bluuebunny/crossref_metadata_2025 huggingface dataset:
Effort in Oculomotor Control: Role of Instructions and Reward on Spatio-temporal Eye Movement Dynamics
Authors: Wolf Christian , Steinborn Michael B , Huestegge Lynn
Published: September 2024

Effort is an important construct in several psychological disciplines, yet there is little consensus on how it manifests in behavior. Here, we focus on effort in terms of performance improvements beyond speed-accuracy tradeoffs and argue that oculomotor kinematics are conducive to a more fine-grained understanding of effortful behavior. Specifically, we investigated the efficiency and persistence of mere task instructions to induce transient effort. In a saccadic selection task, participants were instructed to look at targets as quickly and accurately as possible (standard instructions) or to mobilize all resources and respond even faster and more accurately ('to give 110%', effort instructions). We compared results to standard speeded performance (baseline block) and to a potential upper performance limit linking effort to performance-contingent rewards (reward block). Performance improved beyond speed-accuracy tradeoffs when reward was present. Effort instructions reduced saccade latencies, increased amplitudes and changed the saccade main sequence relationship. Yet, these effects were more strongly pronounced and more persistent over time when effort was additionally rewarded. Altogether, the present findings underscore the possibility to intentionally activate cognitive resources for regulating oculomotor performance. Yet, its effectiveness and maintenance over time are more successful when behavior is rendered purposeful by the presence of reward.
Test-retest reliability of resting-state EEG intrinsic neural timescales
Authors: Tang Xiaoling , Wang Shan , Xu Xinye , Luo Wenbo , Zhang Mingming
Published: September 2024

Intrinsic neural timescales (INTs), which reflect the duration of neural information storage within local brain regions and capacity for information integration, are typically measured using autocorrelation windows (ACWs). Extraction of INTs from resting-state brain activity has been extensively applied in psychiatric disease research. Given the potential of INTs as a neural marker for psychiatric disorders, investigating their reliability is crucial. This study, using an open-source database, aimed to evaluate the test-retest reliability of ACW-0 and ACW-50 under both eyes-open and eyes-closed conditions across three sessions. The intraclass correlation coefficients (ICCs) were employed to quantify the reliability of the INTs. Our results showed that INTs exhibited good reliability (ICC > 0.6) at the whole-brain level across different index types and eye states. Spatially, except for the right temporal region in the eyes-open condition, all other regions showed moderate-to-high ICCs. Over 60% of the electrodes demonstrated moderate-to-high INT ICCs under both eyes-open and eyes-closed conditions, with ACW-0 being more stable than ACW-50. This present study comprehensively assessed the reliability of INT under various conditions, providing robust evidence for their stability in neuroscience and psychiatry.
Advanced Tissue Technologies of Blood-Brain Barrier Organoids as High Throughput Toxicity Readouts in Drug Development
Authors: Bell Luisa , Simonneau Claire , Zanini Chiara , Kassianidou Elena , Zundel Christelle , Neff Rachel , Steinhuber Bernd , Tecilla Marco , Odermatt Alex , Villaseñor Roberto , Stokar-Regenscheit Nadine
Published: September 2024

Recent advancements in engineering Complexin vitromodels (CIVMs) such as Blood-brain barrier (BBB) organoids offer promising platforms for preclinical drug testing. However, their application in drug development, and especially for the regulatory purposes of toxicity assessment, requires robust and reproducible techniques. Here, we developed an adapted set of orthogonal image-based tissue methods including hematoxylin and eosin staining (HE), immunohistochemistry (IHC), multiplex immunofluorescence (mIF), and Matrix Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) to validate CIVMs for drug toxicity assessments. We developed an artificial intelligence (AI) algorithm to increase the throughput and the reliability of histomorphologic evaluations of apoptosis forin vitrotoxicity studies. Our data highlight the potential to integrate advanced morphology-based readouts such as histological techniques and digital pathology algorithms for use on CIVMs, as part of a standard preclinical drug development assessment.

Graphical abstract

The graphical abstract was partially created with biorender.com.

Highlights

Advanced Complexin vitromodels (CIVMs) like Blood-brain barrier (BBB) organoids show promise for preclinical drug testing. However, robust and reproducible techniques are crucial for the acceptance of CIVMs in drug development processes, especially for toxicity assessments which are highly regulated by health authorities.

We developed orthogonal image-based readouts on histological sections to enable the use of BBB organoids for future compound toxicity assessment.

