bluuebunny/crossref_metadata_2025 huggingface dataset:
Data-driven spatio-temporal modelling of glioblastoma
Authors: Jørgensen Andreas Christ Sølvsten , Hill Ciaran Scott , Sturrock Marc , Tang Wenhao , Karamched Saketh R. , Gorup Dunja , Lythgoe Mark F. , Parrinello Simona , Marguerat Samuel , Shahrezaei Vahid
Published: March 2023

Mathematical oncology provides unique and invaluable insights into tumour growth on both the microscopic and macroscopic levels. This review presents state-of-the-art modelling techniques and focuses on their role in understanding glioblastoma, a malignant form of brain cancer. For each approach, we summarize the scope, drawbacks and assets. We highlight the potential clinical applications of each modelling technique and discuss the connections between the mathematical models and the molecular and imaging data used to inform them. By doing so, we aim to prime cancer researchers with current and emerging computational tools for understanding tumour progression. By providing an in-depth picture of the different modelling techniques, we also aim to assist researchers who seek to build and develop their own models and the associated inference frameworks. Our article thus strikes a unique balance. On the one hand, we provide a comprehensive overview of the available modelling techniques and their applications, including key mathematical expressions. On the other hand, the content is accessible to mathematicians and biomedical scientists alike to accommodate the interdisciplinary nature of cancer research.
Snakes on a slope: strong anti-gravitactic responses and differential habitat use in the Saharan horned viper (
Cerastes cerastes
) in the Negev desert
Authors: Dorfman Arik , Subach Aziz , Scharf Inon
Published: March 2023

The way species use their habitat dictates their intra- and interspecific interactions. We studied the effects of the microhabitat type and slope on the movement behaviour of the Saharan horned viper (
Cerastes cerastes
) in its natural habitat. This viper occurs in sand dunes and moves mostly by sidewinding. Additionally, we studied the microhabitat preference of desert rodents—the vipers' main prey. We placed the vipers on different natural dune slopes and recorded their behaviour. We found a strong anti-gravitactic response: vipers moved more frequently towards the top of the dune than in any other direction, despite a decrease in stride length with increasing slope. The foraging-related behaviour of the vipers was concentrated in the dune semi-stable areas rather than its stable or shifting sand areas. We measured rodent activity by placing seed trays in the dune allowing the rodents to collect seeds. Rodent activity was the highest in the shifting sands, closely followed by the semi-stable microhabitat. These results suggest the vipers use the semi-stable microhabitat mainly for foraging and may use the shifting sand areas as commuting routes between such areas. This study may be of use for conservation efforts of psammophilic species in desert dunes.
A new Middle Triassic (Ladinian) trilophosaurid stem-archosaur from Germany increases diversity and temporal range of this clade
Authors: Sues Hans-Dieter , Schoch Rainer R.
Published: March 2023

We report the first trilophosaurid stem-archosaur from Central Europe,
Rutiotomodon tytthos
gen. et sp. nov., from the Middle Triassic (Ladinian) Erfurt Formation of Baden-Württemberg (Germany). It is currently known from two jaw fragments with distinctive teeth. The labiolingually wide but mesiodistally narrow maxillary and dentary teeth each have a large labial cusp from which an occlusal ridge extends lingually to a small lingual cusp. A mesial and a distal cingulum extend between the labial and lingual cusps. The mesial and distal faces of the labial cusp each bear three prominent, lingually curved apicobasal ridges (arrises). A referred partial dentary has an edentulous, expanded symphysis similar to the mandibular ‘beak' in
Trilophosaurus buettneri
. A review of
Coelodontognathus ricovi
, from the Lower Triassic (Olenekian) of southwestern Russia, supports its referral to Trilophosauridae rather than Procolophonidae. Based on this reassessment and the new material from the Middle Triassic, the temporal range of trilophosaurids now spans nearly the entire Triassic Period, from the Olenekian to the Rhaetian. Trilophosaurids present craniodental features that indicate omnivory or herbivory with limited oral food processing. They were more diverse in terms of dental structure (and presumably diet) than previously assumed.
Staphylococcus aureus FadB is a dehydrogenase that mediates cholate resistance and survival under human colonic conditions
Authors: Alsultan Amjed , Walton Gemma , Andrews Simon C. , Clarke Simon R.
Published: March 2023

Staphylococcus aureus

is a common colonizer of the human gut and in doing so it must be able to resist the actions of the host’s innate defences. Bile salts are a class of molecules that possess potent antibacterial activity that control growth. Bacteria that colonize and survive in that niche must be able to resist the action of bile salts, but the mechanisms by which

S. aureus

does so are poorly understood. Here we show that FadB is a bile-induced oxidoreductase which mediates bile salt resistance and when heterologously expressed in

Escherichia coli

renders them resistant. Deletion of fadB attenuated survival of

S. aureus

in a model of the human distal colon.
Fungal organic acid uptake of mineral derived K is dependent on distance from carbon hotspot
Authors: Bhattacharjee Arunima , Velickovic Dusan , Richardson Jocelyn A. , Couvillion Sneha P. , Vandergrift Gregory W. , Qafoku Odeta , Taylor Michael J. , Jansson Janet K. , Hofmockel Kirsten S. , Anderton Christopher R.
Published: March 2023

