bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Correlates of Impulsive Behavior in Healthy Individuals: A Diffusion MRI Study
Authors: Rashidi Fatemeh , Parsaei Mohammadamin , Kiani Iman , Sadri Arash , Aarabi Mohammad Hadi , Darijani Seyed Reza , Lee Yune Sang , Moghaddam Hossein Sanjari
Published: October 2023

Background

Impulsivity is closely related to the tendency to engage in risky behaviors. Previous research identified macrostructural brain alterations in individuals exhibiting impulsive behaviors. Understanding the microstructural brain changes linked to impulsivity can elucidate its underlying mechanisms and guide effective treatment strategies. In this study, we employed diffusion magnetic resonance imaging (DMRI) connectometry to investigate white matter tracts associated with impulsivity while considering potential sex differences.

Methods

We enrolled 218 healthy participants from the Leipzig Study for Mind-Body-Emotion Interactions (LEMON) database. Correlations between DMRI-derived white matter changes and impulsivity were assessed using scores from the UPPS Impulsive Behavior Scale’s four subscales (lack of perseverance (PE), lack of premeditation (PM), sensation seeking (SS), and negative urgency (NU)).

Results

Our findings revealed negative correlations between quantitative anisotropy (QA) values in bilateral cerebellum, middle cerebellar peduncle (MCP), and the severity of PE and PM across the cohort. Additionally, QA values within MCP, corpus callosum (CC) body, and forceps major exhibited negative correlations with SS. Conversely, QA values in forceps minor were positively correlated with PM, and QA values in both the forceps minor and bilateral cingulum showed positive correlations with SS. Remarkably, the observed correlations between UPPS subscale scores and QA value alterations within white matter tracts varied between males and females.

Conclusions

Impulsivity is correlated with discernible alterations in white matter integrity across diverse tracts, including CC, cerebellum, and cingulum. Moreover, males and females show distinct patterns of correlations between white matter integrity and impulsivity.

Highlights

Impulsivity is associated with QA changes and white matter alterations in various brain tracts.

Lower white matter integrity in the cerebellum is negatively correlated with impulsivity.

QA values in the CC parts showed divergent correlations with impulsive behavior.

The patterns of correlations across various tracts varied between males and females.
TALEN-induced contraction of CTG trinucleotide repeats in myotonic dystrophy type 1 cells
Authors: Bétemps Laureline , Descorps-Declère Stéphane , Frenoy Olivia , Poggi Lucie , Mosbach Valentine , Tomé Stéphanie , Viterbo David , Klein Arnaud , Ma Laurence , Lameiras Sonia , Cokelaer Thomas , Monot Marc , Dumas Bruno , Gourdon Geneviève , Furling Denis , Richard Guy-Franck
Published: October 2023

Trinucleotide repeat expansions are the cause of two dozen neurodegenerative and developmental disorders. One of these, myotonic dystrophy type 1 (Steinert disease, or DM1) is due to the expansion of a CTG triplet in the 3’ UTR of theDMPKgene. We used highly specific DNA endonucleases to induce a double-strand break in the repeat tract to contract it below pathological length. Expression of a TALE Nuclease (TALEN) in human DM1 cells induced moderate CTG repeat contractions in 27% of the clones analyzed. These clones exhibited large internal deletions within the TALEN, occurring by homologous recombination between internal TALE repeats, inactivating the nuclease, and explaining its reduced efficacy. Taking advantage of the degeneracy of the genetic code, we recoded the TALEN sequence, to decrease internal redundancy and optimize codon usage. The new recoded TALEN showed increased efficacy in DM1 cells, with 68% of clones exhibiting a moderate to large contraction of the CTG repeat tract. In contrast,Staphylococcus aureusCas9 (SaCas9) was unable to contract the CTG repeat tract. In parallel, we completely sequenced to very high coverage the DM1 genome using the PacBio technology. Several clones in which the TALEN was induced were also totally sequenced. In some of them, length changes of other long CTG repeats were detected, possibly corresponding to off-target effects, all of them in introns or intergenic regions. Repeat contractions were never associated with recombination of flanking markers, suggesting that contractions most probably occur by an intra-allelic mechanism such as single-strand annealing. TALENs should now be considered as a promising gene therapy approach, not only for DM1 but also for many other microsatellite expansion disorders.
Myofascial Trigger Point (MTrP) Size and Elasticity Properties Can Be Used to Differentiate Active and Latent MTrPs in Lower Back Skeletal Muscle
Authors: Tsai P. , Edison J. , Wang C. , Sefton J. , Manning K. , Gramlich M.W.
Published: October 2023