A newly established artificial intelligence (AI) algorithm provides automated and label-free detection of apoptotic cells in drug screening using BBB organoids and provides an alternative killing assay on single cell resolution (40×) to current standards.
Multiplexing of functionally distinct inputs by intrinsic modulation of spike timing in a monoaminergic nucleus
Authors: Lynn Michael , Maler Leonard , Béïque Jean-Claude
Published: September 2024

Monoaminergic nuclei such as the serotonergic dorsal raphe nucleus (DRN) receive synaptic inputs containing functionally distinct streams of information, yet the dimensionality of the resulting output population code and its cellular underpinning are currently unknown. By combining electrophysiological and computational approaches, here we uncover separable neural encoding of two excitatory inputs conveying disjunct information to DRN 5-HT neurons - the lateral habenula (LHb) and medial prefrontal cortex (mPFC). Dual-color opsin strategies revealed that a population of 5-HT neurons receive inputs from both mPFC and LHb. Subthreshold excitatory postsynaptic potentials triggered by both inputs were largely indistinguishable, yet suprathreshold spiking behavior exhibited input-specific latencies and dispersion statistics. A support vector machine classifier demonstrated that input identity can be accurately decoded from spike timing, but not subthreshold events, of under ten 5-HT neurons. Upon examining the intrinsic cellular mechanisms in 5-HT neurons that couple EPSPs to spiking dynamics, we uncovered two likely candidate mechanisms: a low-threshold calcium conductance that selectively boosts slow excitatory inputs, and a subthreshold, voltage-dependent membrane noise that generates variation of spike latency and jitter. Stochastic simulations suggest that these two intrinsic properties of 5-HT neurons are sufficient to transform LHb and mPFC inputs into distinct output spiking patterns. These results reveal that hub-like networks like the DRN can segregate distinct informational streams by a cell-intrinsic mechanism. The resulting emergent population spike synchrony code provides a means for the DRN to widely broadcast these streams as a multiplexed signal.

Significance statement

Phylogenetically old neuromodulatory systems in the brain, such as the serotonergic dorsal raphe nucleus, are compact yet richly innervated structures. Here, we use the raphe as a testbed to ask how distinct informational sources to hub-like networks are processed or integrated into a coherent neural code. Using electrophysiological and computational methods, including biophysically grounded stochastic simulations, we find that intrinsic noise mechanisms in serotonergic neurons are critical to transform approximately matched subthreshold excitation into distinct spike timing profiles. Thus, cell-intrinsic noise mechanisms can effectively synthesize a spike synchrony code that, we hypothesize, multiplexes input information to hub-like networks at the population level even in the absence of strong local circuit interactions.
Environment-mediated interactions cause an externalized and collective memory in microbes
Authors: Gajrani Shubham , Ye Xiaozhou , Ratzke Christoph
Published: September 2024

Microbes usually live in complex communities interacting with many other microbial species. These interactions determine who can persist in a community and how the overall community forms and functions. Microbes often exert interactions by chemically changing the environment, like taking up nutrients or producing toxins. These environmental changes can persist over time. We show here that such lasting environmental changes can cause a memory effect where current growth conditions alter interaction outcomes in the future. Importantly, this memory is only stored in the environment and not inside the bacterial cells. Only the collective effort of many bacteria can build up this memory, making it an emergent property of bacterial populations. This “population memory” can also impact the assembly of more complex communities and lead to different final communities depending on the system’s past. Overall, we show that to understand interaction outcomes fully, we not only have to consider the interacting species and abiotic conditions but also the system’s history.
Targets of influenza Human T cell response are mostly conserved in H5N1
Authors: Sidney John , Kim A-Reum , de Vries Rory D. , Peters Bjoern , Meade Philip S. , Krammer Florian , Grifoni Alba , Sette Alessandro
Published: September 2024

Frequent recent spillovers of subtype H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus into poultry and mammals, especially dairy cattle, including several human cases, increased concerns over a possible future pandemic. Here, we performed an analysis of epitope data curated in the Immune Epitope Database (IEDB). We found that the patterns of immunodominance of seasonal influenza viruses circulating in humans and H5N1 are similar. We further conclude that a significant fraction of the T cell epitopes is conserved at a level associated with cross-reactivity between avian and seasonal sequences, and we further experimentally demonstrate extensive cross-reactivity in the most dominant T cell epitopes curated in the IEDB. Based on these observations, and the overall similarity of the neuraminidase (NA) N1 subtype encoded in both HPAI and seasonal H1N1 influenza virus as well as cross-reactive group 1 HA stalk-reactive antibodies, we expect that a degree of pre-existing immunity is present in the general human population that could blunt the severity of human H5N1 infections.
Ultrastructural analysis of the brain endothelium by electron tomography
Authors: Kotchetkov Pavel , Lacoste Baptiste
Published: September 2024

