bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors
Authors: Jiao Dongyue , Chang Kun , Chen Yingji , Jin Jiamin , Mo Ren , Zhang Yucong , Gao Kun , Xu Yaoting , Wang Lixin , Wang Chenji
Published: April 2024

Anti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, contributing to the initiation and development of cancer, as well as intrinsic or acquired resistance to therapy. Although BCL-2 family protein inhibitors, such as Venetoclax, have demonstrated efficacy in hematological neoplasms, their effectiveness as single agents in solid tumors is limited. Identifying alternative molecular targets that can overcome intrinsic resistance to BCL-2 family protein inhibitors is of great clinical importance. Here, we present evidence of strong synthetic lethal interactions between WSB2, a relatively unexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and multiple anti-apoptotic BCL-2 family proteins. Mechanistically, an assembled CRL5WSB2E3 ubiquitin ligase complex targets NOXA, a pro-apoptotic BCL-2 family protein, for degradation via the ubiquitin-proteasomal pathway. Ablation of WSB2 leads to a remarkable accumulation of NOXA proteins in cultured cell lines and knockout mouse organs. While WSB2 deficiency alone has a minimal effect on spontaneous apoptosis, it renders cancer cells more susceptible to apoptosis when anti-apoptotic BCL-2 family proteins are genetically depleted or pharmacologically inhibited. These findings establish WSB2 as a critical regulator of mitochondrial apoptosis and highlight the dysregulation of the WSB2-NOXA regulatory axis as a contributing factor to apoptosis resistance in cancer cells. Synergistically targeting WSB2 and anti-apoptotic BCL-2 family proteins holds promising clinical potential in the treatment of human cancers.
CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres
Authors: Cappelletti Eleonora , Piras Francesca M. , Biundo Marialaura , Raimondi Elena , Nergadze Solomon G. , Giulotto Elena
Published: April 2024

Background

While CENP-A is the epigenetic determinant of the centromeric function, the role of CENP-B, the sole centromeric protein binding a specific DNA sequence (CENP-B-box), remains elusive. In the few mammalian species analyzed so far, the CENP-B box is contained in the major satellite repeat that is present at all centromeres. We previously demonstrated that, in the genusEquus, some centromeres lack any satellite repeat.

Results

Here, we show that, in fourEquusspecies, CENP-B is expressed but does not bind the numerous satellite-free and the majority of satellite-based centromeres while it is localized at several ancestral now inactive centromeres. The absence of CENP-B is related to the lack of CENP-B boxes rather than to peculiar features of the protein itself. CENP-B boxes are comprised in a previously undescribed repeat which is not the major satellite bound by CENP-A. Comparative sequence analysis suggests that this satellite was centromeric in the equid ancestor, lost centromeric function during evolution and gave rise to a short CENP-A bound repeat not containing the CENP-B box but being enriched in dyad symmetries. Centromeres lacking CENP-B are functional and recruit normal amounts of the centromeric proteins CENP-A and CENP-C.

Conclusions

We propose that the uncoupling between CENP-B and CENP-A may have played a role in the evolutionary reshuffling of equid centromeres. This study provides new insights into the complexity of centromere organization in a largely biodiverse world where the majority of mammalian species still have to be studied.
Adaptive Integration of Perceptual and Reward Information in an Uncertain World
Authors: Ganesh Prashanti , Cichy Radoslaw M. , Schuck Nicolas W. , Finke Carsten , Bruckner Rasmus
Published: April 2024

Perceptual uncertainty and salience both impact decision-making, but how these factors precisely impact trial-and-error reinforcement learning is not well understood. Here, we test the hypotheses that (H1) perceptual uncertainty modulates reward-based learning and that (H2) economic decision-making is driven by the value and the salience of sensory information. For this, we combined computational modeling with a perceptual uncertainty-augmented reward-learning task in a human behavioral experiment (N= 98). In line with our hypotheses, we found that subjects regulated learning behavior in response to the uncertainty with which they could distinguish choice options based on sensory information (belief state), in addition to the errors they made in predicting outcomes. Moreover, subjects considered a combination of expected values and sensory salience for economic decision-making. Taken together, this shows that perceptual and economic decision-making are closely intertwined and share a common basis for behavior in the real world.
Damage explains function in spiking neural networks representing central pattern generator
Authors: Pryyma Yuriy , Yakovenko Sergiy
Published: April 2024

