bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a Behavioral Therapy-Based Virtual Reality Application on Quality of Life in Chronic Low Back Pain
Authors: Groenveld Tjitske D. , Smits Merlijn L.M. , Knoop Jesper , Kallewaard Jan Willem , Staal J. Bart , de Vries Marjan , van Goor Harry
Published: April 2023

Objectives:

Low back pain is the leading cause of years lived with disability with a large impact on quality of life and resistance to a broad array of current treatments. This study aimed to investigate the effect of a novel self-administered behavioral therapy-based virtual reality (VR) application on the quality of life of patients with nonspecific chronic low back pain (CLBP).

Methods:

A pilot randomized controlled trial was conducted in adults with nonspecific CLBP with moderate to severe pain, waiting for treatment in a teaching hospital-based pain clinic. The intervention group used a self-administered behavioral therapy-based VR application for at least 10 minutes daily for 4 weeks. The control group received standard care. The primary outcome was quality of life at 4 weeks measured by the short form-12 physical and mental scores. Secondary outcomes were daily worst and least pain, pain coping strategies, activities of daily living, positive health, anxiety, and depression. Discontinuation of therapy and adverse events were analyzed as well.

Results:

Forty-one patients were included. One patient withdrew due to personal reasons. No significant treatment effect was found for the short form-12 physical score (mean difference: 2.6 points; 95% CI: −5.60 to 0.48) and mental score (−1.75; −6.04 to 2.53) at 4 weeks. There was a significant treatment effect for daily “worst pain score” (F [1, 91.425] = 33.3, P < 0.001) and “least pain score” (F [1, 30.069] = 11.5, P = 0.002). Three patients reported mild and temporary dizziness.

Discussion:

Four weeks of self-administered VR for CLBP does not improve quality of life, however, it may positively affect daily pain experience.
Long-Term Clinical Outcomes of Keratolimbal Allograft Alone or in Combination With Keratoplasty in Chronic and Delayed-Onset Mustard Gas Keratopathy
Authors: Karimian Farid , Jafarinasab Mohammad-Reza , Feizi Sepehr , Javadi Mohammadali , Ansari Mohammad-Hassan , Hassanpour Kiana
Published: March 2023

Purpose:

The purpose of this study was to investigate the long-term clinical outcome of keratolimbal allograft (KLAL) alone or in combination with keratoplasty, in the management of patients with chronic and delayed-onset mustard gas keratopathy (MGK).

Methods:

Patients who had KLAL for MGK with or without corneal transplantation between 2002 and 2016 were recalled to be enrolled in this retrospective interventional case series. The primary outcome was the success rate of the KLAL demonstrated by Kaplan–Meier cumulative survival analysis. The secondary outcomes were postoperative BCVA and the need for further surgery.

Results:

A total of 108 eyes of 68 patients with MGK underwent KLAL. All patients were male with an average age of 54 ± 6 years with an average follow-up duration of 81.9 ± 38.4 months. Sectoral KLAL alone was performed in 62 eyes (57.4%), combined with lamellar keratoplasty (LKP) in 40 eyes (37%) and combined with penetrating keratoplasty in 6 eyes (5.6%). The cumulative probability of success was 75% within the follow-up duration. The mean duration of successful KLAL survival was 80.6 ± 38 months. 88.1% of these eyes needed only 1 operation to stabilize the ocular surface. Average BCVA did not improve significantly after KLAL alone, except in those accompanied by keratoplasty. KLAL combined with LKP achieved the superior clinical outcome compared with KLAL alone. Infectious keratitis occurred in 6 eyes (5.5%). No adverse event due to postoperative systemic immunosuppression was observed.

Conclusions:

KLAL alone or combined with LKP is effective, durable, and visually acceptable in the reconstruction of ocular surface in patients with limbal stem cell deficiency secondary to MGK.
Research hotspots and trends of the tele-rehabilitation for stroke survivors based on CiteSpace: A review
Authors: Li Linzhang , Sun Yan
Published: March 2023