Transmission electron microscopy (TEM) is a powerful imaging technique, yielding ultrastructural investigation of organic and non-organic samples. Despite its ability to reach nanoscale resolutions, conventional TEM presents a major disadvantage by only acquiring two-dimensional snapshots, thus hindering our volumetric understanding of samples. Electron tomography (ET) overcomes this limitation by offering detailed views of a thin specimen in 3 dimensions (3D). This technique is widely used in biology and has expanded our understanding of mitochondrial structure or synaptic organization. Proper brain functioning is highly reliable on a constant nutritional support through its microvasculature lined by endothelial cells. These unique cells form a selective and protective barrier, known as the blood-brain barrier (BBB), which limits the entrance of blood-borne molecules into the brain. In pathological conditions, the BBB is disrupted, resulting in neuronal damage. Understanding the fine changes underlying BBB disruption requires advanced imaging tools such as ET, to detect the finest changes in endothelial ultrastructure. This manuscript briefly explains how TEM and ET function, and then provides a detailed, didactic method for sample preparation, tomogram generation and 3D segmentation of brain endothelial cells using ET.
The level of endothelial glycocalyx maturity modulates interactions with charged nanomaterials
Authors: Bridges Claire A. , Fu Lu , Yeow Jonathan , Huang Xiaojing , Jackson Miriam , Kuchel Rhiannon P. , Sterling James D. , Baker Shenda M. , Lord Megan S.
Published: September 2024

Nanomaterials have been extensively investigated for their potential in delivering therapeutics to target tissues, but few have advanced to clinical application. The luminal surface of endothelial cells that line blood vessels are covered by a glycocalyx, a complex extracellular matrix rich in anionic glycans. However, the role of this glycocalyx in governing nanomaterial-cell interactions is often overlooked. In this study, we demonstrate that gold nanoparticles functionalized with branched polyethyleneimine (AuNP+) bind to primary human endothelial cells expressing either a developing or mature glycocalyx, with the interaction involving hyaluronan and heparan sulfate. Notably, the mature glycocalyx decreases the toxicity of AuNP+. In contrast, lipoic acid-functionalized gold nanoparticles (AuNP-) bind to endothelial cells with a developing glycocalyx, but not a mature glycocalyx. To further investigate this phenomenon, we studied charged polymers, including poly(arginine) (polyR) and poly(glutamic acid) (polyE). PolyE does not associate with endothelial cells regardless of glycocalyx maturity, but when glycans are enzymatically degraded, it can bind to the cells. Conversely, polyR associates with endothelial cells irrespective of glycocalyx maturity or glycan degradation. These findings highlight the intricate relationship between nanomaterial charge and presentation in interactions with endothelial cells, offering insights for modulating nanomaterial interactions with the blood vessel wall.
How does co-occurrence ofDaphniaspecies affect their gut microbiome?
Authors: Houwenhuyse Shira , Massol Francois , Macke Emilie , De Meester Luc , Vanoverberghe Isabel , Stoks Robby , Decaestecker Ellen
Published: September 2024

Species co-occurrence can lead to competitive interactions that influence fitness. Competition is typically assumed to be modulated by species niche, especially food–acquisition related traits. The influence of interspecific interactions on host microbiome communities has rarely been considered, and yet may provide an alternative mechanism regarding the effect of host species co-occurrence on their fitness. Here, we investigated whether the composition of the gut microbial community differs between twoDaphniaspecies (D. magnaandD. pulex), and whether the gut microbiome of one species depends on the presence of the other. We hypothesized the stronger filter-feederD. magnato have a larger effect on the gut microbiome of the weaker filter-feederD. pulexthanvice versa. To this purpose, threeD. magnaand threeD. pulexgenotypes were first made axenic and then grown in monocultures or in cocultures in natural environmental bacterioplankton-enriched water, before assessing the community composition of the gut microbiomes and bacterioplankton. We found that the composition of the gut microbiome of the twoDaphniaspecies did not significantly differ overall. However, subtle differences between mono- and cocultures were found at theDaphniagenotype level. For most genotype combinations (six out of nine), the microbiome ofD. pulexchanged more when grown in cocultures withD. magnathan in monocultures. This provides limited support for our hypothesis that the stronger competitor has a larger effect on the gut microbiome of the weaker one thanvice versa, and that this effect is possibly mediated via the bacterioplankton community.
Predicting Task Activation Maps from Resting-State Functional Connectivity using Deep Learning
Authors: Madsen Soren J. , Uddin Lucina Q. , Mumford Jeanette A. , Barch Deanna M. , Fair Damien A. , Gotlib Ian H. , Poldrack Russell A. , Kuceyeski Amy , Saggar Manish
Published: September 2024

Recent work has shown that deep learning is a powerful tool for predicting brain activation patterns evoked through various tasks using resting state features. We replicate and improve upon this recent work to introduce two models, BrainSERF and BrainSurfGCN, that perform at least as well as the state-of-the-art while greatly reducing memory and computational footprints. Our performance analysis observed that low predictability was associated with a possible lack of task engagement derived from behavioral performance. Furthermore, a deficiency in model performance was also observed for closely matched task contrasts, likely due to high individual variability confirmed by low test-retest reliability. Overall, we successfully replicate recently developed deep learning architecture and provide scalable models for further research.
Anisotropy of object nonrigidity: High-level perceptual consequences of cortical anisotropy
Authors: Maruya Akihito , Zaidi Qasim
Published: September 2024

