bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety Monitoring of Bivalent COVID-19 mRNA Vaccines Among Recipients 6 months and Older in the United States
Authors: Lloyd Patricia C. , Smith Elizabeth R. , Gruber Joann F. , Ondari Michelle , Wong Hui Lee , Hu Mao , Clarke Tainya C. , McEvoy Rowan , Amend Kandace L. , Beachler Daniel C. , McMahill-Walraven Cheryl N , Seeger John D. , Secora Alex , Djibo Djeneba Audrey , Song Jennifer , Selvam Nandini , DeShazo Jonathan P. , Clifford Robin , Abente Eugenio , Chillarige Yoganand , Forshee Richard A. , Anderson Steven A. , Shoaibi Azadeh
Published: January 2024

Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes post-licensure.

Objective

To evaluate health outcomes following bivalent COVID-19 Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273.222) vaccination among individuals 6 months and older in the United States.

Design

Monthly monitoring of health outcomes from August 2022 to July 2023 in four administrative claims databases. Descriptive analyses monitored vaccine uptake, outcome counts and coadministration of bivalent COVID-19 and influenza vaccines. Sequential analyses tested for elevated risk of each outcome in a prespecified post-vaccination risk interval, or a period of hypothesized elevation based on clinical guidance, compared to a historical baseline.

Participants and Exposures

Persons 6 months and older who received a bivalent COVID-19 BNT162b2 or mRNA-1273.222 vaccine during the study period, with continuous enrollment in a medical insurance plan from the start of an outcome-specific clean interval to the COVID-19 vaccination date. Vaccines were identified using product-specific codes from medical coding systems.

Health Outcomes

Twenty outcomes were monitored in BNT162b2 vaccine recipients 6 months-4 years, and mRNA-1273.222 vaccine recipients 6 months-5 years. Twenty-one outcomes were monitored in BNT162b2 vaccine recipients 5-17 years and mRNA-1273.222 vaccine recipients 6-17 years. Eighteen outcomes were monitored in persons 18 years and older for both mRNA vaccines.

Results

Overall, 13.9 million individuals 6 months and older received a single bivalent COVID-19 mRNA vaccine. The statistical threshold for a signal was met for two outcomes in one database: anaphylaxis following bivalent BNT162b2 and mRNA-1273.222 vaccines in persons 18-64 years and myocarditis/pericarditis following bivalent BNT162b2 vaccines in individuals 18-35 years. There were no signals identified in young children.

Conclusions

Results were consistent with prior observations from published studies on COVID-19 vaccine safety. This study supports the safety profile of bivalent COVID-19 mRNA vaccines and the conclusion that the benefits of vaccination outweigh the risks.
Evaluating the Diagnostic and Treatment Recommendation Capabilities of GPT-4 Vision in Dermatology
Authors: Pillai Abhinav , Joseph Sharon Parappally , Kreutz Jason , Trabousi Danya , Gandhi Maharshi , Hardin Jori
Published: January 2024

Background

The integration of artificial intelligence (AI) in dermatology presents a promising frontier for enhancing diagnostic accuracy and treatment planning. However, general purpose AI models require rigorous evaluation before being applied to real-world medical cases.

Objective

This project specifically evaluates GPT-4V’s performance in accurately diagnosing and generating treatment plans for common dermatological conditions, comparing its assessment of textual versus image data and its performance with multimodal inputs. Beyond the immediate scope, this study contributes to the broader trajectory of integrating AI in healthcare, highlighting the limitations of these technologies, as well as their potential to enhance efficiency, and education within medical training and practice.

Methods

A dataset of 102 images representing nine common dermatological conditions was compiled from open-access websites. Fifty-four images were ultimately selected by two board-certified dermatologists as being representative and typical of the common conditions. Additionally, nine clinical scenarios corresponding to these conditions were developed. GPT-4V’s diagnostic capabilities were assessed in three setups: Image Prompt (image-based), Scenario Prompt (text-based), and Image and Scenario Prompt (combining both modalities). The model’s performance was evaluated based on diagnostic accuracy, differential diagnosis, and treatment recommendations.

Results

In the Image Prompt setup, GPT-4V correctly identified the primary diagnosis for 29 of 54 images. The Scenario Prompt setup showed a higher accuracy rate of 89% in identifying the primary diagnosis. The multimodal Image and Scenario Prompt setup also achieved an 89% accuracy rate. However, a notable bias towards textual data over visual data was observed. Treatment recommendations were evaluated by the same two dermatologists, using a modified Entrustment Scale, showing competent but not expert-level performance.