Complex biological systems evolved to control dynamics in the presence of noisy and often unpredictable inputs. The staple example is locomotor control, which is vital for survival. Control of locomotion results from interactions between multiple systems--from passive dynamics of inverted pendulum governing body motion to coupled neural oscillators that integrate predictive forward and sensory feedback signals. The neural dynamic computations are expressed in the rhythmogenic spinal network termed the central pattern generator (CPG). While a system of ordinary differential equations or a rate model is typically “good enough” to describe the CPG function, the computations performed by thousands of neurons in vertebrates are poorly understood. To study the distributed computations of a well-defined neural dynamic system, we developed a CPG model for gait expressed with the spiking neural networks (SNN). The SNN-CPG model faithfully recreated the input-output relationship of the rate model, describing the modulation of gait phase characteristics. The degradation of distributed computation within elements of the SNN-CPG model was further studied with “lesion” experiments. We found that lesioning flexor or extensor elements, with otherwise identical structural organization of reciprocal networks, affected differently the overall CPG computation. This result mimics experimental observations. Moreover, the increasing general excitability within the network can compensate for the loss of function after progressive lesions. This observation may explain the response to spinal stimulation and propose a novel theoretical framework for degraded computations and their applications within restorative technologies.
Impact of photobleaching of fluorescent proteins on FRET measurements under two-photon excitation
Authors: Adhikari Dhruba P. , Stoneman Michael R. , Raicu Valerica
Published: April 2024

Förster resonance energy transfer (FRET) is a widely used technique for nanoscale molecular distance measurements, which makes FRET ideal for studying protein interactions and quaternary structure of protein complexes. In this work, we were interested in how photobleaching of donor and acceptor molecules affects the FRET results under various excitation conditions. We conducted a systematic study, under two-photon excitation, of the effects of the excitation power and the choice of excitation wavelengths upon the measured FRET efficiencies of multiplex protein constructs, consisting of one donor and either one or two acceptors, using both the kinetic theory of FRET and numerical simulations under given excitation conditions. We found that under low excitation power and properly chosen excitation wavelengths the relationship between the FRET efficiency of a trimeric construct ADA agrees within 2% with the FRET efficiency computed (via the kinetic theory of FRET in the absence of photobleaching) from two dimeric constructs ADN and NDA. By contrast, at higher excitation powers the FRET efficiencies changed significantly, due to the photobleaching of both the donor (through direct excitation) and the acceptor (mostly through FRET-induced excitation). Based on these results and numerical simulations using a simple but powerful algorithm, we also provide guidelines for choosing appropriate experimental conditions for reliable FRET measurements in complexes of associating molecules of biological interest.
A multiplexed and quantitative assay for small-molecule detection via photo-crosslinking of structure switching aptamers
Authors: Newman Sharon S. , Wilson Brandon , Zheng Liwei , Eisenstein Michael , Soh Tom
Published: April 2024

There is an unmet need for molecular detection assays that enable the multiplexed, quantification of smallmolecule analytes. We present xPlex, an assay that combines aptamer switches with ultraviolet-crosslinkable complementary strands to record target-binding events. When the aptamer’s small-molecule target is present, the crosslinkable strand is displaced, enabling PCR amplification and detection of the relevant aptamer. In the absence of that target, the aptamer is readily cross-linked to the strand, preventing amplification from happening. The resulting aptamer-specific amplicons can be detected and quantified in a multiplexed fashion using high-throughput sequencing. We demonstrate quantitative performance for a pair of small-molecule analytes, dopamine and glucose, and show that this assay retains good specificity with mixtures of the two molecules at various concentrations. We further show that xPlex can effectively evaluate the specificity of cross-reactive aptamers to a range of different small-molecule analytes. We believe the xPlex assay format could offer a useful strategy for achieving multiplexed analysis of small-molecule targets in a variety of scenarios.
CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression
Authors: Zhang Wei , Wang Jiesi , Dai Jiajie , Zhuo Linan , Zhao Mingyue , Ye Haimou , Wang Weiwen
Published: April 2024