We demonstrate an unexpected anisotropy in perceived object non-rigidity, a higher-level perceptual phenomenon, and explain it by the population distribution of low-level neuronal properties in primary visual cortex. We measured the visual interpretation of two rigidly connected rotating circular rings. In videos where observers predominantly perceived rigidly-connected horizontally rotating rings, they predominantly perceived non-rigid independently wobbling rings if the video was rotated by 90°. Additionally, vertically rotating rings appeared narrower and longer than horizontally rotating counterparts. We decoded these perceived shape changes from V1 outputs incorporating documented cortical anisotropies in orientation selectivity: more cells and narrower tuning for the horizontal orientation than for vertical. Even when shapes were matched, the non-rigidity anisotropy persisted, suggesting uneven distributions of motion-direction mechanisms. When cortical anisotropies were incorporated into optic flow computations, the kinematic gradients (Divergence, Curl, Deformation) for vertical rotations aligned more with derived gradients for physical non-rigidity, while those for horizontal rotations aligned closer to rigidity. Our results reveal how high-level non-rigidity percepts can be shaped by hardwired cortical anisotropies. Cortical anisotropies are claimed to promote efficient encoding of statistical properties of natural images, but their surprising contribution to failures of shape constancy and object rigidity raise questions about their evolutionary function.
Interpreting prediction intervals and distributions for decoding biological generality in meta-analyses
Authors: Yang Yefeng , Noble Daniel W. A. , Senior Alistair M. , Lagisz Malgorzata , Nakagawa Shinichi
Published: September 2024

Despite the importance of identifying predictable regularities for knowledge transfer across contexts, the generality of ecological and evolutionary findings is yet to be systematically quantified. We present the first large-scale evaluation of generality using new metrics. By focusing on biologically relevant study levels, we show that generalization is not uncommon. Overall, 20% of meta-analyses will produce a non-zero effect 95% of the time in future replication studies with a 70% probability of observing meaningful effects in study-level contexts. We argue that the misconception that generalization is exceedingly rare is due to conflating within-study and between-study variances in ecological and evolutionary meta-analyses, which results from focusing too much on total heterogeneity (the sum of within-study and between-study variances). We encourage using our proposed approach to elucidate general patterns underpinning ecological and evolutionary phenomena.
AI-generated small binder improves prime editing
Authors: Park Ju-Chan , Uhm Heesoo , Kim Yong-Woo , Oh Ye Eun , Bae Sangsu
Published: September 2024

The prime editing 2 (PE2) system comprises a nickase Cas9 fused to a reverse transcriptase utilizing a prime editing guide RNA (pegRNA) to introduce desired mutations at target genomic sites. However, the PE efficiency is limited by mismatch repair (MMR) that excises the DNA strand containing desired edits. Thus, inhibiting key components of MMR complex through transient expression of a dominant negative MLH1 (MLH1dn) exhibited approximately 7.7-fold increase in PE efficiency over PE2, generating PE4. Herein, by utilizing a generative artificial intelligence (AI) technologies, RFdiffusion and AlphaFold 3, we ultimately generated a de novo MLH1 small binder (named MLH1-SB), which bind to the dimeric interface of MLH1 and PMS2 to disrupt the formation of key MMR components. MLH1-SB’s small size (82 amino acids) allowed it to be integrated into pre-existing PE architectures via the 2A system, creating a novel PE-SB platform. Resultantly, by incorporating MLH1-SB into PE7, we have developed an improved PE architecture called PE7-SB, which demonstrates the highest PE efficiency to date (29.4-fold over PE2 and 2.4-fold over PE7 in HeLa cells), providing an insight that generative AI technologies will boost up the improvement of genome editing tools.
Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism
Authors: Isik Melis , Eylem Cemil Can , Erdogan-Gover Kubra , Aytar-Celik Pinar , Enuh Blaise Manga , Emregul Emel , Cabuk Ahmet , Yildirim Yalin , Nemutlu Emirhan , Muotri Alysson Renato , Derkus Burak
Published: September 2024

This study investigated the impact of different bacterial populations on the biomolecular structures of cerebral organoids (COs) at various levels. COs were co-cultured with non-pathogenic (NM) and pathogenic (PM) bacterial populations. PM reduced the number of TUJ1+ neurons and disrupted the intact structure of COs. In addition, PM was found to induce changes in the transcript profile of COs, including a decrease in the activity of the glycolysis pathway and an increase in the pentose phosphate pathway, leading to deterioration in cellular energy metabolism, which is linked to neurodegenerative diseases. Proteomic analysis revealed a unique cluster of proteins in COs. PM exposure upregulated proteins related to neurological diseases, consistent with RNA-seq data. Communication between bacteria and neural cells was demonstrated using18O-stable isotope labeling (SIL)-based metabolic flux analysis. COs showed higher18O-enrichment of TCA cycle intermediates when co-cultured with NM and PM, indicating increased oxidative phosphorylation activity upon exposure to bacteria. This study provides a useful platform to monitor metabolic signals and communication between microbiotas and human brain cells. The findings suggest that pathogenic bacteria release metabolites that alter biomolecular structures in brain organoids, potentially contributing to neurodegenerative diseases.
Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving
Authors: Hwang Eun-Kyung , Wunsch Amanda M. , Wolf Marina E.
Published: September 2024