Conclusion

GPT-4V demonstrates promising capabilities in dermatological diagnosis and treatment recommendations, particularly in text-based scenarios. However, its performance in image-based diagnosis and integration of multimodal data highlights areas for improvement. The study underscores the potential of AI in augmenting dermatological practice, emphasizing the need for further development, and fine-tuning of such models to ensure their efficacy and reliability in clinical settings.
Global heterogeneity of latitudinal patterns in herbivory between native and exotic plants
Authors: Guo Yaolin , Parepa Madalin , Wang Hui , Wang Min , Wu Jihua , Li Bo , Ju Rui-Ting , Bossdorf Oliver
Published: January 2024

Latitudinal gradient of herbivory that differs between native and exotic plants has been an open issue. It is expected that a latitudinal gradient of herbivory will be evident for native plants; this gradient in exotic plants may lag behind native plants in terms of co-evolution with local abiotic and biotic factors in introduced area. Our study aims to elucidate the difference in latitudinal gradient of herbivory between native and exotic plants globally, while exploring the underlying mechanisms driving the latitudinal gradient of herbivory with biotic and abiotic factors. To achieve this, we analyzed herbivory data from 94 studies and calculated 862 herbivory effect sizes (zr) to quantitatively characterize the intensity of latitudinal herbivory gradient. For each herbivory data, we matched the corresponding plant identity (native/exotic), herbivore feeding guilds and climate data to reveal the contribution of these factors tozr. Our findings demonstrate a significant decrease in the latitudinal gradients of with increasing latitude for native plants, a pattern not observed for exotic plants. The heterogeneity in latitudinal gradients of herbivory between native and exotic plants is mediated by herbivore feeding guilds. There is a significant influence of climatic factors on the latitudinal gradient of herbivory for native plants, but not for exotic plants. Overall, our results underscore a general heterogeneity in global macroecological herbivory patterns between native and exotic plants, and highlight the role of biotic and abiotic factors in explaining these global-scale differences.
A new mRNA structure prediction based approach to identifying improved signal peptides for bone morphogenetic protein 2
Authors: Wilkinson Piers , Jackson Brian , Fermor Hazel , Davies Robert
Published: January 2024

Background

Signal peptide (SP) engineering has proven able to improve production of many proteins yet is a laborious process that still relies on trial and error. mRNA structure around the translational start site is important in translation initiation and has rarely been considered in this context, with recent improvements inin silicomRNA structure potentially rendering it a useful predictive tool for SP selection. Here we attempt to create a method to systematically screen candidate signal peptide sequencesin silicobased on both their nucleotide and amino acid sequences. Several recently released computational tools were used to predict signal peptide activity (SignalP), localization target (DeepLoc) and predicted mRNA structure (MXFold2). The method was tested with Bone Morphogenetic Protein 2 (BMP2), an osteogenic growth factor used clinically for bone regeneration. It was hoped more effective BMP2 SPs could improve BMP2-based gene therapies and reduce the cost of recombinant BMP2 production.

Results

Amino acid sequence analysis indicated 2,611 SPs from the TGF-β superfamily were predicted to function when attached to BMP2. mRNA structure prediction indicated structures at the translational start site were likely highly variable. The five sequences with the most accessible translational start sites, a codon optimized BMP2 SP variant and the well-established hIL2 SP sequence were taken forward toin vitrotesting. The top five candidates showed non-significant improvements in BMP2 secretion in HEK293T cells. All showed reductions in secretion versus the native sequence in C2C12 cells, with several showing large and significant decreases. None of the tested sequences were able to increase alkaline phosphatase activity above background in C2C12s. The codon optimized control sequence and hIL2 SP showed reasonable activity in HEK293T but very poor activity in C2C12.

Conclusions

These results support the use of peptide sequence basedin silicotools for basic predictions around signal peptide activity in a synthetic biology context. However, mRNA structure prediction requires improvement before it can produce reliable predictions for this application. The poor activity of the codon optimized BMP2 SP variant in C2C12 emphasizes the importance of codon choice, mRNA structure, and cellular context for SP activity.
Functional benefit of CRISPR/Cas9-induced allele deletion forRYR1dominant mutation
Authors: Beaufils Mathilde , Melka Margaux , Brocard Julie , Benoit Clement , Debbah Nagi , Mamchaoui Kamel , Romero Norma B. , Dalmas-Laurent Anne Frédérique , Quijano-Roy Susana , Fauré Julien , Rendu John , Marty Isabelle
Published: January 2024

More than 700 pathogenic or probably pathogenic variations have been identified in theRYR1gene causing various myopathies collectively known as “RYR1-related myopathies”. Currently, there is no treatment for these myopathies, and gene therapy stands out as one of the most promising approaches. In the context of a dominant form of Central Core Disease due to aRYR1mutation, we aimed at showing the functional benefit of inactivating specifically the mutatedRYR1allele by guiding CRISPR/Cas9 cleavages onto frequent single nucleotide polymorphisms (SNPs) segregating on the same chromosome. Whole-genome sequencing was used to pinpoint SNPs localized on the mutantRYR1allele and identified specific CRISPR/Cas9 guide-RNAs. Lentiviruses encoding these guide-RNAs and theSpCas9nuclease were used to transduce immortalized patient muscle cells, inducing the specific deletion of the mutantRYR1allele. The efficiency of the deletion was assessed at both DNA and RNA levels and at the functional level after monitoring calcium release induced by the stimulation of the RyR1-channel. This study providesin-celluloproof of concept regarding the benefits of mutantRYR1allele deletion, in the case of a dominantRYR1mutation, from both a molecular and functional perspective.