Myofascial Trigger Points (MTrPs) are localized contraction knots that develop after muscle overuse or an acute trauma. Significant work has been done to understand, diagnose, and treat MTrPs in order to improve patients suffering from their effects. However, effective non-invasive diagnostic tools are still a missing gap in both understanding and treating MTrPs. Effective treatments for patients suffering from MTrP mediated pain require a means to measure MTrP properties quantitatively and diagnostically both prior to and during intervention. Further, quantitative measurements of MTrPs are often limited by the availability of equipment and training. Here we develop ultrasound (US) based diagnostic metrics that clinicians can use during patient diagnosis and treatment. We highlight the advantages and limitations of previous US-based approaches that utilize elasticity theory. We show how US-based measurements can distinguishActivefromLatentMTrPs. We demonstrate that Active MTrPs tend to be smaller, stiffer, and deeper in the muscle tissue. We provide evidence that more than one MTrP within a single US-image field increases the stiffness of neighboring MTrPs. Finally, we highlight a combination of metrics (depth, thickness, and stiffness) that can be used to assess individual MTrPs in combination with standard clinical assessments.
Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice
Authors: Izquierdo María Concepción , Harris Michael , Shanmugarajah Niroshan , Zhong Kendra , Ozcan Lale , Fredman Gabrielle , Haeusler Rebecca A.
Published: October 2023

Background

Type 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis.

Methods

We used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9D377Yand by crossing with Ldlr−/−mice.

Results

We verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice.

Conclusions

These findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.

Non-standard Abbreviations and Acronyms

Ldlr, low-density lipoprotein receptor; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein
The increased hinge flexibility of an IgG1-IgG3 hybrid monoclonal enhances Fc-mediated protection against group A streptococci
Authors: Izadi Arman , Karami Yasaman , Bratanis Eleni , Wrighton Sebastian , Khakzad Hamed , Nyblom Maria , Olofsson Berit , Happonen Lotta , Tang Di , Nilges Michael , Malmström Johan , Bahnan Wael , Shannon Oonagh , Malmström Lars , Nordenfelt Pontus
Published: October 2023

Antibodies are central to the immune response against microbes. We have previously generated a protective IgG1 monoclonal antibody targeting the M protein, a critical virulence factor ofStreptococcus pyogenes.Here, we generated this antibody in all human IgG subclasses and evaluated their function. Despite significantly reduced binding, the IgG3 subclass antibody demonstrated remarkably enhanced opsonic function. We hypothesized that increased Fc flexibility could explain this improved efficacy. We engineered a hybrid IgG subclass antibody, IgGh, containing the backbone of IgG1 with the hinge of IgG3, leaving the Fabs unchanged. The IgGh maintained a similar binding ability as IgG1 while gaining the strong opsonic function seen with IgG3. Molecular dynamics simulations of the different antibodies showed altered IgG Fab-antigen interactions, reflecting the differences observed in affinity. More importantly, when the antibodies were bound to the antigen, the simulations showed that the Fc of both IgGh and IgG3 exhibited extensive movement in 3D space relative to the M protein. The increased flexibility of IgGh directly translated to enhanced opsonic function and significantly increased the protection against infection withStreptococcus pyogenesin mice. Our findings demonstrate how altering Fc flexibility can improve Fc-mediated opsonic function and how modifications in the constant domain can regulate Fab-antigen interactions. In addition, the enhancedin vivofunction of a more flexible IgG provides new therapeutic opportunities for monoclonal antibodies.

One sentence summary

Antibody Fc flexibility in 3D space correlates with efficient Fc-mediated phagocytosis of streptococci
Biodesign of Frugal CRISPR Kits for Equitable and Accessible Education
Authors: Collins Marvin C. , Lau Matthew B. , Ma William , Shen Aidan , Russa Marie La , Qi Lei S.
Published: October 2023

Equitable and accessible education on life sciences and bioengineering is crucial to training the next generation of scientists, fostering transparency in public decision-making, and ensuring biotechnology democratization that can benefit a wide-ranging population. As a ground-breaking technology for genome engineering, CRISPR has transformed research and therapeutics. However, hands-on exposure to this technology for educational purposes has remained restricted, primarily due to extensive resources required to execute CRISPR experiments. In this study, we develop an accessible and frugal CRISPR kit, tailored for K-12 education settings. Our CRISPR kit eliminates the need for equipment, prioritizes biosafety, and utilizes cost-effective reagents. By combining CRISPRi gene regulation, chromoproteins, cell-free transcription-translation systems, and smartphone-based quantification, our kit offers a user-friendly approach and a reliable assessment of CRISPR activity, eliminating the need for a traditional laboratory setup. Experiments conducted by high school students in real-world settings highlight the kit’s utility for conducting reliable CRISPR experiments. The frugal CRISPR kit provides a modular and expandable platform to offer hands-on experience in genome engineering, and will facilitate equitable and accessible education and technology democratization for communities of diverse socioeconomic and geographic backgrounds.
Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia
Authors: Bhattacharya Rachita , Kumari Jaya , Banerjee Shweta , Tripathi Jyoti , Mohan Nitin , Sinha Pradip
Published: October 2023