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of ‘incubated rats’ normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.
Assessment of the hypoglycemic activity of trans-cinnamic acid isolated from the extract ofhairy rots Scutellaria baicalensisinin vivoexperiments
Authors: Mikhailovna Fedorova Anastasia , Sergeevna Milentyeva Irina , Konstantinovna Asyakina Lyudmila , Yuryevich Prosekov Alexander
Published: September 2024

Annotation

Hypoglycemia is the process of reducing blood glucose concentration to below 2.5–2.8 mmol/L in men and less than 1.9–2.2 mmol/L in women. Prolonged hyperglycemia can lead to a range of serious chronic complications such as diabetic nephropathy, diabetic retinopathy, cardiovascular diseases in diabetes, and so forth, threatening human life, health, and safety.Scutellaria baicalensisis one of the most commonly used remedies in traditional Chinese medicine. This plant contains a number of biologically active compounds that contribute to improving kidney function, insulin resistance, and retinopathy in patients with type 2 diabetes, but few researchers study the toxic effects of medicinal plant components. Therefore, the aim of this study was to evaluate the hypoglycemic activity of trans-cinnamic acid isolated from the extract ofhairy rots of Scutellaria baicalensisinin vivoexperiments. This study involved intraperitoneal administration of alloxan at a dose of 150.0 mg/kg and oral administration of trans-cinnamic acid at doses of 50.0 and 100.0 mg/kg. During the experiment, it was found that trans-cinnamic acid at the presented doses does not affect the body weight dynamics of experimental animals with diabetes. Thus, this study demonstrates that trans-cinnamic acid at the presented dosage can be safely used as an ingredient in the creation of dietary supplements for the prevention of diabetes, thereby contributing to healthy aging.
Monovalent XBB.1.5 mRNA Vaccine Recalls a More Durable and Coordinated Antibody Response to SARS-CoV-2 Spike than the Bivalent WT/BA.5 mRNA Vaccine
Authors: Barouch Susanna E , Levine Kate S , Blanc Ross , Wang Qixin , Tong Xin , McNamara Ryan P
Published: September 2024

In the fall of 2023, the monovalent XBB.1.5 mRNA vaccine for COVID-19 became available. However, the comparative magnitude, durability, and functionality of antibody responses induced by the XBB.1.5 vaccine compared with the 2022-2023 bivalent wildtype (WT) + Omicron BA.5 vaccine remains to be fully determined. In this study, we compared antibody profiles generated by these two vaccines in healthcare workers. We show that the monovalent XBB.1.5 vaccine induced higher magnitude binding, neutralizing, and Fc-gamma receptor (FcγR) binding antibodies to the XBB.1.5 spike compared with the bivalent vaccine against the WT and BA.5 spikes, both at both peak immunogenicity and at 6 months post-vaccination. Moreover, antibody interaction architectures and correlations remained more robust at 6 months post-vaccination with the XBB.1.5 vaccine, whereas these correlations were largely lost at 6 months with the bivalent vaccine. Our results suggest that the XBB.1.5 vaccine led to a more durable and functionally coordinated antibody response compared to the bivalent vaccine.
The role of feedback in responding to gradual and abrupt visuo-proprioceptive cue conflict
Authors: Babu R. , Matharu R. , Lo C. , Block H.J
Published: September 2024

When people observe conflicting visual and proprioceptive cues about their static hand position, visuo-proprioceptive recalibration results. Recalibration also occurs during gradual or abrupt visuomotor adaptation, in response to both the cue conflict and sensory prediction errors experienced as the hand reaches to a target. Here we asked whether creating a cue conflict gradually vs. abruptly, or providing error feedback, affects recalibration in a static hand. We examined participants’ responses to a 70 mm visuo-proprioceptive conflict, imposed by shifting the visual cue forward from the proprioceptive cue (static left hand). Participants pointed with their unseen right hand to indicate perceived bimodal and unimodal cue positions. Conflict was introduced gradually (groups 1 and 2) or abruptly (groups 3 and 4), with performance feedback present (groups 2 and 4) or absent (groups 1 and 3). For abrupt groups, most behavioral change occurred immediately after the conflict began. No-feedback groups (1 and 3) showed comparable magnitudes of overall recalibration, indicating that abrupt and gradual conflicts result in similar recalibration but with different timings. Motor adaptation was evident in the indicator hand with performance feedback (groups 2 and 4). However, performance on a static ruler task suggests proprioceptive recalibration also occurred despite the presence of feedback. Control groups confirmed accurate performance on the pointing task despite the visual cue shift. These findings highlight the distinct timing of recalibration mechanisms for gradual versus abrupt cue conflicts and potential smaller contribution of error mechanisms for a static conflict.