Graphical abstract

eTOC synopsis

Mutations in theRYR1gene, encoding a calcium channel required for muscle contraction, cause severe myopathies. In this study, Marty and colleagues demonstrate the functional benefit of suppression of a mutantRYR1allele using CRISPR/Cas9, in the case of a dominant mutation, leaving the wild type allele alone.
CHMP4B contributes to maintaining the follicular cells integrity in the panoistic ovary of the cockroachBlattella germanica
Authors: Farrus N. , Maestro J.L. , Piulachs M.D.
Published: January 2024

The Endosomal Sorting Complex Required for Transport (ESCRT) is a highly conserved cellular machinery essential for many cellular functions, including transmembrane protein sorting, endosomal trafficking and membrane scission. CHMP4B is a key component of ESCRT-III subcomplex and has been thoroughly studied in the meroistic ovaries ofDrosophila melanogastershowing its relevance in maintaining this reproductive organ during the life of the fly. However, the role of the CHMP4B in the most basal panoistic ovaries remains elusive. Using RNAi, we examined the function of CHMP4B in the ovary ofBlattella germanicain two different physiological stages: in last instar nymphs, with proliferative follicular cells, and in vitellogenic adults when follicular cells enter in polyploidy and endoreplication.

InChmp4b-depleted specimens, the expression of actin in the basal pole of the follicular cells increased, leading to an excess of actin bundles that surrounded the basal ovarian follicle and modifying their shape. Depletion ofChmp4balso caused a loss of planar polarity in the follicular epithelium due to the actin increase in cell membranes, resulting in different cell morphologies and sizes, as well as an absence of patency. In these cells, the nuclei appeared unusually elongated, suggesting an incomplete karyokinesis.

These results proved CHMP4B essential in preserving the proper expression of cytoskeleton proteins vital for basal ovarian follicle growth and maturation, and for yolk proteins incorporation. Moreover, the correct distribution of actin fibers in the basal ovarian follicle emerged as a critical factor for the successful completion of ovulation and oviposition. The overall of the results, obtained in two different proliferative stages, suggest that the function of CHMP4B inB. germanicafollicular epithelium is independent of the proliferative stage of the tissue.
Grasp context-dependent uncertainty alters the relative contribution of anticipatory and feedback-based mechanisms in object manipulation
Authors: Dutta Swarnab , SKM Varadhan
Published: January 2024

Predictive control within dexterous object manipulation while allowing for the choice of contact points has been shown to employ a predominantly feedback-based force modulation. Anticipation is thought to be facilitated through the internal representation of the object dynamics being integrated and updated on a trial-to-trial basis with the feedback of contact locations on the object. This is as opposed to the classically studied memory representation-based fingertip force control for grasping with pre-selected contact locations. We designed a study to examine this grasp context-dependent asymmetry in sensorimotor integration by introducing binary uncertainty about the grasp type before movement initiation within the framework of motor planning. An inverted T-shaped instrumented object was presented to 24 participants as the manipulandum, and they were asked to reach, grasp, and lift it while minimising the roll. We dissociated the planning and the execution phases by pseudo-randomly manipulating the availability of visual contact cues on the object after movement onset. Our results suggest that uncertainty about the grasp type during movement preparation anterogradely modulated the differential weighting of feedback and feedforward mechanisms in anticipatory coordination.
Acquiring musculoskeletal skills with curriculum-based reinforcement learning
Authors: Chiappa Alberto Silvio , Tano Pablo , Patel Nisheet , Ingster Abigail , Pouget Alexandre , Mathis Alexander
Published: January 2024

Efficient musculoskeletal simulators and powerful learning algorithms provide computational tools to tackle the grand challenge of understanding biological motor control. Our winning solution for the inaugural NeurIPS MyoChallenge leverages an approach mirroring human skill learning. Using a novel curriculum learning approach, we trained a recurrent neural network to control a realistic model of the human hand with 39 muscles to rotate two Baoding balls in the palm of the hand. In agreement with data from human subjects, the policy uncovers a small number of kinematic synergies even though it is not explicitly biased towards low-dimensional solutions. However, by selectively inactivating parts of the control signal, we found that more dimensions contribute to the task performance than suggested by traditional synergy analysis. Overall, our work illustrates the emerging possibilities at the interface of musculoskeletal physics engines, reinforcement learning and neuroscience to advance our understanding of biological motor control.
Elucidating the effect of cations onKlebsiella pneumoniaebiofilm and related genes
Authors: Murugavel Aravind , Gunasekaran Srinithi , Ramakrishnan Jayapradha
Published: January 2024