Depression is a heterogeneous psychiatric disorder characterized by multiple symptom clusters. N-methyl-d-aspartic acid receptors (NMDARs), consisting of various subunit proteins GluN1-3, are known to be critical molecular bases for the occurrence and treatment of depression. However, the involvement of the NMDAR subunit GluN3A in the heterogeneity of depressive symptoms and antidepressant effects remains unclear. Here, we found that chronic social defeat stress (CSDS) induced a range of depression-related behaviors, including decreased social interest, increased helplessness and anxiety-like behavior, and reduced GluN3A mRNA and protein expression in the hippocampal CA1 intermediate (CA1i) region. Additionally, GluN3A knockout (KO) mice exhibited pronounced helplessness behavior. Increasing GluN3A expression in the CA1i in both models specifically reversed the increased helplessness behavior but not social interest and anxiety-like behavior. Furthermore, the lack of CA1i GluN3A expression reduced the activity of CA1i pyramidal neurons in mice during helplessness behavior, a phenomenon also reversed by upregulating CA1i GluN3A expression. Further bidirectional modulation of CA1i pyramidal neuron activity directly mimicked or reversed CSDS-induced helplessness behavior. Finally, injection of D-serine into the CA1i rapidly improved helplessness behavior in CSDS mice while increasing the activity of CA1i pyramidal neurons, whereas knockout of the GluN3A or inhibition of CA1i neuron activity prevented the effect of D-serine. Our study elucidates the critical role of GluN3A subunit in regulating depression-related helplessness behavior and its mechanisms, as well as its role in the rapid antidepressant effect of D-serine, which deepen the understanding of the complex pathophysiology of depression and develop a potential clinical treatment new target.
CaClust: linking genotype to transcriptional heterogeneity of follicular lymphoma using BCR and exomic variants
Authors: Oksza-Orzechowski Kazimierz , Quinten Edwin , Darvish-Shafighi Shadi , Kiełbasa Szymon M. , van Kessel Hugo W. , de Groen Ruben A. L. , Vermaat Joost S. P. , Yáñez Julieta H. Sepúlveda , Navarrete Marcelo A. , Veelken Hendrik , van Bergen Cornelis A. M. , Szczurek Ewa
Published: April 2024

Tumor tissues exhibit high genotypic and transcriptional heterogeneity, resulting from tumor evolution and affecting cancer progression and treatment. These two types of heterogeneity in follicular lymphoma were so far predominantly studied in separation. To comprehensively investigate the evolution and genotype to phenotype maps in follicular lymphoma, we introduce CaClust, a probabilistic graphical model that integrates deep whole exome, single-cell RNA and B-cell receptor sequencing data to infer clone genotypes, cell-to-clone mapping, and single-cell genotyping. CaClust outperforms a state-of-the-art model on simulated and patient data. In-depth analysis of 22492 single cells and whole exomes from four follicular lymphoma samples using CaClust gives insights into effects of driver mutations, follicular lymphoma evolution, and possible therapeutic targets. CaClust single-cell genotyping agrees with genotypes observed in an independent targeted resequencing experiment. Our approach is the first to evaluate the strength of genotype to phenotype links in follicular lymphoma in the evolutionary context of the disease.
Native Proteomics by Capillary Zone Electrophoresis-Mass Spectrometry
Authors: Wang Qianyi , Wang Qianjie , Qi Zihao , Moeller William , Wysocki Vicki H , Sun Liangliang
Published: April 2024

Native proteomics measures endogenous proteoforms and protein complexes under a near physiological condition using native mass spectrometry (nMS) coupled with liquid-phase separations. Native proteomics should provide the most accurate bird’s-eye view of proteome dynamics within cells, which is fundamental for understanding almost all biological processes. nMS has been widely employed to characterize well-purified protein complexes. However, there are only very few trials of utilizing nMS to measure proteoforms and protein complexes in a complex sample (i.e., a whole cell lysate). Here, we pioneer the native proteomics measurement of large proteoforms or protein complexes up to 400 kDa from a complex proteome via online coupling of native capillary zone electrophoresis (nCZE) to an ultra-high mass range (UHMR) Orbitrap mass spectrometer. The nCZE-MS technique enabled the measurement of a 115-kDa standard protein complex while consuming only about 0.1 ng of protein material. nCZE-MS analysis of anE.colicell lysate detected 72 proteoforms or protein complexes in a mass range of 30-400 kDa in a single run while consuming only 50-ng protein material. The mass distribution of detected proteoforms or protein complexes agreed well with that from mass photometry measurement. This work represents a technical breakthrough in native proteomics for measuring complex proteomes.
Pear (Pyrus communisL. cv. Conference) has shade-tolerant features allowing for consistent agrivoltaic crop yield
Authors: Reher Thomas , Willockx Brecht , Schenk Ann , Bisschop Jolien , Huyghe Yasmin , Nicolaï Bart M. , Martens Johan A. , Diels Jan , Cappelle Jan , Van de Poel Bram
Published: April 2024