Out-of-context gain of nuclear signaling of mammalian YAP/TAZ orDrosophilaYki—the transcription cofactors of the highly conserved Hippo tumor suppressor pathway—is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs ofDrosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2—aDrosophilahomolog of mammalian IGFBP7—without arresting tumor progressionper se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs inDrosophilaby arresting runaway PI3K/Akt/TOR signaling.
Bayesian nonparametric (non-)renewal processes for analyzing neural spike train variability
Authors: Liu David , Lengyel Máté
Published: October 2023

Neural spiking activity is generally variable, non-stationary, and exhibits complex dependencies on covariates, such as sensory input or behavior. These dependencies have been proposed to be signatures of specific computations, and so characterizing them with quantitative rigor is critical for understanding neural computations. Approaches based on point processes provide a principled statistical framework for modeling neural spiking activity. However, currently, they only allow the instantaneous mean, but not the instantaneous variability, of responses to depend on covariates. To resolve this limitation, we propose a scalable Bayesian approach generalizing modulated renewal processes using sparse variational Gaussian processes. We leverage pathwise conditioning for computing nonparametric priors over conditional interspike interval distributions and rely on automatic relevance determination to detect lagging interspike interval dependencies beyond renewal order. After systematically validating our method on synthetic data, we apply it to two foundational datasets of animal navigation: head direction cells in freely moving mice and hippocampal place cells in rats running along a linear track. Our model exhibits competitive or better predictive power compared to state-of-the-art baselines, and outperforms them in terms of capturing interspike interval statistics. These results confirm the importance of modelingcovariate-dependentspiking variability, and further analyses of our fitted models reveal rich patterns of variability modulation beyond the temporal resolution of flexible count-based approaches.
The role of immune inflammatory response and inflammatory infiltrates in major depression disorder and atopic dermatitis: new insights from machine learning
Authors: Jiang Han , Gong Bizhen , Yao Mengxi , Pan Bo , Zhang Hongya
Published: October 2023

Background

Major depression disorder (MDD) and atopic dermatitis (AD) are distinct disorders involving immune inflammatory responses. This study aimed to investigate the comorbid relationship between AD and MDD and to identify possible common mechanisms.

Methods

We obtained AD and MDD data from the Gene Expression Omnibus (GEO) database. Differential expression analysis and the Genecard database were employed to identify shared genes associated with inflammatory diseases. These shared genes were then subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Hub genes were selected based on the protein-protein interactions using CytoHubba, and key regulatory genes were identified through enrichment analysis. Subsequently, we conducted immune infiltration and correlation analyses of the shared genes in AD. Finally, we employed three machine learning models to predict the significance of shared genes.

Results

A total of 17 shared genes were identified in the AD_Inflammatory_MDD dataset (S100A9, PTGER2, PI3, SNCA, DAB2, PDGFA, FSTL1, CALD1, XK, UTS2, DHRS9, PARD3, NFIB,TMEM158, LIPH, RAB27B, and SH3BRL2). These genes were associated with biological processes such as the regulation of mesenchymal cell proliferation, mesenchymal cell proliferation, and glial cell differentiation. The neuroactive ligand-receptor interaction, IL-17 signaling, and Rap1 signaling pathways were significantly enriched in KEGG analysis. SNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as hub genes contributing to comorbid AD and MDD development. The three machine learning models consistently identified SNCA and PARD3 as important biomarkers.

Conclusion

SNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as significant genes contributing to the development of AD and MDD comorbidities. Immune infiltration analysis showed a notable increase in the infiltration of various subtypes of CD4+ T cells, suggesting a potential association between the development of skin inflammation and the immune response. Across different machine learning models, SNCA and PARD3 consistently emerged as important biomarkers.
Micronucleus Is Not a Potent Inducer of cGAS-STING Pathway
Authors: Sato Yuki , Hayashi Makoto T.
Published: October 2023