K. pneumoniaeis a non-motile, encapsulated bacterium from the Enterobacteriaceae family. The illnesses related to this opportunistic pathogen are pneumonia, Urinary Tract Infection (UTI), pyogenic liver abscess, endophthalmitis, and meningitis. Among them, UTI is predominant due to its biofilm formation leading to the mortality of 150 million people worldwide. The function of monovalent and divalent ions onKlebsiellabiofilm, aside from physiochemical variables, remains unclear. Hence the present study was performed to analyze the role of K+, Ca2+, Na+, Mg2+, NH+4in biofilm formation and its influence on biofilm-related genes. Among the tested cations, K+and Ca2+yielded strong biofilm in clinical and environment isolates in pH between 6.5 to 9.5. Increasing Ca2+ions concertation reduced theKlebsiellabiofilm. When compared to the hypercalciuria condition (Ca2+level > 5 mM), 2.5 mM resulted in high biofilm mass. Cations concurrently enhanced the size of the capsule and cell density ofKlebsiellabut were not correlated with biofilm mass. Expression of the LPS gene (WbaG) either in planktonic or biofilm stage promoted biofilm formation in the presence of K+, Ca2+and Na+. Whereas, expression of fimbriae genes (FimHandmrkD) was co- regulation, and capsule genes (RmpAandWcab) were absent. Stating, the primary component needed for theKlebsiellabiofilm is not the capsule or fimbriae, rather LPS. Resulting as a potent target in the treatment ofKlebsiellabiofilm in UTI. To the best of our knowledge, this is the first kind of study on the effect of cation ions on biofilm and planktonic cells ofKlebsiellaspp. and demonstrating the role of LPS biosynthesis gene (WbaG) in biofilm development.
High-speed two-photon microscopy with adaptive line-excitation
Authors: Li Yunyang , Guo Shu , Mattison Ben , Yang Weijian
Published: January 2024

We present a two-photon fluorescence microscope designed for high-speed imaging of neural activity in cellular resolution. Our microscope uses a new adaptive sampling scheme with line illumination. Instead of building images pixel by pixel via scanning a diffraction-limited spot across the sample, our scheme only illuminates the regions of interest (i.e., neuronal cell bodies), and samples a large area of them in a single measurement. Such a scheme significantly increases the imaging speed and reduces the overall laser power on the brain tissue. Using this approach, we performed high-speed imaging of the neural activity of mouse cortexin vivo. Our method provides a new sampling strategy in laser-scanning two-photon microscopy, and will be powerful for high-throughput imaging of neural activity.
Processed food intake assortativity in the personal networks of older adults
Authors: Hancean Marian-Gabriel , Lerner Juergen , Perc Matjaz , Molina Jose Luis , Geanta Marius , Oana Iulian , Pintoiu Mihaila Bianca Elena
Published: January 2024

Coalescing evidence shows that food habits circulate through social relationships. However, seniors' social networks and unhealthy dietary choices remain underexplored, particularly within rural Eastern Europe's unique socioeconomic and cultural contexts. We investigate how social networks affect the consumption of processed foods high in salt among community-dwelling older adults (64 years of age and older) from a Romanian rural community. We use an observational cross-sectional quantitative approach (a personal network research design) to collect self-reported information about the study participants (egos; n = 83), their social contacts (alters), and the relationships among them (ego-alter and alter-alter ties). We fit multi-level, mixed-effects models, clustering alters by their egos, and show that older adults eating processed food high in salt are more likely to be connected to alters with similar eating habits (assortativity). This result is of particular relevance when considering the nutritional health of older adults, as it implies that interventions targeting this demographic should extend beyond the individual to encompass their social environment. Despite the cross-sectional approach limitations, our work may enrich the understanding of dietary patterns among rural Eastern European seniors and provide an empirical foundation for designing targeted interventions that can mitigate health risks associated with high-salt diets in older populations.
A small molecule VHL molecular glue degrader for cysteine dioxygenase 1
Authors: Tutter Antonin , Buckley Dennis , Golosov Andrei A. , Ma Xiaolei , Shu Wei , McKay Daniel J. J. , Darsigny Veronique , Dovala Dustin , Beckwith Rohan , Solomon Jonathan , Rao Pasupuleti , Xu Lei , Fazal Aleem , Lingel Andreas , Wartchow Charles , Cobb Jennifer S. , Hachey Amanda , Tullai Jennifer , Michaud Gregory A.
Published: January 2024