Our first goal is to understand the research status and popularity of telerehabilitation research for stroke survivors since 2012; the second goal is to analyze the research trends and frontiers in this field, and provide a scientific basis for the future application of telerehabilitation technology in patients with poststroke functional defects. We searched the Web of Science Core Collection (WoSCC) for literature on telerehabilitation for stroke survivors published from 2012 to 2022. The included articles were visually analyzed using CiteSpace6.1.6R (64-bit). In total, 968 eligible articles were included in this study. In the past 10 years, the number of papers published on telerehabilitation after stroke has been increasing annually, with the largest number of papers published in the United States and Australia, with 101 papers published by Chinese scholars. Some subsets of cooperative networks have been formed among major research institutions and their authors, but the scale remains small, and academic exchanges and cooperation need to be strengthened further. Research on virtual reality (VR) technology and rehabilitation robot technology is popular, and the choice of time and intensity of rehabilitation exercises, patients’ participation in rehabilitation exercises, and care are also worth attention. In the last 10 years, research on telerehabilitation technology in the field of rehabilitation for stroke survivors has steadily developed, and is characterized by multidisciplinary joint development. Countries around the world can combine their own characteristics and advantages, strengthen academic exchanges and cooperation with mature research institutions or authors, and explore suitable poststroke remote rehabilitation technologies and service models in different environments.
IDENTIFICATION AND CLINICAL VALIDATION OF HYPOXIA-INDUCIBLE FACTOR 1α PROTEIN AS THE POTENTIAL BIOMARKER IN PATIENTS WITH SEPSIS
Authors: Ruan Hang , Li Yao-zhuo , Zhang Qin , Wang Bin-ran , Wu Rongxue , Li Shu-sheng , Ran Xiao
Published: April 2023

Objective: Sepsis is a complex disease characterized by an inflammatory response and tissue hypoxia. Hypoxia-inducible factor 1α (HIF-1α) expression level is regulated by hypoxia and inflammation. This study aimed to explore the correlation between HIF-1α expression level and sepsis by bioinformatics analysis and clinical investigation. Methods: Bioinformatics tools were used to identify differentially expressed genes between sepsis and nonsepsis groups using the Gene Expression Omnibus data set. A clinical investigation was carried out to validate HIF-1α protein level in 54 nonseptic patients and 173 septic patients who were followed up for 28 days. Results: Bioinformatics analysis revealed that HIF-1α messenger RNA level was significantly different between septic and nonseptic patients (P < 0.05). Consistent with the study hypothesis, higher HIF-1α levels in plasma were found in septic patients compared with those in nonseptic patients. The diagnostic accuracy for sepsis, as quantified by the area under the curve, was 0.926 (0.885–0.968) for HIF-1α expression level combined with oxygen saturation to fraction of inspired oxygen (SpO2/FiO2), white blood cell, and blood urea nitrogen. The HIF-1α expression level was also significantly correlated with the severity of the disease. The results of the restricted cubic splines model indicated a U-shaped relationship between HIF-1α expression level and intensive care unit (ICU) mortality. Univariate and multivariate linear regression analyses indicated that septic patients with the elevated HIF-1α expression levels had shorter length of ICU stay versus those with the lower HIF-1α expression levels. Conclusion: Hypoxia-inducible factor 1α expression level can be used for diagnosing disease, assessing severity, and predicting length of ICU stay in septic patients.
Assessing Random Forest self-reproducibility for optimal short biomarker signature discovery
Authors: Poulet Christophe , Debit Ahmed , Josse Claire , Jerusalem Guy , Azencott Chloe-Agathe , Bours Vincent , Van Steen Kristel
Published: April 2023

Biomarker signature discovery remains the main path to develop clinical diagnostic tools when the biological knowledge on a pathology is weak. Shortest signatures are often preferred to reduce the cost of the diagnostic. The ability to find the best and shortest signature relies on the robustness of the models that can be built on such set of molecules. The classification algorithm that will be used is selected based on the average performance of its models, often expressed via the average AUC. However, it is not garanteed that an algorithm with a large AUC distribution will keep a stable performance when facing data. Here, we propose two AUC-derived hyper-stability scores, the HRS and the HSS, as complementary metrics to the average AUC, that should bring confidence in the choice for the best classification algorithm. To emphasize the importance of these scores, we compared 15 different Random Forests implementation. Additionally, the modelization time of each implementation was computed to further help deciding the best strategy. Our findings show that the Random Forest implementation should be chosen according to the data at hand and the classification question being evaluated. No Random Forest implementation can be used universally for any classification and on any dataset. Each of them should be tested for both their average AUC performance and AUC-derived stability, prior to analysis.

Author summary

To better measure the performance of a Machine Learning (ML) implementation, we introduce a new metric, the AUC hyper-stability, to be used in parallel with the average AUC. This AUC hyper-stability is able to discriminate ML implementations that show the same AUC performance. This metric can therefore help researchers in choosing the best ML method to get stable short predictive biomarker signatures. More specifically, we advocate a tradeoff between the average AUC performance, the hyper-stability scores, and the modeling time.
Large-scale Annotation of Biochemically Relevant Pockets and Tunnels in Cognate Enzyme-Ligand Complexes
Authors: Vavra O. , Tyzack J. , Haddadi F. , Stourac J. , Damborsky J. , Mazurenko S. , Thornton J. , Bednar D.
Published: March 2023

