowledge on the consequences of emerging contaminants, such as pharmaceutical pollutants, for the commonly observed trade-off between a pathogen’s growth within the host and the damage it causes, termed its virulence. Here, we investigated how exposure to fluoxetine (Prozac), a commonly detected psychoactive pollutant, could alter this key relationship using the water fleaDaphnia magnaand its bacterial pathogenPasteuria ramosaas a model system. Across a variety of fluoxetine concentrations, we found that fluoxetine shaped the damage a pathogen caused, such as the reduction in fecundity or intrinsic growth experienced by infected individuals, but with minimal change in average pathogen spore loads. Instead, fluoxetine modified the relationship between the degree of pathogen proliferation and its virulence, with both the strength of this trade-off and the component of host fitness most affected varying by fluoxetine concentration and host genotype. Our study underscores the potential for pharmaceutical pollution to modify the virulence of an invading pathogen, as well as the fundamental trade-off between host and pathogen fitness, even at the trace amounts increasingly found in natural waterways.