The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1-α binding pocket on pVHL and functions as a molecular glue degrader of the neosubstrate cysteine dioxygenase (CDO1) by recruiting it into the VHL-cullin-ring E3 ligase complex and leading to its selective degradation. The CDO1 binding region involved in VHL recruitment was characterized through a combination of mutagenesis and protein-protein docking coupled with molecular dynamics-based solvation analysis. The X-ray structure of the ternary complexes of VHL, CDO1, and degrader molecules confirms the binding region prediction and provides atomic insights into key molecular glue interactions.
Regional specialization manifests in the reliability of neural population codes
Authors: Guidera Jennifer A. , Gramling Daniel P. , Comrie Alison E. , Joshi Abhilasha , Denovellis Eric L. , Lee Kyu Hyun , Zhou Jenny , Thompson Paige , Hernandez Jose , Yorita Allison , Haque Razi , Kirst Christoph , Frank Loren M.
Published: January 2024

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1–3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4–6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9and learning from2,7,9–12the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13–20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials (“reliable”). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.
Stepwise recruitment of Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibre disassembly
Authors: Monistrol Jim , Beton Joseph G , Johnston Erin C , Saibil Helen R
Published: January 2024

To understand the action of co-chaperones of the J-domain protein family in the assembly of disaggregation-active Hsc70 complexes on the surface of amyloid fibres, we used cryo-EM and tomography to compare the assemblies with wild-type co-chaperones or an activity deficient mutant. We show that human DNAJB1 binds uniformly and densely along α-synuclein amyloid fibres in an asymmetric orientation, with one subunit of the DNAJB1 dimer lying along the fibre surface and the other subunit further away. It acts in a 2-step recruitment of Hsc70 to the fibres, first releasing DNAJB1 auto-inhibition and then activating the Hsc70 ATPase by the J domain, with ATPase recycling stimulated by the nucleotide exchange factor Apg2. When the auto-inhibition is removed by mutating the H5 inhibitory binding site on DNAJB1 (Δ1H5 DNAJB1 mutant), Hsc70 is recruited to the fibres at a normal level, but the resulting complex is inactive in disaggregation. Cryo tomography of the wild-type DNAJB1:Hsc70:Apg2:αSyn fibre complex shows dense arrays of the chaperones extending out from the fibre surface along spiral tracks, with the Hsc70 density on the outer surface of the DNAJB1 layer. The Δ1H5 DNAJB1:Hsc70:Apg2:αSyn fibre complex results in equally dense but less organised binding all over the fibre surface and lacks the ordered clusters. On the basis of these findings, we propose that 2-step activation of DNAJB1 regulates Hsc70 access to the fibre substrate. Since the DNAJB1 dimers are bound every 40 Å, the J domain released by Hsc70 binding to one dimer could activate the ATPase of an Hsc70 bound to the adjacent dimer. This could trigger a cascade of recruitment and activation in a localised, dense cloud of Hsc70 molecules to give coordinated, sequential binding and disaggregation from an exposed fibre end, as observed by cryo-EM and earlier fluorescence and AFM studies.
Excessive F-Actin and Microtubule Formation Mediates Primary Cilia Shortening and Loss in Response to Increased Extracellular Osmotic Pressure
Authors: Otani Hiroshi , Nakazato Ryota , Ijaz Faryal , Koike Kanae , Ikegami Koji
Published: January 2024

The primary cilium is a small organelle protruding from the cell surface and is recognized as an antenna for signals from the extracellular milieu. Maintenance of primary cilia structure is crucial for proper behaviors of cells, tissues, and organs. While a dozen of studies have reported that several genetic factors impair the structure of primary cilia, evidence for environmental stimuli affecting primary cilia structures is limited. Here, we investigated an extracellular stress that affected primary cilia morphology and its underlying mechanisms. Hyperosmotic shock with increased extracellular sodium chloride concentration induced shortenings and disassembly of primary cilia in murine intramedullary collecting ducts cells. The shortening of primary cilia caused by hyperosmotic shock followed a loss of axonemal microtubules and delocalization of pericentriolar materials (PCMs). The primary cilia shortening/disassembly and PCMs delocalization were reversible. In parallel with these hyperosmotic shock-induced changes of primary cilia and PCMs, excessive microtubule and F-actin formation occurred in the cytoplasm. A microtubule-disrupting agent, Nocodazole, prevented the hyperosmotic shock-induced primary cilia disassembly partially, while preventing the delocalization of PCMs almost 100%. An actin polymerization inhibitor, Latrunculin A, also prevented partially the hyperosmotic shock-induced primary cilia shortening and disassembly, while preventing the delocalization of PCMs almost 100%. Taken together, we demonstrate that hyperosmotic shock induces reversible morphological changes in primary cilia and PCMs in a manner dependent on excessive formation of microtubule and F-actin.
Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation
Authors: Griffin Casey , Saint-Jeannet Jean-Pierre
Published: January 2024