Micronucleus (MN) has been associated with the innate immune response. The abrupt rupture of MN membranes results in the accumulation of cGAS, potentially activating STING and downstream interferon-responsive genes. However, direct evidence connecting MN and cGAS activation has been lacking. We have developed the FuVis2 reporter system, which enables the visualization of cell nucleus carrying a single sister chromatid fusion and, consequently, MN. Using this FuVis2 reporter equipped with cGAS and STING reporters, we rigorously assessed the potency of cGAS activation by MN in individual living cells. Our findings reveal that cGAS localization to membrane-ruptured MN during interphase is infrequent, with cGAS primarily capturing MN during mitosis and remaining bound to cytosolic chromatin. We found that cGAS accumulation during mitosis neither activates STING in the subsequent interphase nor triggers the interferon response. Gamma-ray irradiation activates STING independently of MN formation and cGAS localization to MN. These results suggest that cGAS accumulation in the cytosol is not a robust indicator of its activation and that MN is not the primary trigger of the cGAS/STING pathway.
Establishing an AI-based evaluation system that quantifies social/pathophysiological behaviors of common marmosets
Authors: Kaneko Takaaki , Matsumoto Jumpei , Lu Wanyi , Zhao Xincheng , Ueno-Nigh Louie Richard , Oishi Takao , Kimura Kei , Otsuka Yukiko , Zheng Andi , Ikenaka Kensuke , Baba Kousuke , Mochizuki Hideki , Nishijo Hisao , Inoue Ken-ichi , Takada Masahiko
Published: October 2023

Nonhuman primates (NHPs) are indispensable animal models by virtue of the continuity of behavioral repertoires across primates, including humans. However, behavioral assessment at the laboratory level has so far been limited. By applying multiple deep neural networks trained with large-scale datasets, we established an evaluation system that could reconstruct and estimate three-dimensional (3D) poses of common marmosets, a small NHP that is suitable for analyzing complex natural behaviors in laboratory setups. We further developed downstream analytic methodologies to quantify a variety of behavioral parameters beyond simple motion kinematics, such as social interactions and the internal state behind actions, obtained solely from 3D pose data. Moreover, a fully unsupervised approach enabled us to detect progressively-appearing symptomatic behaviors over a year in a Parkinson’s disease model. The high-throughput and versatile nature of our analytic pipeline will open a new avenue for neuroscience research dealing with big-data analyses of social/pathophysiological behaviors in NHPs.
Sensing, Feeling, and Regulating: Investigating the Association of Focal Brain Damage with Voluntary Respiratory and Motor Control
Authors: Bischoff Henrik , Kovach Christopher , Kumar Sukbhinder , Bruss Joel , Tranel Daniel , Khalsa Sahib S
Published: October 2023

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal, or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia, and left medial temporal lobe showed reduced performance than individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60-bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal, or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing.

Highlights

Impaired human respiratory regulation is associated with cortical/subcortical brain lesions

Frontolimbic/temporal regions contribute to rhythmic breathing and hand motor control

Frontolimbic/temporal damage is associated with anxiety during tachypnea/irregular breathing

The human forebrain is vital for affective and interoceptive experiences during breathing
Electrical brain activations in preadolescents during a probabilistic reward-learning task reflect cognitive processes and behavioral strategy
Authors: Chung Yu Sun , van den Berg Berry , Roberts Kenneth C. , Bagdasarov Armen , Woldorff Marty G. , Gaffrey Michael S.
Published: October 2023

Both adults and children learn through feedback which environmental events and choices are associated with higher probability of reward, an ability thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, tasks and measures effective for assaying the cascade of reward-learning neural processes in children have been limited. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (8-12 years old; n=30), namely: (1) reward-feedback sensitivity, as measured by the early-latency, reward-related, frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavioral strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate preadolescents can learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward-feedback sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli as we have observed in adults. Lastly, we found the behavioral learning strategy (i.e., Win-Stay-Lose-Shift) reflected by the feedback-elicited parietal P300. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.
The role of RNA in the maintenance of chromatin domains as revealed by antibody mediated proximity labelling coupled to mass spectrometry
Authors: Choudhury Rupam , Venkatasubramani Anuroop Venkateswaran , Hua Jie , Borsò Marco , Forne Ignasi , Imhof Axel
Published: October 2023