Fungal mineral weathering processes regulate the bioavailability of inorganic nutrients from mineral surfaces to organic matter and increase the bioavailable fraction of nutrients. Fungal mineral weathering strategies can be classified as biomechanical (direct) or biochemical (indirect). In the case of fungal uptake of mineral nutrients through indirect weathering, it is widely hypothesized that uptake of mineral derived nutrients occurs through organic acid chelation, but such processes have not been directly visualized. This is in part due to challenges in probing the complex and heterogeneous soil environment. Here, using an epoxy-based mineral doped soil micromodel platform that we developed, which mimics soil mineralogy and structure, it permitted us to visualize and spatially probe the molecular mechanisms of mineral weathering. Mass spectrometry imaging revealed differences in the distribution of fungal exudates, citric acid and tartaric acid, on the soil micromodels in presence of minerals. Citric acid was detected closer to the nutrient rich inoculation point, whereas tartaric acid was highly abundant away from inoculation point. This suggested that the organic acid exuded by the fungi depended on the proximity from the carbon rich organic substrate at the point of inoculation. Using a combination of X-ray fluorescence and X-ray near edge structure analysis, we identified citric acid- and tartaric acid-bound K within fungal hyphae networks grown in the presence of minerals. Combined our results provide direct evidence that fungi uptake and transport mineral derived nutrient organic acid chelation. The results of this study provided unprecedented visualization of fungal weathering of soil minerals and hyphal K+transport, while resolving the indirect weathering mechanism of fungal K uptake from mineral interfaces.
Phyllosphere fungal diversity generates pervasive non-additive effects on plant performance
Authors: Almeida Brianna K. , Tran Elan H. , Afkhami Michelle E.
Published: March 2023

All plants naturally harbor diverse microbiomes that can dramatically impact their health and productivity. However, it remains unclear how microbiome diversity, especially in the phyllosphere, impacts intermicrobial interactions and consequent non-additive effects on plant productivity.

Combining manipulative experiments, field collections, culturing, microbiome sequencing, and synthetic consortia, we experimentally tested for the first time how foliar fungal community diversity impacts plant productivity. We inoculated morning glories with 32 synthetic phyllosphere communities of either low or high diversity or with single fungal taxa, and measured effects on plant productivity and allocation.

We found 1) non-additive effects were pervasive with 56% of microbial communities interacting synergistically or antagonistically to impact plant productivity, including some consortia capable of generating acute synergism (e.g., >1000% increase in productivity above the additive expectation), 2) interactions among ‘commensal’ fungi were responsible for this non-additivity in diverse communities, 3) synergistic interactions were ~4 times stronger than antagonistic effects, 4) fungal diversity affected the magnitude but not frequency or direction of non-additivity, and 5) diversity affected plant performance nonlinearly with highest performance in low microbial diversity treatments.

These findings highlight the importance of interpreting plant-microbial interactions under a framework that incorporates intermicrobial interactions and non-additive outcomes to understand natural complexity.
RecurringEPHB1mutations in human cancers alter receptor signalling and compartmentalisation of colorectal cancer cells
Authors: Kundu Snehangshu , Nunes Luís , Adler Jeremy , Mathot Lucy , Stoimenov Ivaylo , Sjöblom Tobias
Published: March 2023

Ephrin (EPH) receptors have been implicated in tumorigenesis and metastasis, but the functional understanding of mutations observed in human cancers is limited. We previously demonstrated reduced cell compartmentalisation for somaticEPHB1mutations found in metastatic colorectal cancer cases. We, therefore, integrated pan-cancer and pan-EPH mutational data to prioritise recurrentEPHB1mutations for functional studies to understand their contribution to cancer development and metastasis. Here, 79,151 somatic mutations in 9,898 samples of 33 different tumour types were analysed to find 3D-mutated cluster pairs and recurring hotspot mutations in EPH receptors. From these, 15 recurringEPHB1mutations were stably expressed in colorectal cancer cells. Whereas the ligand-binding domain mutations C61Y, R90C, and R170W, the fibronectin domain mutation R351L, and the kinase domain mutation D762N displayed reduced to strongly compromised cell compartmentalisation, the kinase domain mutations R743W and G821R enhanced this phenotype. While mutants with reduced compartmentalisation also had reduced ligand induced receptor phosphorylation, the enhanced compartmentalisation was not linked to receptor phosphorylation level. Phosphoproteome mapping pinpointed the PI3K pathway and PIK3C2B phosphorylation in cells harbouring mutants with reduced compartmentalisation. This is the first integrative study of pan-cancer EPH receptor mutations followed byin vitrovalidation, a robust way to identify cancer-causing mutations.
Kinetic stabilization of translation-repression condensates by a neuron-specific microexon
Authors: Garcia-Cabau Carla , Bartomeu Anna , Tesei Giulio , Cheung Kai Chit , Pose-Utrilla Julia , Picó Sara , Balaceanu Andreea , Duran-Arqué Berta , Fernández-Alfara Marcos , Martín Judit , Pace Cesare De , Ruiz-Pérez Lorena , García Jesús , Battaglia Giuseppe , Lucas José J. , Hervás Rubén , Lindorff-Larsen Kresten , Méndez Raúl , Salvatella Xavier
Published: March 2023