Tunnels in enzymes with buried active sites are key structural features allowing the entry of substrates and the release of products, thus contributing to the catalytic efficiency. Targeting the bottlenecks of protein tunnels is also a powerful protein engineering strategy. However, the identification of functional tunnels in multiple protein structures is a non-trivial task that can only be addressed computationally. We present a pipeline integrating automated structural analysis with anin-housemachine-learning predictor for the annotation of protein pockets, followed by the calculation of the energetics of ligand transport via biochemically relevant tunnels. A thorough validation using eight distinct molecular systems revealed that CaverDock analysis of ligand un/binding is on par with time-consuming molecular dynamics simulations, but much faster. The optimized and validated pipeline was applied to annotate more than 17,000 cognate enzyme-ligand complexes. Analysis of ligand un/binding energetics indicates that the top priority tunnel has the most favourable energies in 75 % of cases. Moreover, energy profiles of cognate ligands revealed that a simple geometry analysis can correctly identify tunnel bottlenecks only in 50 % of cases. Our study provides essential information for the interpretation of results from tunnel calculation and energy profiling in mechanistic enzymology and protein engineering. We formulated several simple rules allowing identification of biochemically relevant tunnels based on the binding pockets, tunnel geometry, and ligand transport energy profiles.
In Rhesus monkeys, CSF-contacting neurons are the only neurons present in the medullo-spinal peri-ependymal zone
Authors: Kastner Anne , Wanaverbecq Nicolas
Published: April 2023

In spinal cord and medulla, ependymal cells re organized in a monolayer forming the central canal (cc). In rodents, this region, also known as a stem cell niche, was shown to contain cerebrospinal fluid-contacting neurons (CSF-cNs). These neurons are GABAergic and because of their chemo- and mechanosensory properties they would represent a novel sensory system intrinsic to the central nervous system. In primates, little is known about these neurons and more generally about the region around the cc. Here, using immunohistochemical approaches, we investigated the organization of the cc region and CSF-cN properties inMacaca mulattaRhesus monkey. In contrast to rodent, we observe along the whole medullo-spinal axis a large zone around the cc delimited by long radial ependymal fibers that is enriched with astrocytes and microglia but largely devoid of neuronal elements except for CSF-cNs. These primate CSF-cNs share with rodent CSF-cNs similar morphological and phenotypical features with a largely immature profile. Our data suggest that they extend their axons in the longitudinal axis to form fiber bundles close to the cc and we further show that CSF-cNs receive GABAergic and serotoninergic synaptic contacts on their soma and dendrite. Taken together our results reveal inRh.monkey a specific organization of the region around the cc potentially forming a buffer zone between CSF and parenchyma where CSF-cNs would play a crucial role in the detection of CSF signals and their transmission to the central nervous system, a role that would need to be further investigated.
Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury
Authors: Somasundaram Preethi , Farley Madeline M. , Rudy Melissa A. , Sigal Katya , Asencor Andoni I. , Stefanoff David G. , Shah Malay , Goli Puneetha , Heo Jenny , Wang Shufang , Tran Nicholas M. , Watkins Trent A.
Published: April 2023

Stress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.
A concurrently available negative reinforcer robustly decreases cocaine self-administration in male and female rats
Authors: Marcus Madison M. , Banks Matthew L.
Published: April 2023

Continued drug-taking despite adverse consequences is hypothesized to be an insidious behavioral hallmark of drug addiction. Although most preclinical research has focused on drug self-administration in the presence of positive punishment, another source of potential adverse consequences is behavioral allocation away from negative reinforcers (i.e., escape/avoid electric shock) and towards drug reinforcers. The goals of the present study were to establish a discrete-trial cocaine-vs-negative reinforcer choice procedure in male and female rats and determine sensitivity of choice behavior to environmental and pharmacological manipulations. Rats could make up to nine discrete choices between an intravenous cocaine infusion (0.32 – 1.8 mg/kg/inf) under a fixed-ratio (FR) 3 schedule and a negative reinforcer (escape or avoidance of electric shock, 0.1 – 0.7 mA) under an FR1 schedule. The negative reinforcer was consistently chosen over all cocaine doses. Lowering shock magnitude decreased negative reinforcer trials, increased omitted trials, and failed to promote behavioral reallocation towards cocaine. Increasing the negative reinforcement response requirement between sessions only increased omitted trials. Introduction of 12-hr extended access cocaine self-administration sessions across two weeks resulted in high daily cocaine intakes but failed to significantly increase cocaine choice. Acute diazepam pretreatment also did not impact choice behavior up to doses that produced behavioral depression. Overall, the lack of behavioral allocation between cocaine infusions and a negative reinforcer suggests these two reinforcers may be economic independents. Additionally, the failure of extended cocaine access to increase cocaine choice highlights the importance of alternative reinforcers and environmental context in preclinical models of drug addiction.
Effects of six pyrimidine analogs on the growth ofTetrahymena thermophilaand their implications in pyrimidine metabolism
Authors: Harpel Zander , Chang Wei-Jen , Circelli Jacob , Chen Richard , Chang Ian , Rivera Jason , Wu Stephanie , Wei Zonhan
Published: April 2023