Eukaryotic chromatin is organised in individual domains, which are defined by their location within the nuclear space, the molecular interactions within each other and their distinct proteomic compositions. In contrast to cellular organelles surrounded by lipid membranes, the composition of distinct chromatin domains is rather ill described and highly dynamic. To identify proteins associated with a specific chromatin domain and to better understand how those domains are established and maintained, we used a new method, which we termed AMPL-MS (Antibody mediated proximity labelling mass spectrometry). This method is based on antibodies and does not require the expression of fusion proteins and therefore constitutes a versatile and very sensitive method to characterize chromatin domains containing specific signature proteins or histone modifications. We used AMPL-MS to characterize the composition of chromocenter as well as the chromosome territory containing the hyperactive X-chromosome inDrosophila. As an outcome of this method, we show the importance of RNA in maintaining the integrity of these domains as treatment with RNAse alters their proteomic composition. Our data demonstrate the power of AMPL-MS to characterize the composition of non-membranous nuclear domains.
Age-related disparities in oscillatory dynamics within scene-selective regions during spatial navigation
Authors: Durteste Marion , Delaux Alexandre , Ariztégui Ainhoa , Cottereau Benoit R. , Sheynikhovich Denis , Ramanoël Stephen , Arleo Angelo
Published: October 2023

Position is a key property that allows certain objects in the environment to attain navigational relevance. Symmetrical processing of object position across the horizontal meridian remains an unchallenged assumption of the spatial navigation literature. Nonetheless, a growing body of research reports vertical inhomogeneities in perceptual tasks, and recent evidence points towards a lower visual field preference in healthy aging. Factoring in the vertical position of objects to better apprehend spatial navigation abilities across the lifespan is essential. The occipital place area (OPA), parahippocampal place area (PPA), and medial place area (MPA) are ideal candidates to support the processing of the vertical location of navigational cues. Indeed, they are implicated in scene processing and spatial cognition, functions that may interact with their underlying retinotopic codes. This study aimed to elucidate whether young and older participants adjusted their gaze patterns and EEG activity within scene-selective regions in response to the vertical arrangement of landmarks. A sample of 21 young and 21 older participants completed a desktop-based task requiring them to navigate using objects at different vertical locations. We equipped them with an eye tracker and a high-density EEG cap. We used a fMRI-informed source-reconstruction algorithm to study the OPA, PPA and MPA with high spatial and temporal precision. Older adults exhibited a higher number of errors compared to young adults during reorientation. This age-related decline in accuracy was accompanied by a tendency among older participants to fixate objects in the lower half of the screen. This gaze bias was absent in young participants, who instead adapted their oculomotor behaviour based on the position of navigationally-relevant information. Another primary finding pertains to the differential pattern of theta and beta band activity in the OPA, PPA and RSC for environments that only contained relevant cues in the upper visual field. It thus appears that scene-selective regions process some aspect of the vertical position of information, irrespectively of their inherent retinotopic biases. Moreover, we revealed striking disparities between age groups in beta/gamma band synchronization in all scene-selective regions, indicating compromised top-down attentional mechanisms during spatial navigation in ageing. These age-related disparities in attentional dynamics might account for performance deficits in older participants. This study sheds light on a systematic downward gaze bias and altered attentional dynamics within scene-selective regions during spatial navigation in older age. It also emphasises the importance of considering vertical positioning as a fundamental property of objects within scenes.
Overcoming Pitfalls when Estimating Variation in Parental Care: A Simulation Study
Authors: Mundry R. , Dal Pesco F. , Avilès de Diego A. , Fischer J.
Published: October 2023

1.

Background

In many animal species, parents allocate resources to enhance offspring survival and thereby reproductive success (‘parental investment’). Parental care behaviors are a crucial part of parental investment, and one critical question in behavioral ecology is to which degree variation in parental care affects offspring development and survival. Crucially, parental care behaviors vary with offspring age, which creates non-trivial problems for statistical analyses, specifically when sampling is incomplete or biased.

2.

Methods

We conducted a simulation study to illustrate the problem when analyzing average parental care behaviors while not correcting for offspring age (‘conventional approach’), and propose a modeling approach to correct for offspring age and sampling biases. We simulated a set of different scenarios, varying with regard to sample size, sampling scheme, and variation in parental behavior. To model parent behavior as a function of offspring age, we fitted a Generalized Linear Mixed Model to each simulated data set. We included offspring age as a fixed effect and extracted Best Linear Unbiased Predictors (BLUPs) for the random intercept of parent identity. These BLUPs represent the parental behavior corrected for offspring age. Finally, we assessed how our proposed modeling approach compares to the conventional approach.

3.

Results

The proposed modeling approach was superior to the conventional approach. More specifically, the conventional approach clearly overestimated the variation between parents, and even diagnosed appreciable variation when there was none in the simulated data. This bias was exacerbated in incomplete or unbalanced sampling schemes.

4.

Conclusion.