The inclusion of microexons by alternative splicing is frequent in neuronal proteins. The roles of these sequences are in most cases unknown, but changes in their degree of inclusion are associated with neurodevelopmental diseases. We recently found that the decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, an RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD). Why this microexon is required and how small changes in its degree of inclusion generate a dominant-negative effect on the expression of ASD-linked genes is not clear. Here we show that neuronal CPEB4 forms condensates that dissolve upon depolarization, a transition associated with a switch from translational repression to activation. Heterotypic intermolecular interactions between the microexon and a cluster of histidine residues kinetically stabilize the condensates by competing with homotypic interactions between clusters, that otherwise lead to the irreversible aggregation of CPEB4. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.
Exploiting cryo-EM structures of actomyosin-5a to reveal the physical properties of its lever
Authors: Gravett Molly S.C. , Klebl David P. , Harlen Oliver G. , Read Daniel J. , Harris Sarah A. , Muench Stephen P. , Peckham Michelle
Published: March 2023

Myosin 5a transports cellular cargos along actin filaments towards the cell periphery. Its long lever plays a key role in determining the large size of its powerstoke, stepping distance along F-actin, ability to bear load and its regulation by Ca2+. Despite this, little is known about the physical properties of the lever and how they contribute to the mechanics of walking. Using a combination of cryo-electron microscopy and molecular dynamics simulations, we resolved the first structure of myosin 5a comprising the motor domain and full-length lever (subfragment-1) bound to actin. From the flexibility captured in the cryo-electron microscopy data, we were able to characterise the stiffness of the lever. Here, we demonstrate how the structure and flexibility of the lever contribute to the regulation and walking behaviour of myosin 5a.
Ability of Caprini and Padua Risk-Assessment Models to Predict Venous Thromboembolism in a Nationwide Study
Authors: Hayssen Hilary , Sahoo Shalini , Nguyen Phuong , Mayorga-Carlin Minerva , Siddiqui Tariq , Englum Brian , Slejko Julia F , Mullins C. Daniel , Yesha Yelena , Sorkin John D , Lal Brajesh K
Published: March 2023

Background

Venous thromboembolism (VTE) is a preventable complication of hospitalization. Risk-stratification is the cornerstone of prevention. The Caprini and Padua are the most commonly used risk-assessment models to quantify VTE risk. Both models perform well in select, high-risk cohorts. While VTE risk-stratification is recommended for all hospital admissions, few studies have evaluated the models in a large, unselected cohort of patients.

Methods

We analyzed consecutive first hospital admissions of 1,252,460 unique surgical and non-surgical patients to 1,298 VA facilities nationwide between January 2016 and December 2021. Caprini and Padua scores were generated using the VA’s national data repository. We first assessed the ability of the two RAMs to predict VTE within 90 days of admission. In secondary analyses, we evaluated prediction at 30 and 60 days, in surgical versus non-surgical patients, after excluding patients with upper extremity DVT, in patients hospitalized ≥72 hours, after including all-cause mortality in the composite outcome, and after accounting for prophylaxis in the predictive model. We used area under the receiver-operating characteristic curves (AUC) as the metric of prediction.

Results

A total of 330,388 (26.4%) surgical and 922,072 (73.6%) non-surgical consecutively hospitalized patients (total n=1,252,460) were analyzed. Caprini scores ranged from 0-28 (median, interquartile range: 4, 3-6); Padua scores ranged from 0-13 (1, 1-3). The RAMs showed good calibration and higher scores were associated with higher VTE rates. VTE developed in 35,557 patients (2.8%) within 90 days of admission. The ability of both models to predict 90-day VTE was low (AUCs: Caprini 0.56 [95% CI 0.56-0.56], Padua 0.59 [0.58-0.59]). Prediction remained low for surgical (Caprini 0.54 [0.53-0.54], Padua 0.56 [0.56-0.57]) and non-surgical patients (Caprini 0.59 [0.58-0.59], Padua 0.59 [0.59-0.60]). There was no clinically meaningful change in predictive performance in patients admitted for ≥72 hours, after excluding upper extremity DVT from the outcome, after including all-cause mortality in the outcome, or after accounting for ongoing VTE prophylaxis.