Tetrahymenaare ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5’-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, cytarabine) on wild-type CU428 and conditional mutant NP1Tetrahymena thermophilaat room temperature and the restrictive temperature (37°C) where NP1 does not form the oral apparatus. We found that cytarabine was the only tested analog that did not inhibit growth, and phagocytosis was not required for pyrimidine analog entry. IC50 values did not significantly differ between strains for the same analog at either temperature. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, 5-methyluridine) to help determine whether the inhibitory effects from analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5’-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibitT. thermophilagrowth and that nucleobases and nucleosides are metabolized differently.
A method for extracting effective interactions from Hi-C data with applications to interphase chromosomes and inverted nuclei
Authors: Shin Sucheol , Shi Guang , Thirumalai D.
Published: April 2023

Contact probabilities between loci, separated by arbitrary genomic distance, for a number of cell types have been reported using genome-wide chromosome conformation capture (Hi-C) experiments. How to extract the effective interaction energies between active euchromatin (A) and inactive het-erochromatin (B) directly from the experimental data, without an underlying polymer model, is unsolved. Here, we first calculate the pairwise effective interaction energies (A-A, B-B, or A-B) for interphase chromosomes based on Hi-C data by using the concept of Statistical Potential (SP), which assumes that the interaction energy between two loci is proportional to the logarithm of the frequency with which they interact. Polymer simulations, using the extracted interaction energy valueswithout any parameters, reproduce the segregation between A and B type loci (compartments), and the emergence of topologically associating domains (TADs), features that are prominent in the Hi-C data for interphase chromosomes. Remarkably, the values of the SP automatically satisfy the Flory-Huggins phase separation criterion for all the chromosomes, which explains the mechanism of compartment formation in interphase chromosomes. Strikingly, simulations using the SP that accounts for pericentromeric constitutive heterochromatin (C-type), show hierarchical structuring with the high density of C-type loci in the nuclear center, followed by localization of the B type loci, with euchromatin being confined to the nuclear periphery, which differs from the expected nuclear organization of interphase chromosomes, but is in accord with imaging data. Such an unusual organization of chromosomes is found in inverted nuclei of photoreceptor rods in nocturnal mammals. The proposed method without free parameters and its applications show that compartment formation in conventional and inverted nuclei is best explained by the inequality between the effective interaction energies, with heterochromatin attraction being the dominant driving force.
PySilSub: An open-source Python toolbox for implementing the method of silent substitution in vision and non-visual photoreception research
Authors: Martin Joel T. , Boynton Geoffrey M. , Baker Daniel H. , Wade Alex R. , Spitschan Manuel
Published: April 2023

The normal human retina contains several classes of photosensitive cell—rods for low-light vision, three cone classes for daylight vision, and intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin for non-image-forming functions including pupil control, melatonin suppression and circadian photoentrainment. The spectral sensitivities of the photoreceptors overlap significantly, which means that most lights will stimulate all photoreceptors, to varying degrees. The method of silent substitution is a powerful tool for stimulating individual photoreceptor classes selectively and has found much use in research and clinical settings. The main hardware requirement for silent substitution is a spectrally calibrated light stimulation system with at least as many primaries as there are photoreceptors under consideration. Device settings that will produce lights to selectively stimulate the photoreceptor(s) of interest can be found using a variety of analytic and algorithmic approaches. Here we presentPySilSub(https://github.com/PySilentSubstitution/pysilsub), a novel Python package for silent substitution featuring flexible object-oriented support for individual colorimetric observer models (including human and mouse observers), multi-primary stimulation devices, and solving silent substitution problems with linear algebra and constrained numerical optimisation. The toolbox is registered with the Python Package Index and includes example data sets from various multi-primary systems. We hope thatPySilSubwill facilitate the application of silent substitution in research and clinical settings.
Direct single cell observation of a keyE. colicell cycle oscillator
Authors: Iuliani Ilaria , Mbemba Gladys , Lagomarsino Marco Cosentino , Sclavi Bianca
Published: April 2023