Our simulation study clearly demonstrates the necessity of correcting for offspring age in analyses of parental behavior. We strongly suggest including random slopes of offspring age within parent-offspring dyads, because doing so can reveal parent-specific trajectories of the modeled behavior against offspring age. Our approach allows for the inclusion of further categorical and continuous predictor variables that may affect parental behavior, such as parity or ecological conditions. In summary, the proposed modeling approach has several advantages over conventional methods.
Cell type specificity of mosaic chromosome 1q gain resolved by snRNA-seq in a case of epilepsy with hyaline protoplasmic astrocytopathy
Authors: Leng Kun , Cadwell Cathryn R. , Devine W. Patrick , Tihan Tarik , Qi Zhongxia , Singhal Nilika , Glenn Orit , Kamiya Sherry , Wiita Arun , Berger Amy , Shieh Joseph T. , Titus Erron W. , Paredes Mercedes F. , Upadhyay Vaibhav
Published: October 2023

STRUCTURED ABSTRACT

Introduction

Mosaic gain of chromosome 1q (chr1q) has been associated with malformation of cortical development (MCD) and epilepsy. Hyaline protoplasmic astrocytopathy (HPA) is a rare neuropathological finding seen in cases of epilepsy with MCD. The cell-type specificity of mosaic chr1q gain in the brain and the molecular signatures of HPA are unknown.

Methods

We present a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and HPA. We performed single-nuclei RNA-sequencing (snRNA-seq) of brain tissue from the second resection.

Results

snRNA-seq showed increased expression of chr1q genes specifically in subsets of neurons and astrocytes. Differentially expressed genes associated with inferred chr1q gain includedAKT3and genes associated with cell adhesion or migration. A subpopulation of astrocytes demonstrated marked enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in HPA.

Discussion

snRNA-seq may be used to infer the cell type-specificity of mosaic chromosomal copy number changes and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of HPA.
Structural covariation between cerebellum and cerebral cortex is atypically modulated by thalamus in autism spectrum disorder
Authors: d’Oleire Uquillas Federico , Sefik Esra , Li Bing , Trotter Matthew A. , Steele Kara , Seidlitz Jakob , Gesue Rowen , Latif Mariam , Fasulo Tristano , Zhang Veronica , Kislin Mikhail , Verpeut Jessica L. , Cohen Jonathan D. , Sepulcre Jorge , Wang Samuel S.-H. , Gomez Jesse
Published: October 2023

Despite its strong interconnectivity with the cerebral cortex, the influence of the human cerebellum on neocortical structure and its role in the development of neuropsychiatric disorders is unclear. Because cerebellar damage in early postnatal life creates a high risk for autism spectrum disorder (ASD), we investigated inter-relationships in cerebello-cerebral morphology. Leveraging a large structural brain MRI dataset in neurotypical children (n=375) and those diagnosed with ASD (n=373), we examined whether volumetric variation in cerebellar structure across individuals was correlated with neocortical variation during development, modeling the thalamus as a moderating coupling factor. We found negative covariation between cerebellar cortical regions and thalamic/sensorimotor neocortical regions, and positive covariation between thalamic and sensorimotor neocortical regions. This pattern aligned with the major disynaptic path of cerebellar inhibition to thalamocortical excitation. Examining the dependence of this structural covariation on ASD diagnosis, we found that neurotypical and ASD children displayed inverted hemispheric biases. In ASD, the thalamus moderated structural associations between the left cerebellum and right sensorimotor cortex. For neurotypical children, right cerebellum and left sensorimotor cortex were coupled. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, a time during which behavioral differences were smallest between typically developing and autistic children. In addition to the sensorimotor cortex, cerebellar dentate nuclei in ASD displayed greater coupling to broad neocortical regions, and these nuclei related to cognitive function differently such that greater dentate nuclear volume was associated with greater behavioral impairment in ASD but not in controls. Graph analyses demonstrated that the cerebello-thalamocortical network was more densely and less prolifically interconnected in ASD than in typical development. Taken as a whole, our study reveals a developmental interplay between the cerebellum, thalamus, and neocortex which differs in ASD from neurotypical children. This pattern is consistent with a model of ASD in which early developmental influences of cerebellar output on brain maturation are specifically moderated by cerebello-thalamocortical pathways.
Modeling the roles of cohesotaxis, cell-intercalation, and tissue geometry in collective cell migration ofXenopusmesendoderm
Authors: Comlekoglu Tien , Dzamba Bette J. , Pacheco Gustavo G. , Shook David R. , Sego T.J. , Glazier James A. , Peirce Shayn M. , DeSimone Douglas W.
Published: October 2023