Conclusions

Caprini and Padua risk-assessment model scores have low ability to predict VTE events in a cohort of unselected consecutive hospitalizations. Improved VTE risk-assessment models must be developed before they can be applied to a general hospital population.
The correlation between medial pattern of intracranial arterial calcification and white matter hyperintensities
Authors: Du Heng , Zheng Jianrong , Li Xuelong , Dong Yanjing , Cheng Yajing , Liu Cong , Hu Jun , Chen Xiangyan
Published: March 2023

Background

Despite previously reported correlations between intracranial arterial calcification (IAC) and white matter hyperintensities (WMH), little is known about the relationship between IAC pattern and WMH. By differentiating intimal and medical IAC, we aimed to investigate the relationship between IAC pattern and WMH.

Methods

Consecutive patients with acute ischemic stroke were included. IAC pattern was categorized as intimal or medial on plain brain CT. The number of cerebral arteries involved by IAC for each patient was recorded. IAC severity of each artery was defined as focal or diffuse. On brain MRI, the burden of WMH was graded on a visual rating scale and classified as absent mild, moderate and severe. Multiple logistic regression was performed to examine the relationship between IAC and WMH.

Results

Among 265 recruited patients, intimal IAC was detected in 54.7% patients, medial IAC in 48.5% patients and coexistent (intimal and medial) IAC in 52.1% patients. Diffuse IAC was in 27.9% patients, all of which were medial IACs. WMH was found in 75.5% patients, including 105 patients (39.6%) with mild WMH, 69 (26.0%) with moderate WMH and 26 (9.8%) with severe WMH. The presence and severity of medial IAC were correlated with WMH occurrence (p<0.001, respectively). Chi-square linear trend suggested the number of arteries involved by medial IAC (p<0.001) and the severity of medial IAC (p<0.001) were correlated with WMH burden. After adjusting age, hypertension, history of stroke and history of ischemic heart disease, multiple ordinal regression demonstrated a positive correlation between the number of arteries involved by medial IAC (p<0.001) and the severity of medial IAC (p<0.001) with the overall burden of WMH.

Conclusions

Medial IAC was correlated with the burden of WMH. The dose-effect relationship between IAC and WMH suggests the need of further investigations on shared underlying mechanisms of intracranial large artery disease and cerebral small vessel disease.
Reproductive tactics, birth timing and the trade-off between risk avoidance and foraging in an income breeder
Authors: Benoit Laura , Morellet Nicolas , Bonnot Nadège C. , Cargnelutti Bruno , Chaval Yannick , Gaillard Jean-Michel , Loison Anne , Lourtet Bruno , Marchand Pascal , Coulon Aurélie , Hewison A.J. Mark
Published: March 2023

The behavioural trade-off between foraging and risk avoidance is expected to be particularly acute during gestation and lactation, when the energetic demands of reproduction peak. We investigated how female roe deer, an income breeding ungulate, adjust their management of this trade-off during the birth period in terms of foraging activity and habitat use. We showed that activity levels of reproductive females more than doubled immediately following parturition, when energy demand is highest. Moreover, reproductive females increased their use of open habitat during daytime and ranged closer to roads, but slightly further from refuge woodland, compared to non-reproductive females. However, these post-partum modifications in behaviour were particularly pronounced in late-parturient females who adopted a more risk prone tactic, presumably to compensate for the fitness handicap of their late-born offspring. In income breeders, individuals that give birth late may be forced to trade risk avoidance for resource acquisition during peak allocation to reproduction, likely with significant fitness consequences.
Repetitive transcranial magnetic stimulation (rTMS) triggers dose-dependent homeostatic rewiring in recurrent neuronal networks
Authors: Anil Swathi , Lu Han , Rotter Stefan , Vlachos Andreas
Published: March 2023

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to induce neuronal plasticity in healthy individuals and patients. Designing effective and reproducible rTMS protocols poses a major challenge in the field as the underlying biomechanisms remain elusive. Current clinical protocol designs are often based on studies reporting rTMS-induced long-term potentiation or depression of synaptic transmission. Herein, we employed computational modeling to explore the effects of rTMS on long-term structural plasticity and changes in network connectivity. We simulated a recurrent neuronal network with homeostatic structural plasticity between excitatory neurons, and demonstrated that this mechanism was sensitive to specific parameters of the stimulation protocol (i.e., frequency, intensity, and duration of stimulation). The feedback-inhibition initiated by network stimulation influenced the net stimulation outcome and hindered the rTMS-induced homeostatic structural plasticity, highlighting the role of inhibitory networks. These findings suggest a novel mechanism for the lasting effects of rTMS, i.e., rTMS-induced homeostatic structural plasticity, and highlight the importance of network inhibition in careful protocol design, standardization, and optimization of stimulation.

Author summary

The cellular and molecular mechanisms of clinically employed repetitive transcranial magnetic stimulation (rTMS) protocols remain not well understood. However, it is clear that stimulation outcomes depend heavily on protocol designs. Current protocol designs are mainly based on experimental studies that explored functional synaptic plasticity, such as long-term potentiation of excitatory neurotransmission. Using a computational approach, we sought to address the dose-dependent effects of rTMS on the structural remodeling of stimulated and non-stimulated connected networks. Our results suggest a new mechanism of action—activity-dependent homeostatic structural remodeling—through which rTMS may assert its lasting effects on neuronal networks.