A long-standing hypothesis sees DNA replication control inE. colias a central cell cycle os-cillator at whose core is the DnaA protein. The consensus is that the activity of the DnaA protein, which is dependent on its nucleotide bound state, is an effector of initiation of DNA replication and a sensor of cell size. However, while several processes are known to regulate DnaA activity as a function of the cell cycle, the oscillations in DnaA expression and DnaA ac-tivity have never been observed at the single cell level, and their correlation with cell volume has yet to be established. In this study, we measured the volume-specific production rate of a reporter protein under control of thednaAP2 promoter in single cells. By a careful dissection of the effects of DnaA-ATP-and SeqA-dependent regulation, two distinct cell cycle oscilla-tors emerge. The first oscillator, driven by gene dosage, DnaA activity and SeqA repression oscillates synchronously, and shows a causal relationship, with cell size and divisions, sim-ilarly to initiation events. The second one, a reporter of dosage and DnaA activity only, is strongly coupled to cell size, but loses the synchrony and causality properties, suggesting that DnaA activity peaks do not correspond directly to initiation events. These findings suggest that while transcription regulation by DnaA activity performs volume sensing, transient in-hibition of gene expression by SeqA following replication fork passage keeps DnaA activity oscillations in phase with initiation events.
Patterned embryonic invagination evolved in response to mechanical instability
Authors: Vellutini Bruno C. , Cuenca Marina B. , Krishna Abhijeet , Szałapak Alicja , Modes Carl D. , Tomančák Pavel
Published: April 2023

Mechanical forces are crucial for driving and shaping the morphogenesis of tissues and organs during embryonic development. However, their relevance for the evolution of morphogenetic processes remains poorly understood. Here we show that a morphogenetic innovation present in fly embryos—a deep epithelial fold known as the cephalic furrow—plays a mechanical role duringDrosophilagastrulation. By integratingin vivoexperiments andin silicosimulations, we find that the formation of the cephalic furrow effectively prevents mechanical instabilities at the head–trunk epithelium by absorbing the compressive stresses generated by concurrent morphogenetic movements. Furthermore, by comparing the expression of known and novel genes involved in cephalic furrow formation between fly species, we find that the presence of the cephalic furrow is linked to the appearance of a novelbuttonheadexpression domain at the head–trunk boundary. These data suggest that the genetic control of cephalic furrow formation was established through the integration of a new player into the ancestral head–trunk patterning system, and that mechanical instability may have been the selective pressure associated with the evolution of the cephalic furrow. Our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.
Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development
Authors: DeMoya Ricardo A. , Forman-Rubinsky Rachel E. , Fontaine Deon , Shin Joseph , Watkins Simon C. , Lo Cecilia , Tsang Michael
Published: April 2023

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa (Sap130), a protein in the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the digenic etiology of HLHS. Here, we report the role of zebrafishsap130genes in heart development. Loss ofsap130a,one of twoSap130orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role ofsap130ain gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cell communication were dysregulated insap130a, but not insap130bmutants. Confocal light sheet analysis measured deficits in cardiac output inMZsap130asupporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest thatsap130ais involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction betweenhdac1andsap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.
Assessing bias and robustness of social network metrics using GPS based radio-telemetry data
Authors: Kaur Prabhleen , Ciuti Simone , Ossi Federico , Cagnacci Francesca , Morellet Nicolas , Loison Anne , Atmeh Kamal , McLoughlin Philip , Reinking Adele K. , Beck Jeffrey L. , Ortega Anna C. , Kauffman Matthew , Boyce Mark S. , Salter-Townshend Michael
Published: April 2023

Social network analysis of animal societies allows scientists to test hypotheses about social evolution, behaviour, dynamical processes, and transmission events such as the spread of disease. However, the accuracy of estimated social network metrics depends on the proportion of individuals sampled, actual sample size, and frequency of observations. Robustness of network metrics derived from a sample has thus far been examined through various simulation studies. However, simulated data do not necessarily reflect the nuances of real empirical data.

We used some of the largest available GPS telemetry relocation datasets from five species of ungulates characterised by different behavioural and ecological traits and living in distinct environmental contexts to study the bias and robustness of social network metrics. We introduced novel statistical methods to quantify the uncertainty in network metrics obtained from a partial population suited to autocorrelated data such as telemetry relocations. We analysed how social network metrics respond to down-sampling from the observed data and applied pre-network data permutation techniques, a bootstrapping approach, correlation, and regression analyses to assess the stability of network metrics when based on samples of a population.

We found that global network metrics like density remain robust when the sample size is lowered, whereas some local network metrics, such as eigenvector centrality, are entirely unreliable when a large proportion of the population is not monitored. We show how to construct confidence intervals around the point estimates of these metrics representing the uncertainty as a function of the number of nodes in the network.