In vitromodeling is a powerful approach to investigate the pathomechanisms driving human congenital conditions. Here we use human embryonic stem cells (hESCs) to model Nager and Rodriguez syndromes, two craniofacial conditions characterized by hypoplastic neural crest-derived craniofacial bones, caused by pathogenic variants of SF3B4, a core component of the spliceosome. We observed that siRNA-mediated knockdown ofSF3B4interferes with the production of hESC-derived neural crest cells, as seen by a marked reduction in neural crest gene expression. This phenotype is associated with an increase in neural crest cell apoptosis and premature neuronal differentiation. Altogether these results point at a role of SF3B4 in neural crest cell survival, maintenance, and differentiation. We propose that the dysregulation of these processes may contribute to Nager/Rodriguez syndrome associated craniofacial defects.
The Temporal Dynamics of Aperiodic Neural Activity Track Changes in Sleep Architecture
Authors: Ameen Mohamed S , Jacobs Joshua , Schabus Manuel , Hoedlmoser Kerstin , Donoghue Thomas
Published: January 2024

The aperiodic (1/f-like) component of electrophysiological data - whereby power systematically decreases with increasing frequency, as quantified by the aperiodic exponent - has been shown to differentiate sleep stages. Earlier work, however, has typically focused on measuring the aperiodic exponent across a narrow frequency range. In this work, we sought to further investigate aperiodic activity during sleep by extending these analyses across broader frequency ranges and considering alternate model definitions. This included measuring ‘knees’ in the aperiodic component, which reflect bends in the power spectrum, indicating a change in the exponent. We also sought to evaluate the temporal dynamics of aperiodic activity during sleep. To do so, we analyzed data from two sources: intracranial EEG (iEEG) from 106 epilepsy patients and high-density EEG from 17 healthy individuals, and measured aperiodic activity, explicitly comparing different frequency ranges and model forms. In doing so, we find that fitting broadband aperiodic models and incorporating a ‘knee’ feature effectively captures sleep-stage-dependent differences in aperiodic activity as well as temporal dynamics that relate to sleep stage transitions and responses to external stimuli. In particular, the knee parameter shows stage-specific variation, suggesting an interpretation of varying timescales across sleep stages. These results demonstrate that examining broader frequency ranges with the more complex aperiodic models reveals novel insights and interpretations for understanding aperiodic neural activity during sleep.
Exploring the Categorical Nature of Colour Perception: Insights from Artificial Networks
Authors: Akbarinia Arash
Published: January 2024

This study delves into the categorical aspects of colour perception, employing the odd-one-out paradigm on artificial neural networks. We reveal a significant alignment between human data and unimodal vision networks (e.g., ImageNet object recognition). Vision-language models (e.g., CLIP text-image matching) account for the remaining unexplained data even in non-linguistic experiments. These results suggest that categorical colour perception is a language-independent representation, albeit partly shaped by linguistic colour terms during its development. Exploring the ubiquity of colour categories in Taskonomy unimodal vision networks highlights the task-dependent nature of colour categories, predominantly in semantic and 3D tasks, with a notable absence in low-level tasks. To explain this difference, we analysed kernels’ responses before the winnertaking-all, observing that networks with mismatching colour categories align in continuous representations. Our findings quantify the dual influence of visual signals and linguistic factors in categorical colour perception, thereby formalising a harmonious reconciliation of the universal and relative debates.
Probing the Link Between Vision and Language in Material Perception Using Psychophysics and Unsupervised Learning
Authors: Liao Chenxi , Sawayama Masataka , Xiao Bei
Published: January 2024

We can visually discriminate and recognize a wide range of materials. Meanwhile, we use language to express our subjective understanding of visual input and communicate relevant information about the materials. Here, we investigate the relationship between visual judgment and language expression in material perception to understand how visual features relate to semantic representations. We use deep generative networks to construct an expandable image space to systematically create materials of well-defined and ambiguous categories. From such a space, we sampled diverse stimuli and compared the representations of materials from two behavioral tasks: visual material similarity judgments and free-form verbal descriptions. Our findings reveal a moderate but significant correlation between vision and language on a categorical level. However, analyzing the representations with an unsupervised alignment method, we discover structural differences that arise at the image-to-image level, especially among materials morphed between known categories. Moreover, visual judgments exhibit more individual differences compared to verbal descriptions. Our results show that while verbal descriptions capture material qualities on the coarse level, they may not fully convey the visual features that characterize the material’s optical properties. Analyzing the image representation of materials obtained from various pre-trained data-rich deep neural networks, we find that human visual judgments’ similarity structures align more closely with those of the text-guided visual-semantic model than purely vision-based models. Our findings suggest that while semantic representations facilitate material categorization, non-semantic visual features also play a significant role in discriminating materials at a finer level. This work illustrates the need to consider the vision-language relationship in building a comprehensive model for material perception. Moreover, we propose a novel framework for quantitatively evaluating the alignment and misalignment between representations from different modalities, leveraging information from human behaviors and computational models.
Exposure to epoxiconazole induces hyperlocomotion in adult zebrafish
Authors: Reis Carlos G. , Chitolina Rafael , Bastos Leonardo M. , Portela Stefani M. , Stahlhofer-Buss Thailana , Piato Angelo
Published: January 2024