We showed that the effect of rTMS on structural plasticity critically depends on stimulation intensity, frequency, and duration and that recurrent inhibition can affect the outcome of rTMS-induced homeostatic structural plasticity. These findings emphasize the use of computational approaches for an optimized rTMS protocol design, which may support the development of more effective rTMS-based therapies.
Involvement of the putative metal efflux protein YbeX in ribosomal metabolism
Authors: Sarıgül İsmail , Žukova Amata , Alparslan Emel , Pihlak Margus , Remm Sille , Tenson Tanel , Maiväli Ülo
Published: March 2023

YbeX ofEscherichia coli, a member of CorC protein family, is a putative Co2+/ Mg2+efflux factor. Here, we describe severalΔybeXphenotypes and report an involvement of YbeX in ribosomal metabolism.E. colilackingybeXhas a longer lag phase on outgrowth from the stationary phase. This phenotype is heterogeneous at the individual cell level and can be rescued by supplementing the growth media with magnesium.ΔybeXstrain is sensitive to elevated growth temperatures and to several ribosome-targeting antibiotics, which have a common ability to induce the cold shock response inE. coli.ΔybeXcells accumulate distinct 16S rRNA degradation intermediates present in both 30S particles and 70S ribosomes. We propose that a function of YbeX is maintaining the magnesium homeostasis in the cell, which is needed for proper ribosomal assembly.
SARS-CoV-2 infection induces dopaminergic neuronal loss in midbrain organoids during short and prolonged cultures
Authors: Jarazo Javier , da Silva Eveline Santos , Glaab Enrico , Perez-Bercoff Danielle , Schwamborn Jens C.
Published: March 2023

COVID-19 is mainly associated with respiratory symptoms, although several reports showed that SARS-CoV-2 affects the nervous system. We evaluated the effects of infection in prolonged culture of midbrain organoids, showing that the virus induces changes in gene expression, and fragmentation and loss of dopaminergic neurons. Our findings highlight the direct viral-induced damage to midbrain organoids indicating the relevance of assessing the neurological long-term evolution of COVID-19 patients.
Understanding accommodative control in the clinic: modeling latency and amplitude for uncorrected refractive error, presbyopia and cycloplegia
Authors: Read Jenny C. A. , Maus Gerrit , Schor Clifton M.
Published: March 2023

Accommodation refers to the process of increasing the optical power of the eye’s crystalline lens so as to focus on objects at different distances. Refractive error is a mismatch between the physical size of the eye and its optical power when accommodation is fully relaxed, while functional presbyopia is a decrease in the range of accommodation with age that results in the near point of accommodation lying beyond the near working distance. Both conditions mean that sharp focus may not be achievable for some distances, and observers will experience sustained defocus. A familiar example is an older person struggling to read text on their phone. Here, we identify a problem with current models of the neural control of accommodation: they predict excessive internal responses to stimuli outside the range of accommodation, leading to unrealistic adaptation effects. Specifically, after a prolonged period of viewing stimuli outside their accommodative range, current models predict that observers would show long latencies in the accommodative response to stimuli within range. These latencies are not observed empirically, indicating a problem with current models. We propose a simple solution, exploiting the predictive nature of accommodative control, and demonstrate that the new model performs correctly. We also model cycloplegia as a change in gain, and include a lower bound on the neural signal driving accommodation so as to model the additional relaxation of accommodation often seen with cycloplegia. We show that with these modifications, we can obtain plausible predictions for the accommodative response and accommodative convergence signal in a wide range of clinically relevant situations such as functional presbyopia, fogging lenses, corrected and uncorrected refractive error, and cycloplegia.
How a highly acidic SH3 domain folds in the absence of its charged peptide target
Authors: Jaramillo-Martinez Valeria , Dominguez Matthew J. , Bell Gemma M , Souness Megan E , Carhart Anna H. , Cuibus M. Adriana , Masoumzadeh Elahe , Lantz Benjamin J , Adkins Aaron J , Latham Michael P , Ball K. Aurelia , Stollar Elliott J
Published: March 2023

Charged residues on the surface of proteins are critical for both protein stability and interactions. However, many proteins contain binding regions with a high net-charge that may destabilize the protein but are useful for binding to oppositely charged targets. We hypothesized that these domains would be marginally stable, as electrostatic repulsion would compete with favorable hydrophobic collapse during folding. Furthermore, by increasing the salt concentration we predict that these protein folds would be stabilized by mimicking some of the favorable electrostatic interactions that take place during target binding. We varied the salt and urea concentrations to probe the contributions of electrostatic and hydrophobic interactions for the folding of the 60-residue yeast SH3 domain found in Abp1p. The SH3 domain was significantly stabilized with increased salt concentrations according to the Debye-Huckel limiting law. Molecular dynamics and NMR show that sodium ions interact with all 15 acidic residues but do little to change backbone dynamics or overall structure. Folding kinetics experiments show that the addition of urea or salt primarily affects the folding rate, indicating that almost all the hydrophobic collapse and electrostatic repulsion occurs in the transition state. After the transition state formation, modest yet favorable short-range salt-bridges are formed along with hydrogen bonds, as the native state fully folds. Thus, hydrophobic collapse offsets electrostatic repulsion to ensure this highly charged binding domain can still fold and be ready to bind to its charged peptide targets, a property that is likely evolutionarily conserved over one billion years.