New and Noteworthy

The brain may handle spatial conflicts between visual and proprioceptive cues differently for a dynamic hand undergoing visuomotor adaptation than for a static hand. In a static hand, abrupt conflict triggered immediate recalibration without further adjustment, and feedback had little impact on recalibration. This suggests varying roles of multisensory and error mechanisms across motor contexts, underscoring the importance of examining a variety of motor contexts to understand and predict behavior.
Donor HLA class 1 evolutionary divergence and late allograft rejection after liver transplantation in children: An emulated target trial
Authors: Dumortier Jérôme , Hamada Sarah , Wischlen Emma , Mandier Céline , Laverdure Noémie , Boillot Olivier , Kounis Ilias , Allain Vincent , Hervieu Valérie , Collardeau-Frachon Sophie , Dubois Valérie , Feray Cyrille
Published: September 2024

HLA evolutionary divergence (HED), a continuous metric quantifying the differences between each amino acid of two homologous HLA alleles, reflects the importance of the immunopeptidome presented to T lymphocytes. It has been associated with rejection after liver transplantation. This retrospective cohort study aimed to analyze the potential effect of donor or recipient HED on liver transplant rejection in a new series of patients transplanted during childhood and followed in adulthood. The study included 120 children who had been transplanted between 1991 and 2010 and were followed by routine biopsies and histological evaluations with a median of 14.1 years post-LT. Liver biopsies were performed routinely 1, 5, 10 and 20 years after transplantation and in the event of liver dysfunction. HED was calculated using the physicochemical Grantham distance for donor and recipient class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1) alleles. The influence of HED on rejection was analyzed using IPW and target trial emulation using the g method. Based on the IPW score, donor HED class I was correlated with the occurrence of late (>90 days) rejection (HR, 1.19, 95% CI: 1.01-1.40) independently of HLA mismatches, donor age and initial induction. This emulated target trial confirmed that donor HED class I has a causal effect on liver graft rejection and this relationship was observed long-term.
Generative AI and Large Language Models in Reducing Medication Related Harm and Adverse Drug Events – A Scoping Review
Authors: Ling Ong Jasmine Chiat , Michael Chen , Ng Ning , Elangovan Kabilan , Ting Tan Nichole Yue , Jin Liyuan , Xie Qihuang , Wei Ting Daniel Shu , Rodriguez-Monguio Rosa , Bates David W. , Liu Nan
Published: September 2024

Background

Medication-related harm has a significant impact on global healthcare costs and patient outcomes, accounting for deaths in 4.3 per 1000 patients. Generative artificial intelligence (GenAI) has emerged as a promising tool in mitigating risks of medication-related harm. In particular, large language models (LLMs) and well-developed generative adversarial networks (GANs) showing promise for healthcare related tasks. This review aims to explore the scope and effectiveness of generative AI in reducing medication-related harm, identifying existing development and challenges in research.

Methods

We searched for peer reviewed articles in PubMed, Web of Science, Embase, and Scopus for literature published from January 2012 to February 2024. We included studies focusing on the development or application of generative AI in mitigating risk for medication-related harm during the entire medication use process. We excluded studies using traditional AI methods only, those unrelated to healthcare settings, or concerning non-prescribed medication uses such as supplements. Extracted variables included study characteristics, AI model specifics and performance, application settings, and any patient outcome evaluated.

Findings

A total of 2203 articles were identified, and 14 met the criteria for inclusion into final review. We found that generative AI and large language models were used in a few key applications: drug-drug interaction identification and prediction; clinical decision support and pharmacovigilance. While the performance and utility of these models varied, they generally showed promise in areas like early identification and classification of adverse drug events and support in decision-making for medication management. However, no studies tested these models prospectively, suggesting a need for further investigation into the integration and real-world application of generative AI tools to improve patient safety and healthcare outcomes effectively.

Interpretation

Generative AI shows promise in mitigating medication-related harms, but there are gaps in research rigor and ethical considerations. Future research should focus on creation of high-quality, task-specific benchmarking datasets for medication safety and real-world implementation outcomes.
Primary Care Physicians’ Practices and Barriers in Evaluating and Managing Chronic Kidney Disease in New Providence, The Bahamas
Authors: Bain W , Pinder-Butler S , Fountain T , Grant I
Published: September 2024

Objectives

To assess the practices and barriers in evaluating and managing chronic kidney disease among primary care physicians in New Providence, The Bahamas.

Methods

A cross-sectional study utilizing an anonymous, self-administered questionnaire was given to General Practitioners, Family Medicine, and Internal Medicine physicians after using a simple random sampling approach. Descriptive and inferential statistical analysis was conducted using IBM SPSS software.