Global agricultural production is sustained by an elevated use of pesticides. Their application in crops results in environmental contamination, which is demonstrated by widespread detections of these chemicals in aquatic ecosystems. This presence poses a risk to non-target organisms and ecological balance since the effects of potential exposure are misunderstood. Epoxiconazole (EPX) is a widely employed triazole fungicide, which has been frequently reported as a contaminant in superficial waters. However, the behavioral effects of EPX exposure in non-target organisms such as fish remain unexplored. We aimed to investigate the effects of EPX exposure on behavioral and biochemical outcomes, using zebrafish as a model organism. For this purpose, a static system was set with concentrations (24, 144, 240 μg/L) based on the fungicide environmental detection. The novel tank test (NTT) was performed after 96 h of exposure. The social preference test (SPT) was executed after 120 h, as well as the biochemical assays. In the NTT, the animals increased distance traveled, crossings, entries in the top area, and mean speed, indicating hyperlocomotion. No significant effects were observed in the SPT and the biochemical analyses. We suggest that the increased locomotion is related to the stimulant properties of EPX. Our results contribute to an in-depth understanding of this fungicide effects in zebrafish, which is essential for environmental contamination monitoring and management.
Dual effects ofARXpoly-alanine mutations in human cortical and interneuron development
Authors: Nieto-Estevez Vanesa , Varma Parul , Mirsadeghi Sara , Caballero Jimena , Gamero-Alameda Sergio , Hosseini Ali , Silvosa Marc J. , Thodeson Drew M. , Lybrand Zane R. , Giugliano Michele , Navara Christopher , Hsieh Jenny
Published: January 2024

Infantile spasms, with an incidence of 1.6 to 4.5 per 10,000 live births, are a relentless and devastating childhood epilepsy marked by severe seizures but also leads to lifelong intellectual disability. Alarmingly, up to 5% of males with this condition carry a mutation in theAristaless-related homeobox(ARX) gene. Our current lack of human-specific models for developmental epilepsy, coupled with discrepancies between animal studies and human data, underscores the gap in knowledge and urgent need for innovative human models, organoids being one of the best available. Here, we used human neural organoid models, cortical organoids (CO) and ganglionic eminences organoids (GEO) which mimic cortical and interneuron development respectively, to study the consequences of PAE mutations, one of the most prevalent mutation inARX. ARXPAEproduces a decrease expression ofARXin GEOs, and an enhancement in interneuron migration. That accelerated migration is cell autonomously driven, and it can be rescued by inhibiting CXCR4. We also found that PAE mutations result in an early increase in radial glia cells and intermediate progenitor cells, followed by a subsequent loss of cortical neurons at later timepoints. Moreover,ARXexpression is upregulated in COs derived from patients at 30 DIV and is associated with alterations in the expression ofCDKN1C. Furthermore, ARXPAEassembloids had hyperactivity which were evident at early stages of development. With effective treatments for infantile spasms and developmental epilepsies still elusive, delving into the role of ARXPAEmutations in human brain organoids represents a pivotal step toward uncovering groundbreaking therapeutic strategies.
Oscillatory Hypoxia Induced Unfolded Protein Folding Response Gene Expression Predicts Low Survival in Human Breast Cancer Patients
Authors: Suhail Yasir , Liu Yamin , Du Wenqiang , Afzal Junaid , Qiu Xihua , Atiq Amina , Vera-Licona Paola , Agmon Eran , Kshitiz
Published: January 2024

Hypoxia is one of the key factors in the tumor microenvironment regulating nearly all steps in the metastatic cascade in many cancers, including in breast cancer. The hypoxic regions can however be dynamic with the availability of oxygen fluctuating or oscillating. The canonical response to hypoxia is relayed by transcription factor HIF-1, which is stabilized in hypoxia and acts as the master regulator of a large number of downstream genes. However, HIF-1 transcriptional activity can also fluctuate either due to unstable hypoxia, or by lactate mediated non-canonical degradation of HIF-1. Our understanding of how oscillatory hypoxia or HIF-1 activity specifically influence cancer malignancy is very limited. Here, using MDA-MB-231 cells as a model of triple negative breast cancer characterized by severe hypoxia, we measured the gene expression changes induced specifically by oscillatory hypoxia. We found that oscillatory hypoxia can specifically regulate gene expression differently, and at times opposite to stable hypoxia. Using The Cancer Genome Atlas (TCGA) RNAseq data of human cancer samples, we show that the oscillatory specific gene expression signature in MDA-MB-231 is enriched in most human cancers, and prognosticate low survival in breast cancer patients. In particular, we found that oscillatory hypoxia, unlike stable hypoxia, induces unfolded protein folding response (UPR) in cells resulting in gene expression predicting reduced survival.
Adult-Onset Deletion ofATP13A2in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities
Authors: Erb Madalynn L. , Sipple Kayla , Levine Nathan , Chen Xi , Moore Darren J.
Published: January 2024