Statement for broader audience

Some protein domains are highly charged because they are adapted to bind oppositely charged proteins and nucleic acids. However, it is unknown how these highly charged domains fold as during folding there will be significant repulsion between like-charges. We investigate how one of these highly charged domains folds in the presence of salt, which can screen the charge repulsion and make folding easier, allowing us to understand how folding occurs despite the protein’s high charge.

Supplementary material

Supplementary material document containing additional details on protein expression methods, thermodynamics and kinetics equations, and the effect of urea on electrostatic interactions, as well as 4 supplemental figures and 4 supplemental data tables. (Supplementary_Material.docx), 15 pages

Supplemental excel file containing covariation data across AbpSH3 orthologs (FileS1.xlsx)
WITHDRAWN: The influence of the bullseye versus standard fixation cross on eye movements and classifying natural images from EEG
Authors: Häberle Greta , Çelikkol Aynur Pelin , Cichy Radoslaw M.
Published: March 2023

Withdrawn Statement

The authors have withdrawn this manuscript because we detected fundamental errors in the formula we used to convert eye tracking data (x and y coordinates) from pixels to degrees. After addressing these errors, the results changed considerably. On the one hand, the behavioral results point towards differences for the bullseye versus the standard fixation cross different and larger than originally reported. However, the eyetracking decoding difference between standard and bullseye fixation cross is no longer significant. Therefore, the main claim of the paper – that bullseye fixation cross leads to lower eye movements compared to standard fixation cross, in turn resulting in lower decoding performance of object identity for eyetracking and EEG data – no longer stands. Given this change in the main results, we therefore withdraw the preprint.. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
MIL Cell – A tool for multi-scale simulation of yeast replication and prion transmission
Authors: Hall Damien
Published: March 2023

Abstract

The single celled baker’s yeast,Saccharomyces cerevisiae, can sustain a number of amyloid-based prions, with the three most prominent examples being [URE3] formed from the Ure2 protein (a regulator of nitrogen catabolism), [PSI+] formed from the Sup35 protein (a yeast translation termination release factor) and [PIN+] formed from the Rnq1 protein (of as yet unknown function). In a laboratory environment, haploidS. cerevisiaecells of a single mating type can acquire an amyloid prion in one of two ways (i.) Spontaneous nucleation of the prion within the yeast cell, and (ii.) Receipt via mother-to-daughter transmission during the cell division cycle. Similarly, prions can be lost from a yeast due to (i) Dissolution of the prion amyloid by its breakage into non-amyloid monomeric units, or (ii) Preferential donation/retention of prions between the mother and daughter during cell division. Here we present a computational tool, called MIL-CELL, for modelling these four general processes using a multiscale approach that is able to describe both spatial and kinetic aspects of the yeast life cycle and the amyloid- prion behavior. The yeast growth cycle is considered in two stages, a mature yeast that is competent to bud (M), and a daughter yeast (D) defined as a fully grown and detached bud. In the virtual plate experiment each transition in yeast growth is stochastically regulated, according to temporal and spatial characteristics, in a manner able to incorporate concepts of confluent growth. Between the relatively coarse time-points used for the particle level description, a set of differential equations, describing the nucleation, growth, fragmentation and clumping of amyloid fibrils, is solved numerically, for each individual yeast cell. Distribution of amyloid between the mother and the daughter is carried out by solving a set of kinetic partition equations between mother and the newly forming (and still attached) daughter during the yeast budding stage. In this paper we describe the workings of the model, the assumptions upon which it is based and some interesting simulation results that pertain to wave-like spread of the epigenetic prion elements through the yeast population. MIL-CELL (MonitoringInduction andLoss of prions inCells) is provided as a stand-alone graphical user interface-based executable program for free download with the paper (supplementary section).

MIL-CELL download:

https://drive.google.com/drive/folders/1xNBSL_2sGNkyXfYLYUyXjyM9ibGAcQUL?usp=sharing
Age differences in neural distinctiveness during memory retrieval versus reinstatement
Authors: Pauley Claire , Kobelt Malte , Werkle-Bergner Markus , Sander Myriam C.
Published: March 2023