Our uncertainty estimates enable the statistical comparison of social network metrics under different conditions, such as analysing daily and seasonal changes in the density of a network. Despite the striking differences in the ecology and sociality among the five different ungulate species, the various social network metrics behave similarly under downsampling, suggesting that our approach can be applied to a wider range of species across vertebrates. Our methods can guide methodological decisions about animal social network research (e.g., sampling design and sample sizes) and allow more accurate ecological inferences from the available data.
The need for hemispheric separation in pairwise structural disconnection studies
Authors: Röhrig Lisa , Rosenzopf Hannah , Wöhrstein Sofia , Karnath Hans-Otto
Published: April 2023

The development of new approaches indirectly measuring the structural disconnectome has recently led to an increase in studies investigating pairwise structural disconnections following brain damage. Previous studies jointly analyzed patients with left hemispheric and patients with right hemispheric lesions when investigating a behavior of interest. An alternative approach would be to perform analyses separated by hemisphere, which has been applied in only a minority of studies to date. The present simulation study investigated whether joint or separate analyses (or both equally) are appropriate to reveal the ground truth disconnections. In fact, both approaches resulted in very different patterns of disconnection. In contrast to analyses separated by hemisphere, joint analyses introduced a bias to the disadvantage of intra-hemispheric disconnections. Intra-hemispheric disconnections were statistically underpowered in the joint analysis and thus surpassed the significance threshold with more difficulty compared to inter-hemispheric disconnections. This statistical imbalance was also shown by a greater number of significant inter-hemispheric than significant intra-hemispheric disconnections. This bias from joint analyses is based on mechanisms similar to those underlying the ‘partial injury problem’. We therefore conclude that pairwise structural disconnections in patients with unilateral left hemispheric and with unilateral right hemispheric lesions exhibiting a specific behavior (or disorder) of interest should be studied separately by hemisphere rather than in a joint analysis.
Electrophysiological indices of hierarchical speech processing differentially reflect the comprehension of speech in noise
Authors: Synigal Shyanthony R. , Anderson Andrew J. , Lalor Edmund C.
Published: April 2023

The past few years have seen an increase in the use of encoding models to explain neural responses to natural speech. The goal of these models is to characterize how the human brain converts acoustic speech energy into different linguistic representations that enable everyday speech comprehension. For example, researchers have shown that electroencephalography (EEG) data can be modeled in terms of acoustic features of speech, such as its amplitude envelope or spectrogram, linguistic features such as phonemes and phoneme probability, and higher-level linguistic features like context-based word predictability. However, it is unclear how reliably EEG indices of these different speech representations reflect speech comprehension in different listening conditions. To address this, we recorded EEG from neurotypical adults who listened to segments of an audiobook in different levels of background noise. We modeled how their EEG responses reflected different acoustic and linguistic speech features and how this varied with speech comprehension across noise levels. In line with our hypothesis, EEG signatures of context-based word predictability and phonetic features were more closely correlated with behavioral measures of speech comprehension and percentage of words heard than EEG measures based on low-level acoustic features. EEG markers of the influence of top- down, context-based prediction on bottom-up acoustic processing also correlated with behavior. These findings help characterize the relationship between brain and behavior by comprehensively linking hierarchical indices of neural speech processing to language comprehension metrics.

SIGNIFICANCE STATEMENT

Acoustic and linguistic features of speech have been shown to be consistently tracked by neural activity even in noisy conditions. However, it is unclear how signatures of low- and high- level features covary with one another and relate to behavior across these listening conditions. Here, we find that categorical phonetic feature processing is more affected by noise than acoustic and word probability-based speech features. We also find that phonetic features and word probability-based features better correlate with measures of intelligibility and comprehension. These results extend our understanding of how various speech features are comparatively reflected in electrical brain activity and how they relate to perception in challenging listening conditions.
Activity-dependent constraints on catecholamine signaling
Authors: Li Li , Rana Akshay , Li Esther M. , Feng Jiesi , Li Yulong , Bruchas Michael R.
Published: April 2023

Catecholamine signaling is thought to modulate cognition in an inverted-U relationship, but the mechanisms are unclear. We measured norepinephrine and dopamine release, postsynaptic calcium responses, and interactions between tonic and phasic firing modes under various stimuli and conditions. High tonic activityin vivodepleted catecholamine stores, desensitized postsynaptic responses, and decreased phasic transmission. Together this provides a clearer understanding of the inverted-U relationship, offering insights into psychiatric disorders and neurodegenerative diseases with impaired catecholamine signaling.
Targeted genomic sequencing of avian influenza viruses in wetlands sediment from wild bird habitats
Authors: Kuchinski Kevin S. , Coombe Michelle , Mansour Sarah C. , Cortez Gabrielle Angelo P. , Kalhor Marzieh , Himsworth Chelsea G. , Prystajecky Natalie A.
Published: April 2023