Results

There were 119 physicians in this study with Family Medicine specialty area representing 52.1%. Seventy-four (74) physicians reported following CKD guidelines. The most common at-risk groups identified were Diabetes Mellitus (100%), Hypertension (98.3%), and use of nephrotoxic agents (97.5%). The most common diagnostic test used to identify CKD was eGFR (97.5%) and 72.2% of physicians used eGFR alone to stage CKD. Physicians overall agreed (40.3 – 50.4%) they were comfortable in diagnosing and managing CKD and its complications except for bone disorders (43.2%) and metabolic acidosis (34.7%) where responses were neutral. Physicians were neutral in having tools/resources to help them manage bone disorders (35.3%) and metabolic acidosis (31.9%) and disagreed to having educational tools for patients to understand bone disorders (32.2%) and metabolic acidosis (32.8%). Physicians agreed-strongly agreed with 12 of 13 perceived barriers, and there were 26 unique barriers expressed (8 patient-level, 7 provider-level, 11 systems-level).

Conclusions

Deficits in the evaluation and management of CKD, and numerous barriers to CKD care were discovered. Recommendations include the development of a national CKD guideline, local CKD continuous medical education seminars, and public health campaigns on CKD education.
Transdiagnostic Symptom Domains are Associated with Head Motion During Multimodal Imaging in Children
Authors: Hercules Kavari , Liu Zhiyuan , Wei Jia , Venegas Gladys , Ciocca Olivia , Dyer Alice , Lee Goeun , Santini-Bishop Sasha , Shappell Heather , Gee Dylan G. , Sukhodolsky Denis G. , Ibrahim Karim
Published: September 2024

Background

Head motion is a challenge for neuroimaging research in developmental populations. However, it is unclear how transdiagnostic symptom domains including attention, disruptive behavior (e.g., externalizing behavior), and internalizing problems are linked to scanner motion in children, particularly across structural and functional MRI. The current study examined whether transdiagnostic domains of attention, disruptive behavior, and internalizing symptoms are associated with scanner motion in children during multimodal imaging.

Methods

In a sample of 9,045 children aged 9-10 years in the Adolescent Brain Cognitive Development (ABCD) Study, logistic regression and linear mixed-effects models were used to examine associations between motion and behavior. Motion was indexed using ABCD Study quality control metrics and mean framewise displacement for the following: T1-weighted structural, resting-state fMRI, diffusion MRI, Stop-Signal Task, Monetary Incentive Delay task, and Emotional n-Back task. The Child Behavior Checklist was used as a continuous measure of symptom severity.

Results

Greater attention and disruptive behavior problem severity was associated with a lower likelihood of passing motion quality control across several imaging modalities. In contrast, increased internalizing severity was associated with a higher likelihood of passing motion quality control. Increased attention and disruptive behavior problem severity was also associated with increased mean motion, whereas increased internalizing problem severity was associated with decreased mean motion.

Conclusion

Transdiagnostic domains emerged as predictors of motion in youths. These findings have implications for advancing development of generalizable and robust brain-based biomarkers, computational approaches for mitigating motion effects, and enhancing accessibility of imaging protocols for children with varying symptom severities.
Contribution of amygdala to dynamic model arbitration under uncertainty
Authors: Woo Jae Hyung , Costa Vincent D. , Taswell Craig A. , Rothenhoefer Kathryn M. , Averbeck Bruno B. , Soltani Alireza
Published: September 2024

Intrinsic uncertainty in the reward environment requires the brain to run multiple models simultaneously to predict outcomes based on preceding cues or actions, commonly referred to as stimulus- and action-based learning. Ultimately, the brain also must adopt appropriate choice behavior using reliability of these models. Here, we combined multiple experimental and computational approaches to quantify concurrent learning in monkeys performing tasks with different levels of uncertainty about the model of the environment. By comparing behavior in control monkeys and monkeys with bilateral lesions to the amygdala or ventral striatum, we found evidence for dynamic, competitive interaction between stimulus-based and action-based learning, and for a distinct role of the amygdala. Specifically, we demonstrate that the amygdala adjusts the initial balance between the two learning systems, thereby altering the interaction between arbitration and learning that shapes the time course of both learning and choice behaviors. This novel role of the amygdala can account for existing contradictory observations and provides testable predictions for future studies into circuit-level mechanisms of flexible learning and choice under uncertainty.
Dynamical Modulation of Hippocampal Replay Sequences through Firing Rate Adaptation
Authors: Ji Zilong , Chu Tianhao , Dong Xingsi , Yu Changmin , Bush Daniel , Burgess Neil , Wu Si
Published: September 2024