Robust evidence points to mnemonic deficits in older adults related to dedifferentiated, i.e., less distinct, neural responses during memory encoding. However, less is known about retrieval-related dedifferentiation and its role in age-related memory decline. In this study, younger and older adults were scanned both while incidentally learning face and house stimuli and while completing a surprise recognition memory test. Using pattern similarity searchlight analyses, we looked for indicators of neural dedifferentiation during retrieval and asked whether this might explain interindividual differences in memory performance. Our findings revealed age-related reductions in neural distinctiveness during memory retrieval as well as in encoding-retrieval reinstatement in visual processing regions. We further demonstrated that the degree to which patterns elicited during encoding were reinstated during retrieval tracked variability in memory performance better than retrieval-related distinctiveness only. All in all, we contribute to meager existing evidence for age-related neural dedifferentiation during memory retrieval. We propose that the recognition task (as opposed to a cued recall task) may have revealed impairment in perceptual processing in older adults, leading to particularly widespread age differences in neural distinctiveness. We additionally provide support for the idea that well-defined reactivation of encoding patterns plays a major role in successful memory retrieval.
A novel miR-99b-5p-Zbp1pathway in microglia contributes to the pathogenesis of schizophrenia
Authors: Kaurani Lalit , Islam Md Rezaul , Heilbronner Urs , Krüger Dennis M. , Zhou Jiayin , Methi Aditi , Strauss Judith , Pradhan Ranjit , Burkhardt Susanne , Pena Tonatiuh , Erlebach Lena , Bühler Anika , Budde Monika , Senner Fanny , Kohshour Mojtaba Oraki , Schulte Eva C. , Schmauß Max , Reininghaus Eva Z. , Juckel Georg , Kronenberg-Versteeg Deborah , Delalle Ivana , Odoardi Francesca , Flügel Alexander , Schulze Thomas G. , Falkai Peter , Sananbenesi Farahnaz , Fischer Andre
Published: March 2023

Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended onZ-DNA binding protein 1(Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) againstZbp1ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibitZbp1could become a novel therapeutic strategy.
A spinal synergy of excitatory and inhibitory neurons coordinates ipsilateral body movements
Authors: Hayashi Marito , Gullo Miriam , Senturk Gokhan , Di Costanzo Stefania , Nagasaki Shinji C. , Kageyama Ryoichiro , Imayoshi Itaru , Goulding Martyn , Pfaff Samuel L. , Gatto Graziana
Published: March 2023

Innate and goal-directed movements require a high-degree of trunk and appendicular muscle coordination to preserve body stability while ensuring the correct execution of the motor action. The spinal neural circuits underlying motor execution and postural stability are finely modulated by propriospinal, sensory and descending feedback, yet how distinct spinal neuron populations cooperate to control body stability and limb coordination remains unclear. Here, we identified a spinal microcircuit composed of V2 lineage-derived excitatory (V2a) and inhibitory (V2b) neurons that together coordinate ipsilateral body movements during locomotion. Inactivation of the entire V2 neuron lineage does not impair intralimb coordination but destabilizes body balance and ipsilateral limb coupling, causing mice to adopt a compensatory festinating gait and be unable to execute skilled locomotor tasks. Taken together our data suggest that during locomotion the excitatory V2a and inhibitory V2b neurons act antagonistically to control intralimb coordination, and synergistically to coordinate forelimb and hindlimb movements. Thus, we suggest a new circuit architecture, by which neurons with distinct neurotransmitter identities employ a dual-mode of operation, exerting either synergistic or opposing functions to control different facets of the same motor behavior.
Resonant inelastic X-ray scattering endstation at the 1C beamline of Pohang Light Source II
Authors: Kim Jin-Kwang , Dietl Christopher , Kim Hyun-Woo J. , Ha Seung-Hyeok , Kim Jimin , Said Ayman H. , Kim Jungho , Kim B. J.
Published: March 2023

An endstation for resonant inelastic X-ray scattering (RIXS), dedicated to operations in the hard X-ray regime, has been constructed at the 1C beamline of Pohang Light Source II. At the Ir L
3-edge, a total energy resolution of 34.2 meV was achieved, close to the theoretical estimation of 34.0 meV, which considers factors such as the incident energy bandpass, intrinsic analyzer resolution, geometrical broadening of the spectrometer, finite beam-size effect and Johann aberration. The performance of the RIXS instrument is demonstrated by measuring the RIXS spectra of Sr2IrO4. The endstation can be easily reconfigured to measure energy-integrated intensities with very low background for diffuse scattering and diffraction experiments.
Politics of accounting evidence in privatising telecommunications in Sri Lanka
Authors: Gunatilake Gayathri , Lord Beverley , Dixon Keith
Published: March 2023

Purpose

This paper illustrates the socio-political nature of accountings, referring to the partial privatisation of the monopoly telecommunications organisation in a lower-middle-income country.

Design/methodology/approach

Actor-network theory and an ANTi-history approach are used to trace circumstances and occurrences. Empirical materials include official documents, print media and retrospective interviews with organisation employees ten years on from the privatisation.

Findings

Proponents of privatisation used retrospectively constructed historical accounts to problematise the natural monopoly of telecommunications and the government organisation administering it. A restructuring programme followed. Proponents addressed controversies pertaining to the programme thus garnering widespread support for complex and controversial changes. Proponents produced and reproduced accounting artefacts as evidence in these processes of history reconstruction, consequent changes and restoring stability to telecommunications in its reconfigured commercial domain. The proponents used selective, controversial accounting evidence to problematise the government organisation's existence, then to mobilise various actors to reduce and close the controversies previously aroused and reinstate stability in a partially privatised telecommunications company. Although no longer having a monopoly this company still dominates. Dissenters did the same but with little success.