Collectively migrating Xenopus mesendoderm cells are arranged into leader and follower rows with distinct adhesive properties and protrusive behaviors. In vivo, leading row mesendoderm cells extend polarized protrusions and migrate along a fibronectin matrix assembled by blastocoel roof cells. Traction stresses generated at the leading row result in the pulling forward of attached follower row cells. Mesendoderm explants removed from embryos provide an experimentally tractable system for characterizing collective cell movements and behaviors, yet the cellular mechanisms responsible for this mode of migration remain elusive. We introduce an agent-based computational model of migrating mesendoderm in the Cellular-Potts computational framework to investigate the relative contributions of multiple parameters specific to the behaviors of leader and follower row cells. Sensitivity analyses identify cohesotaxis, tissue geometry, and cell intercalation as key parameters affecting the migration velocity of collectively migrating cells. The model predicts that cohesotaxis and tissue geometry in combination promote cooperative migration of leader cells resulting in increased migration velocity of the collective. Radial intercalation of cells towards the substrate is an additional mechanism to increase migratory speed of the tissue.

Summary Statement

We present a novel Cellular-Potts model of collective cell migration to investigate the relative roles of cohesotaxis, tissue geometry, and cell intercalation on migration velocity ofXenopusmesendoderm
Noninvasive detection of Phenylalanine in the human brain with MRS at 7T
Authors: Salibi Nouha , Denney Thomas S , Deshpande Gopikrishna
Published: October 2023

We set out to measure phenylalanine in the human brain using magnetic resonance spectroscopy (MRS) in a ultra-high field 7T MRI scanner. Phenylalanine is a precursor to Norepinephrine, a neurotransmitter important for attention and arousal. Depletion in norepinephrine, especially in the locus coeruleus, has been implicated as an etiological factor in Alzheimer’s disease. Therefore, being able to noninvasively measure phenylalaninein vivoin humans has a multitude of translational applications. Using phantom experiments, we first validate and optimize the MRS techniques used for observing phenylalanine in the brain at 7T. However, we failed to detect phenylalanine in human volunteers (N=15). In order to understand the reasons for this failure, we performed experiments in a cat model with external phenylalanine injections to determine the amount of phenylalanine required for it to be detectedin vivoin the brain. This threshold was found to be 3.4 mM. This indicated that phenylalanine concentrations in both healthy and AD patients, that too in a small region such as the locus coeruleus, will likely not meet this threshold. Therefore, we conclude that even with state-of-the-art technologies and 7T MRI, it is not possible to detect phenylalanine in the human brainin vivounder natural conditions.
A Classification-Based Generative Approach to Selective Targeting of Global Slow Oscillations during Sleep
Authors: Alipour Mahmoud , Seok SangCheol , Mednick Sara C. , Malerba Paola
Published: October 2023

Background

Given sleep’s crucial role in health and cognition, numerous sleep-based brain interventions are being developed, aiming to enhance cognitive function, particularly memory consolidation, by improving sleep. Research has shown that Transcranial Alternating Current Stimulation (tACS) during sleep can enhance memory performance, especially when used in a closed-loop (cl-tACS) mode that coordinates with sleep slow oscillations (SOs, 0.5-1.5Hz). However, sleep tACS research is characterized by mixed results across individuals, which are often attributed to individual variability.

Objective/Hypothesis

This study targets a specific type of SOs, widespread on the electrode manifold in a short delay (“global SOs”), due to their close relationship with long-term memory consolidation. We propose a model-based approach to optimize cl-tACS paradigms, targeting global SOs not only by considering their temporal properties but also their spatial profile.

Methods

We introduce selective targeting of global SOs using a classification-based approach. We first estimate the current elicited by various stimulation paradigms, and optimize parameters to match currents found in natural sleep during a global SO. Then, we employ an ensemble classifier trained on sleep data to identify effective paradigms. Finally, the best stimulation protocol is determined based on classification performance.

Results

Our study introduces a model-driven cl-tACS approach that specifically targets global SOs, with the potential to extend to other brain dynamics. This method establishes a connection between brain dynamics and stimulation optimization.

Conclusion

Our research presents a novel approach to optimize cl-tACS during sleep, with a focus on targeting global SOs. This approach holds promise for improving cl-tACS not only for global SOs but also for other physiological events, benefiting both research and clinical applications in sleep and cognition.
Combinatorial binding of semantic information through the sharing of neural oscillatory signals
Authors: Noguchi Yasuki
Published: October 2023