Transitioning to a fossil fuel free society requires an increase in solar energy production. However, expanding solar power to farmland competes with food production. Additionally, climate change threatens food security and leads increasingly to yield losses.

Agrivoltaics (AV) systems produce solar energy and food on the same field, while sheltering crops. In AV systems, crops grow in a modified environment with reduced solar irradiance, a tempered microclimate and a potential physical cover protecting against hail damage.

This research describes pear production under an AV pilot with 24% light reduction for 3 consecutive seasons. AV pear trees yielded 14% less than the reference. Flowering and fruit set was unchanged while AV reduced leaf flavonoid levels. The leaf photosynthetic light response was identical, yet a delayed leaf senescence under AV suggests an adaptation to the modified environment. AV impacted fruit shape, as there was an increase in the number of bottle shaped pears and a reduction in caliber. Other fruit quality traits were broadly unaffected, yet postharvest ethylene production was higher for AV fruit in 2022 than for the control.

This study demonstrates that AV systems hold potential for pear production under temperate climates and highlights plant adaptations that make this possible.

Highlight

Pear cultivation in agrivoltaic systems integrates renewable energy and sustainable fruit production. This study provides insights into crop yield, fruit quality, and plant adaptation towards an agrivoltaic environment.
Expert-guided protein Language Models enable accurate and blazingly fast fitness prediction
Authors: Marquet Celine , Schlensok Julius , Abakarova Marina , Rost Burkhard , Laine Elodie
Published: April 2024

Exhaustive experimental annotation of the effect of all known protein variants remains daunting and expensive, stressing the need for scalable effect predictions. We introduce VespaG, a blazingly fast missense amino acid variant effect predictor, leveraging protein Language Model (pLM) embeddings as input to a minimal deep learning model. To overcome the sparsity of experimental training data, we created a dataset of 39 million single amino acid variants from the human proteome applying the multiple sequence alignment-based effect predictor GEMME as a pseudo standard-of-truth. This setup increases interpretability compared to the baseline pLM and is easily retrainable with novel or updated pLMs. Assessed against the ProteinGym benchmark (217 multiplex assays of variant effect - MAVE - with 2.5 million variants), VespaG achieved a mean Spearman correlation of 0.48 +/- 0.02, matching top-performing methods evaluated on the same data. VespaG has the advantage of being orders of magnitude faster, predicting all mutational landscapes of all proteins in proteomes such as Homo sapiens or Drosophila melanogaster in under 30 minutes on a consumer laptop (12-core CPU, 16 GB RAM).
Imaging demyelinated axons after spinal cord injuries with PET tracer [18F]3F4AP
Authors: Ramos-Torres Karla M. , Conti Sara , Zhou Yu-Peng , Tiss Amal , Caravagna Celine , Takahashi Kazue , He Zhigang , Wilks Moses Q. , Eckl Sophie , Sun Yang , Biundo Jason , Gong Kuang , He Zhigang , Linnman Clas , Brugarolas Pedro
Published: April 2024