Research limitations/implications

The findings demonstrate the importance of tracing the socio-political process of arriving at the dominant outcome about the past. This assists in making sense of present circumstances and re-imagining the future.

Originality/value

The study demonstrates that, during controversial circumstances, taken-for-granted history, as well as what is thought to have not existed in the past, support the dominant network in gaining advantage over their opponents and black-boxing their perspectives of how things should be.
The impact of self-efficacy beliefs of employees on contextual issues of online learning: with reference to the banking sector in Sri Lanka
Authors: Rathnasekara Kushan , Suraweera Namali , Yatigammana Kaushalya
Published: March 2023

Purpose

The paper aims to clarify the relationship between perceived contextual issues and the self-efficacy beliefs of the employees with e-learning engagement for their competency development. It proposes a model for the banks to utilize their e-learning interventions more effectively by managing the identified contextual issues. Simultaneously, this study aims to expand the domain of self-efficacy beliefs and apply its principles to dilute the impact of the negative contextual issues which were not addressed through similar research.

Design/methodology/approach

The paper focuses on an exploratory study using a deductive approach grounded on self-efficacy – one of the main dimensions of Bandura's social cognitive theory. It adopted a mixed methodology, and primary data were collected through an online survey (792 responses analyzed through Statistical Package Social Science [SPSS]) and semi-structured interviews (20 respondents analyzed through thematic analysis). The population comprises employees of private commercial banks who have recently introduced e-learning.

Findings

The paper provides empirical insights into the contextual issues influencing e-learning and how self-efficacy beliefs can be utilized to enhance the effective engagement of employees. Contextual issues related to technological, organizational, personal and time-intensive factors influence e-learning engagement. The strengthening of self-efficacy beliefs (learners' enthusiasm and gaining) can be utilized to manage personal and time-intensive factors. However, technological and organizational factors cannot be managed through a similar approach as they did not report a significant relationship with self-efficacy.

Originality/value

This paper fulfills an identified need to study how e-learning can be utilized as an effective competency development tool in the banking sector.
Does “low-carbon pilot policy” affect the carbon intensity of construction industry? Exploring the implementation mechanism and effectiveness in China
Authors: Wang Qi , Appolloni Andrea , Liu Junqi
Published: March 2023

Purpose

Carbon reduction in the construction industry is related to the achievement of carbon emission peaks and carbon neutrality targets. Therefore, exploring the influence of current carbon reduction policies on the construction industry is necessary. China’s low-carbon pilot (LCP) policy has been extensively studied, while LCPs mechanism and effectiveness on carbon reduction in the construction industry remain to be explored.

Design/methodology/approach

This study selected four provincial LCP regions as case studies and adopted the grounded theory method for case studies to analyze the implementation mechanism of the LCP policy on carbon reduction in the construction industry. Then, this study adopted the propensity score matching and difference-in-differences regression (PSM-DID) approach to evaluate the influence of the LCP policy on carbon intensity (CI) in the construction industry by using panel data taken from 30 provinces in China between 2008 and 2017.

Findings

The authors found that (1) the LCP policy promotes carbon reduction in the construction industry through the crossing implementation mechanism of five vertical support approaches and five horizontal support approaches. (2). The LCP policy can significantly reduce CI in the construction industry.

Originality/value

The study not only explored how is the LCP policy implemented, but also examined the effectiveness of the LCP policy in the construction industry. The policy implications of this study can help policy-makers better achieve low-carbon development targets in the construction industry.
The consumer–activity relationship and separation distress
Authors: Hawkins Matthew A. , Thyroff Anastasia
Published: March 2023

Purpose

Despite the rich history of examining the connections between symbolic consumption and identity formation, nearly all the research has focused on brands and possessions; the role of activities has been critically overlooked. This study aims to expand marketing’s understanding of identity formation by examining it in conjunction with attribution theory, exploring the relationship between activity engagement and separation distress.

Design/methodology/approach

A pilot study (n = 90) using a thematic content analysis reveals six themes (i.e. separation distress, negative emotions, indifference, adapting, positive decision and acceptance), providing support for the conceptual model. The main study (n = 347) tests the conceptual model via five hypotheses.

Findings

Self-worth match with an activity predicts the perceived separation distress of stopping the activity. Furthermore, self-activity connection mediates this relationship, but only if consumers believe they are in control of or the cause for stopping the activity.

Research limitations/implications

This research provides critical baseline understanding of activity consumption. Yet, future research on the topic of activities is needed to advance activity engagement as a unique category of consumer behavior.

Practical implications

To craft effective messaging and strategies, marketers should consider the meaning and value embedded in consumer activities (not just possessions and brands).

Originality/value

This research reveals that consumers use activities to construct their identity and manage their self-worth. It also demonstrates that stopping an activity may lead to separation distress.