During periods of immobility and sleep, the hippocampus generates diverse self-sustaining sequences of “replay” activity, exhibiting stationary, diffusive, and super-diffusive dynamical patterns. However, the neural mechanisms underlying this diversity in hippocampal sequential dynamics remain largely unknown. Here, we propose such a mechanism demonstrating that modulation of firing rate adaptation in a continuous attractor model of place cells causes the emergence of different types of replay. Our model makes several key predictions. First, more diffusive replay sequences positively correlate with longer theta sequences across animals (both reflecting stronger adaptation). Second, replay diffusivity varies within an animal across behavioural states that affect adaptation (such as wake and sleep). Third, increases in neural excitability, incorporated with firing rate adaptation, reduce the step size of decoded movements within individual replay sequences. We provide new experimental evidence for all three predictions. These insights suggested that the diverse replay dynamics observed in the hippocampus can be reconciled through a simple yet effective neural mechanism, shedding light on its role in hippocampal-dependent cognitive functions and its relationship to other aspects of hippocampal electrophysiology.
Meta-awareness, mind-wandering, and the control of 'default' external and internal orientations of attention
Authors: Christian Isaac Ray , Nastase Sam , Yu Mindy , Graziano Michael
Published: September 2024

The "default mode" of cognition usually refers to an automatic tendency to simulate past, future, and hypothetical experiences, rather than attending to external events in the moment. "Mind-wandering" usually refers to moments when attention drifts from external tasks to become engaged in internal, default-mode cognition. Both definitions are perhaps limited: the mind can be caught by external objects when attending internally, and objects in the external world can be just as captivating as internal thought, causing attention to drift. To explore the relationship between prepotent internal and external default modes and the bi-directionality of mind-wandering, we measured brain activity in forty participants using fMRI during performance of a focused attention task. Naturalistic movie clips were presented four times in sequence. When subjects tried to focus attention on the videos, more mind-wandering events (distractions from the externally-focused task) occurred as the videos became less interesting with each repetition, and when less engaging videos were presented. When subjects focused internally on their own breath, more mind-wandering events (distractions from the internally-focused task) occurred when videos were most interesting (i.e. on the first repetition) and when more engaging videos were presented. In the whole-brain fMRI data and also in focused analyses of sensory areas and default mode areas, inter-subject correlation analysis revealed cortical signals of attention that corroborated the behavioral results. We suggest that whether the default state is internal or external, and whether the sources that disrupt it are internal or external, depend on context.
AAV-mediated expression of proneural factors stimulates neurogenesis from adult Müller gliain vivo.
Authors: Pavlou Marina , Probst Marlene , Filippova Elizaveta , Kaplan Lew , Prieve Aric R , Rieke Fred , Reh Thomas A
Published: September 2024

The lack of regeneration in the human central nervous system (CNS) has major health implications. To address this, we previously used transgenic mouse models to show that neurogenesis can be stimulated in the adult mammalian retina by driving regeneration programs that other species activate following injury. Expression of specific proneural factors in adult Müller glia causes them to re-enter the cell cycle and give rise to new neurons following retinal injury. To bring this strategy closer to clinical application, we now show that neurogenesis can also be stimulated when delivering these transcription factors to Müller glia using adeno-associated viral (AAV) vectors. AAV-mediated neurogenesis phenocopies the neurogenesis we observed from transgenic animals, with different proneural factor combinations giving rise to distinct neuronal subtypesin vivo. Vector-borne neurons are morphologically, transcriptomically and physiologically similar to bipolar and amacrine/ganglion-like neurons. These results represent a key step forward in developing a cellular reprogramming approach to regenerative medicine in the CNS.
Genomic Reconstruction and Dietary Response Assessment of ThreeAcutalibacteraceaeBacteria Isolated from Fecal Samples of Singapore Subjects
Authors: Park Mi Ae , Almunawar Sharifah Nora Ahmad , Lim Rachel Rui Xia , Haldar Sumanto , Henry Christiani Jeyakumar , Moskvin Oleg Vladimirovich
Published: September 2024

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Clostridium leptum, a key player in gut butyrate production, has a profound impact on various facets of intestinal health. A recent clinical trial highlighted a significant increase in the relative abundance of this species in response to dietary interventions using beneficial oils. We isolated microbial strains corresponding to“Clostridium leptum”(at the 16S rRNA gene similarity level) and sequenced their genomes. All three genomes were successfully reconstructed, maintaining the chromosome as a single contig. Subsequent genome-wide analysis unveiled the phylogenetic diversity of the isolates, including the discovery of a new species -Gallacutalibacter singaporense. Based on the reconstructed metabolic model, we predicted growth condition patterns of this new species and confirmed the predictionsin vitro. Leveraging the assembled genomes, we dissected the components of the strong dietary intervention response signal previously ascribed to“C.leptum”and revealed distinct individual dynamics of all three bacteria in the clinical trial context. The transitional behavior of the novel species, in particular, revealed intriguing patterns, blazing the path to uncovering previously unrecognized interactions along the diet - gut microbiome - human health axis.