Diverse influenza A viruses (IAVs) circulate in wild birds, including dangerous strains that infect poultry and humans. Consequently, surveillance of IAVs in wild birds is a cornerstone of outbreak prevention and pandemic preparedness. Surveillance is traditionally done by testing birds, but dangerous IAVs are rarely detected before outbreaks begin. Testing environmental specimens from wild bird habitats has been proposed as an alternative. These specimens are thought to contain diverse IAVs deposited by broad range of avian hosts, including species that are not typically sampled by surveillance programs. We developed a targeted genomic sequencing method for recovering IAV genome fragments from these challenging environmental specimens, including purpose-built bioinformatic analysis tools for counting, subtyping, and characterizing each distinct fragment recovered. We demonstrated our method on 90 sediment specimens from wetlands around Vancouver, Canada. We recovered 2,312 IAV genome fragments originating from all 8 IAV genome segments. 11 haemagglutinin (HA) subtypes and 9 neuraminidase subtypes were detected, including H5, the current global surveillance priority. Recovered fragments originated predominantly from IAV lineages that circulate in North American resident wild birds. Our results demonstrate that targeted genomic sequencing of environmental specimens from wild bird habitats can be a valuable complement to avian influenza surveillance programs.
Identification of culturable fungi and bacteria in mosquito saliva and impact on arbovirus infection in vitro
Authors: Wang Lanjiao , Remue Laure , Trappeniers Katrien , Adriaens Nikki , Soto Alina , Verwimp Sam , Rivas Felipe , van Bree Joyce , Garigliany Mutien , Delang Leen
Published: April 2023

Mosquito saliva was shown to play a key role in arbovirus transmission and pathogenesis. In this study, we explored the presence of microbiota in mosquito saliva and their effect on mosquito-borne virus infectionin vitro. Culturable fungal and bacterial colonies were isolated and identified from saliva harvested fromAedes aegypti(lab strain) andCulex pipiens(field-collected mosquitoes). For the first time, the fungal speciesPenicillium crustosumwas identified in mosquitoes. Culturable bacteria detected in mosquito saliva includedSerratia marcescens, Serratia nematodiphila,Enterobacterspp. andKlebsiellaspp., which were previously identified as mosquito or insect endosymbionts in the midgut or other organs. Oral treatment of adult mosquitoes with antibiotics or an antifungal drug resulted in a significant reduction of bacteria or fungi in saliva. (Pre)-Incubation of Semliki Forest virus with saliva from antibiotic- or antifungal-treated mosquitoes triggered a decreasing viral infection in human skin fibroblasts compared to non-treated saliva. These results indicate an important role of the mosquito saliva microbiota in mosquito-borne virus replication and furtherin vivostudies are required to better understand its impact on viral transmission.
Uip4 governs growth phase dependent organelle remodeling by modulatingSaccharomyces cerevisiaelipidome
Authors: Deolal Pallavi , Ramalingam Kathirvel , Das Bhaskar , Mishra Krishnaveni
Published: April 2023

When yeast cells are exposed to nutrient-limiting conditions, they undergo transcriptional and translational reprogramming that results in the remodelling of metabolite utilization and organelle architecture. Organelle membranes and contacts also undergo structural and functional alterations. In the budding yeast Saccharomyces cerevisiae, regulated expression of Uip4 is shown to be a critical effector of nuclear shape and function, particularly during the stationary phase. In this work, we demonstrate that the absence of UIP4 affects the morphology of multiple other organelles including mitochondria, endoplasmic reticulum, vacuole and the distribution of lipid droplets. The results show that modulating carbon source, nitrogen availability and cellular energy state impact Uip4 expression. This expression of Uip4 is controlled by the transcription factor Msn2, downstream of Sch9 signaling pathway. Cells lacking Uip4 have poor survival in the stationary phase of the growth cycle. These cellular changes are concomitant with dysregulation of the global lipidome profile and aberrant organelle interaction. We propose that the dynamic and regulated expression of Uip4 is required to maintain lipid homeostasis and organelle architecture which is ultimately required to survive in nutrient limiting conditions such as stationary phase.
Effect of microstimulation of the inferior temporal cortex on color judgment behavior
Authors: Koida Kowa , Komatsu Hidehiko
Published: April 2023

Within the anterior inferior temporal cortex (AIT) there is a cluster of color selective neurons whose activities correlate with color discrimination behavior. To examine the causal relationship between the activities of these neurons and behavior, we applied electrical microstimulation to modulate neuronal activities within the AIT. We trained monkeys to perform a color judgment task and evaluated the effect of microstimulation in terms of the horizontal shift of the psychometric function. We found large effects of microstimulation on color discrimination behavior, predominantly within a subregion of the AIT. The cortical extent where microstimulation modulated behavior correlated with the presence of color-selective neurons. Unexpectedly, the direction of the modulation of color judgment evoked by microstimulation correlated negatively with the preference of the neurons around the stimulation site. These results support the existence of an anterior inferior temporal color-selective area (AITC) and its causal relationship with the color perception of these animals.
TopBP1 utilises a bipartite GINS binding mode to support genome replication
Authors: Day Matthew , Tetik Bilal , Parlak Milena , Almeida-Hernández Yasser , Räschle Markus , Kaschani Farnusch , Siegert Heike , Marko Anika , Sanchez-Garcia Elsa , Kaiser Markus , Barker Isabel A. , Pearl Laurence H. , Oliver Antony W. , Boos Dominik
Published: April 2023

Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, and as such for faithful genetic inheritance. Our biochemical and structural studies demonstrate that the helicase activator GINS interacts with TopBP1 through two separate binding surfaces, the first involving a stretch of highly conserved amino acids in the TopBP1-GINI region, the second a surface on TopBP1-BRCT4. The two surfaces bind to opposite ends of the A domain of the GINS subunit Psf1. Mutation analysis reveals that either surface is individually able to support TopBP1-GINS interaction, albeit with reduced affinity. Consistently, either surface is sufficient for replication origin firing inXenopusegg extracts and becomes essential in the absence of the other. The TopBP1-GINS interaction appears sterically incompatible with simultaneous binding of DNA polymerase epsilon (Polε) to GINS when bound to Mcm2-7-Cdc45, although TopBP1-BRCT4 and the Polε subunit PolE2 show only partial competitivity in binding to Psf1. Our TopBP1-GINS model improves the understanding of the recently characterised metazoan pre-loading complex. It further predicts the coordination of three molecular origin firing processes, DNA polymerase epsilon arrival, TopBP1 ejection and GINS integration into Mcm2-7-Cdc45.
CryoET shows cofilactin filaments inside the microtubule lumen
Authors: Santos Camilla Ventura , Rogers Stephen L. , Carter Andrew P.
Published: April 2023

Cytoplasmic microtubules are tubular polymers that can harbor small proteins or filaments inside their lumen. The identity of these objects and what causes their accumulation has not been conclusively established. Here, we used cryogenic electron tomography (cryoET) ofDrosophilaS2 cell protrusions and found filaments inside the microtubule lumen, which resemble those reported recently in human HAP1 cells. The frequency of these filaments increased upon inhibition of the sarco/endoplasmic reticulum Ca2+ATPase (SERCA) with the small-molecule drug thapsigargin. Subtomogram averaging showed that the luminal filaments adopt a helical structure reminiscent of cofilin-bound actin (cofilactin). Consistent with this, cofilin was activated in cells under the same conditions that increased luminal filament occurrence. Furthermore, RNAi knock-down of cofilin reduced the frequency of luminal filaments with cofilactin morphology. These results suggest that cofilin activation stimulates its accumulation on actin filaments inside the microtubule lumen.
Preservation of co-expression defines the primary tissue fidelity of human neural organoids
Authors: Werner Jonathan M. , Gillis Jesse
Published: April 2023

Human neural organoid models offer an exciting opportunity for studying often inaccessible human-specific brain development; however, it remains unclear how precisely organoids recapitulate fetal/primary tissue biology. Here, we characterize field-wide replicability and biological fidelity through a meta-analysis of single-cell RNA-sequencing data for first and second trimester human primary brain (2.95 million cells, 51 datasets) and neural organoids (1.63 million cells, 130 datasets). We quantify the degree to which primary tissue cell-type marker expression and co-expression are recapitulated in organoids across 12 different protocol types. By quantifying gene-level preservation of primary tissue co-expression, we show neural organoids lie on a spectrum ranging from virtually no signal to co-expression near indistinguishable from primary tissue data, demonstrating high fidelity is within the scope of current methods. Additionally, we show neural organoids preserve the cell-type specific co-expression of developing rather than adult cells, confirming organoids are an appropriate model for primary tissue development. Overall, quantifying the preservation of primary tissue co-expression is a powerful tool for uncovering unifying axes of variation across heterogeneous neural organoid experiments.
Membrane-induced 2D phase separation of focal adhesion proteins
Authors: Litschel Thomas , Kelley Charlotte F. , Cheng Xiaohang , Babl Leon , Mizuno Naoko , Case Lindsay B. , Schwille Petra
Published: April 2023

Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. Made up of hundreds of proteins, focal adhesions are dynamic structures which can assemble and disassemble quickly, withstand strong actomyosin-applied forces, and form highly stable complexes. How they achieve these flexible characteristics is not well understood. Here, we use recombinant focal adhesion proteins to reconstitute the core structural machineryin vitro, with the goal of understanding the underlying protein dynamics and interactions. We observe liquid-liquid phase separation of the core focal adhesion proteins talin and vinculin for a spectrum of conditions and in combination with several interaction partners. Intriguingly, we show that membrane binding triggers phase separation of these proteins on the membrane, which in turn induces the enrichment of integrin in the clusters. We also introduce a novel experimental setup to probe talin-membrane interactions down to the single protein level. Our results suggest that membrane composition triggers condensate assembly at the membrane, a regulatory mechanism which could widely apply to membrane-localized biomolecular condensates and provide a pathway of how spatial organization of lipids within the membrane can couple into the cytosol.