We comprehend linguistic inputs (e.g. sentence) by retrieving semantic memory of each element (e.g. word) and integrating them. How semantic information is represented and bound as neural (electric) signals is an unsolved issue. I presently used a simple sentence composed of a noun phrase (NP) and a verb (V), comparing human electroencephalography (EEG) responses to a congruent sentence in which the NP and V were semantically related (e.g. “grass grows”) with those to an incongruent sentence (e.g. “a key grows”). In the left temporo-parietal cortex, neural oscillation patterns (8 – 30 Hz) to the second stimulus (V) shifted toward those to the first stimulus (NP), thereby producing coherent (faster and more regular) neural responses to the congruent sentence. No such NP-V interaction was observed in the incongruent sentence. These results indicate that the “semantic unification” as a linguistic concept actually takes place in neural oscillatory signals of the healthy human brain.
Genome wide association study of clinical duration and age at onset of sporadic CJD
Authors: Hummerich Holger , Speedy Helen , Campbell Tracy , Darwent Lee , Hill Elizabeth , Collins Steven , Stehmann Christiane , Kovacs Gabor G , Geschwind Michael D , Frontzek Karl , Budka Herbert , Gelpi Ellen , Aguzzi Adriano , van der Lee Sven J , van Duijn Cornelia M , Liberski Pawel P , Calero Miguel , Sanchez-Juan Pascual , Bouaziz-Amar Elodie , Laplanche Jean-Louis , Haïk Stéphane , Brandel Jean-Phillipe , Mammana Angela , Capellari Sabina , Poleggi Anna , Ladogana Anna , Pocchiari Maurizio , Zafar Saima , Booth Stephanie , Jansen Gerard H , Areškevičiūtė Aušrinė , Lund Eva Løbner , Glisic Katie , Parchi Piero , Hermann Peter , Zerr Inga , Appleby Brian S , Collinge John , Mead Simon
Published: October 2023

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration; all of which were located at chromosome 20 (top SNP rs1799990, pvalue=3.45×10-36, beta=0.34 for an additive model; rs1799990, pvalue=9.92×10-67, beta=0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but theHS6ST3gene was significant (pvalue=1.93 × 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants,PRNPcodon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.
Development and validation of risk prediction model for recurrent cardiovascular events among Chinese: P-CARDIAC model
Authors: Zhou Yekai , Lin Jiaxi , Yu Qiuyan , Blais Joseph Edgar , Wan Eric Yuk Fai , Lee Marco , Wong Emmanuel , Siu David Chung-Wah , Wong Vincent , Chan Esther Wai Yin , Lam Tak-Wah , Chui William , Wong Ian Chi Kei , Luo Ruibang , Chui Celine SL
Published: October 2023

This study aimed to develop and validate a cardiovascular diseases (CVD) risk prediction model, Personalized CARdiovascular DIsease risk Assessment for Chinese (P-CARDIAC), for recurrent cardiovascular events using Machine-Learning technique.

Three cohorts of Chinese patients with established CVD in Hong Kong were included; Hong Kong Island cohort as the derivation cohort, whilst the Kowloon and New Territories cohorts were validation cohorts. The 10-year CVD outcome was a composite of diagnostic or procedure codes for coronary heart disease, ischaemic or haemorrhagic stroke, peripheral artery disease, and revascularization. We estimated incidence of recurrent CVD events for each cohort with reference to the total person-years of each cohort. Multivariate imputation with chained equations (MICE) and XGBoost were applied for the model development. The comparison with TRS-2°P and SMART2 used the validation cohorts with 1000 bootstrap replicates.

A total 48,799, 119,672 and 140,533 patients were included in the derivation and validation cohorts, respectively. A list of 125 risk variables were used to make predictions on CVD risk, of which, eight classes of medications were considered interactive drug use. Model performance in the derivation cohort showed satisfying discrimination and calibration with a C-statistic of 0·69. Internal validation showed good discrimination and calibration performance with C-statistic over 0·6. P-CARDIAC also showed better performance than TRS-2°P and SMART2.

Compared to other risk scores, P-CARDIAC enables to identify unique patterns of Chinese patients with established CVD. We anticipate that P-CARDIAC can be applied in various settings to prevent recurrent CVD events, thus reducing the related healthcare burden.

Condensed Abstract

A CVD risk prediction model named Personalized CARdiovascular DIsease risk Assessment for Chinese (P-CARDIAC), for recurrent cardiovascular events among Chinese adults using Machine-Learning technique was newly developed. It predicted 10-year CVD outcome including a composite of diagnostic or procedure codes for coronary heart disease, ischaemic or haemorrhagic stroke, peripheral artery disease, and revascularization by incidence of recurrent CVD. Model showed satisfying discrimination and calibration with a C-statistic of 0·69. P-CARDIAC also showed better performance than existing risk scores, such as TRS-2°P and SMART2. P-CARDIAC could help predict recurrent CVD risk and reduce the healthcare burden.