Although most cases of Parkinson’s disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of PD. A surprising number of familial PD-linked genes and PD risk genes are involved in intracellular trafficking and protein degradation. Recessive loss-of-function mutations inATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. FamilialATP13A2mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome (KRS), hereditary spastic paraplegias (HSPs), neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis (ALS). Given the severe effects ofATP13A2mutations in humans, it is surprising thatATP13A2knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages. This discrepancy between human subjects and rodents makes it challenging to study the neuropathological effects of ATP13A2 lossin vivo. Germline deletion ofATP13A2in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deletedATP13A2in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditionalloxP-flankedATP13A2KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onsetATP13A2KO also recreates many of the phenotypes observed in aged germlineATP13A2KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion ofATP13A2in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a usefulin vivomodel ofATP13A2-related neurodegenerative diseases.
Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking
Authors: Driskill Christopher M. , Childs Jessica E. , Phensy Aarron J. , Rodriguez Sierra R. , O’Brien John T. , Lindquist Kathy L. , Naderi Aurian , Bordieanu Bogdan , McGinty Jacqueline F. , Kroener Sven
Published: January 2024

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Significance Statement

Extinction training can reverse maladaptive neuroplasticity induced by drugs of abuse, but adjunct treatments are sought that can facilitate the process and consolidate the newly formed memories. Pairing extinction training with vagus nerve stimulation (VNS) facilitates extinction and reduces drug-seeking behavior during reinstatement. Here, we show that rats receiving a single extinction session with VNS exhibit elevated brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC). We also demonstrate that VNS consolidates the extinction of drug-seeking behavior by reversing cocaine-induced changes in synaptic AMPA receptors in the infralimbic cortex (IL) of the mPFC. This effect is blocked by the TrkB antagonist ANA-12, emphasizing the role of BDNF and TrkB receptors in the therapeutic effects of VNS in addiction.
Beav: A bacterial genome and mobile element annotation pipeline
Authors: Jung Jewell M. , Rahman Arafat , Schiffer Andrea M. , Weisberg Alexandra J.
Published: January 2024

Comprehensive and accurate genome annotation is crucial for inferring the predicted functions of an organism. Numerous tools exist to annotate genes, gene clusters, mobile genetic elements, and other diverse features. However, these tools and pipelines can be difficult to install and run, be specialized for a particular element or feature, or lack annotations for larger elements that provide important genomic context. Integrating results across analyses is also important for understanding gene function. To address these challenges, we present the Beav annotation pipeline. Beav is a command-line tool that automates the annotation of bacterial genome sequences, mobile genetic elements, molecular systems and gene clusters, key regulatory features, and other elements. Beav uses existing tools in addition to custom models, scripts, and databases to annotate diverse elements, systems, and sequence features. Custom databases for plant-associated microbes are incorporated to improve annotation of key virulence and symbiosis genes in agriculturally important pathogens and mutualists. Beav includes an optionalAgrobacterium-specific pipeline that identifies and classifies oncogenic plasmids and annotates plasmid-specific features. Following the completion of all analyses, annotations are consolidated to produce a single comprehensive output. Finally, Beav generates publication-quality genome and plasmid maps. Beav is on Bioconda and is available for download athttps://github.com/weisberglab/beav.
Supercontinuum intrinsic fluorescence imaging heralds free view of living systems
Authors: Wang Geng , Li Lianhuang , Liao Xiaoxia , Wang Shu , Mitchell Jennifer , Rabel Chanaka , Luo Shirui , Shi Jindou , Sorrells Janet Elise , Iyer Rishyashring R. , Aksamitiene Edita , Renteria Carlos A. , Chaney Eric J. , Milner Derek J. , Wheeler Matthew B. , Gillette Martha U. , Schwing Alexander , Chen Jianxin , Tu Haohua
Published: January 2024

Optimal imaging strategies remain underdeveloped to maximize information for fluorescence microscopy while minimizing the harm to fragile living systems. Taking hint from the supercontinuum generation in ultrafast laser physics, we generated supercontinuum fluorescence from untreated unlabeled live samples before nonlinear photodamage onset. Our imaging achieved high-content cell phenotyping and tissue histology, identified bovine embryo polarization, quantified aging-related stress across cell types and species, demystified embryogenesis before and after implantation, sensed drug cytotoxicity in real-time, scanned brain area for targeted patching, optimized machine learning to track small moving organisms, induced two-photon phototropism of leaf chloroplasts under two-photon photosynthesis, unraveled microscopic origin of autumn colors, and interrogated intestinal microbiome. The results enable a facility-type microscope to freely explore vital molecular biology across life sciences.