Spinal cord injuries (SCI) often lead to lifelong disability. Among the various types of injuries, incomplete and discomplete injuries, where some axons remain intact, offer potential for recovery. However, demyelination of these spared axons can worsen disability. Demyelination is a reversible phenomenon, and drugs like 4-aminopyridine (4AP), which target K+channels in demyelinated axons, show that conduction can be restored. Yet, accurately assessing and monitoring demyelination post-SCI remains challenging due to the lack of suitable imaging methods. In this study, we introduce a novel approach utilizing the positron emission tomography (PET) tracer, [18F]3F4AP, specifically targeting K+channels in demyelinated axons for SCI imaging. Rats with incomplete contusion injuries were imaged up to one month post-injury, revealing [18F]3F4AP’s exceptional sensitivity to injury and its ability to detect temporal changes. Further validation through autoradiography and immunohistochemistry confirmed [18F]3F4AP’s targeting of demyelinated axons. In a proof-of-concept study involving human subjects, [18F]3F4AP differentiated between a severe and a largely recovered incomplete injury, indicating axonal loss and demyelination, respectively. Moreover, alterations in tracer delivery were evident on dynamic PET images, suggestive of differences in spinal cord blood flow between the injuries. In conclusion, [18F]3F4AP demonstrates efficacy in detecting incomplete SCI in both animal models and humans. The potential for monitoring post-SCI demyelination changes and response to therapy underscores the utility of [18F]3F4AP in advancing our understanding and management of spinal cord injuries.
The Genome Explorer Genome Browser
Authors: Herson James , Krummenacker Markus , Spaulding Aaron , O’Maille Paul , Karp Peter D.
Published: April 2024

Are two adjacent genes in the same operon? What is the order and spacing between several transcription-factor binding sites? Genome browsers are software data-visualization and exploration tools that enable biologists to answer questions such as these. In this paper we report on a major update to our browser, Genome Explorer, that provides nearly instantaneous scaling and traversing of a genome, enabling users to quickly and easily zoom into an area of interest. The user can rapidly move between scales that depict the entire genome, individual genes, and the sequence; Genome Explorer presents the most relevant detail and context for each scale. By downloading the data for the entire genome to the user’s web browser and dynamically generating visualizations locally, we enable fine control of zoom and pan functions and real-time redrawing of the visualization, resulting in smoother and more intuitive exploration of a genome than is possible with other browsers. Further, genome features are presented together, in-line, using familiar graphical depictions. In contrast, many other browsers depict genome features using data tracks, which have low information density and can visually obscure the relative positions of features. Genome Explorer diagrams have high information density that provides larger amounts of genome context and sequence information to be presented in a given sized monitor than for tracks-based browsers. Genome Explorer provides optional data tracks for analysis of large-scale datasets and a unique comparative mode that aligns genomes at orthologous genes with synchronized zooming.
Establishing comprehensive quaternary structural proteomes from genome sequence
Authors: Catoiu Edward Alexander , Mih Nathan , Lu Maxwell , Palsson Bernhard
Published: April 2024

A critical body of knowledge has developed through advances in protein microscopy, protein-fold modeling, structural biology software, availability of sequenced bacterial genomes, large-scale mutation databases, and genome-scale models. Based on these recent advances, we develop a computational framework that; i) identifies the oligomeric structural proteome encoded by an organism’s genome from available structural resources; ii) maps multi-strain alleleomic variation, resulting in the structural proteome for a species; and iii) calculates the 3D orientation of proteins across subcellular compartments with residue-level precision. Using the platform, we; iv) compute the quaternaryE. coliK-12 MG1655 structural proteome; v) use a dataset of 12,000 mutations to build Random Forest classifiers that can predict the severity of mutations; and, in combination with a genome-scale model that computes proteome allocation, vi) obtain the spatial allocation of theE. coliproteome. Thus, in conjunction with relevant datasets and increasingly accurate computational models, we can now annotate quaternary structural proteomes, at genome-scale, to obtain a molecular-level understanding of whole-cell functions.

Significance

Advancements in experimental and computational methods have revealed the shapes of multi-subunit proteins. The absence of a unified platform that maps actionable datatypes onto these increasingly accurate structures creates a barrier to structural analyses, especially at the genome-scale. Here, we describe QSPACE, a computational annotation platform that evaluates existing resources to identify the best-available structure for each protein in a user’s query, maps the 3D location of actionable datatypes (e.g., active sites, published mutations) onto the selected structures, and uses third-party APIs to determine the subcellular compartment of all amino acids of a protein. As proof-of-concept, we deployed QSPACE to generate the quaternary structural proteome ofE. coliMG1655 and demonstrate two use-cases involving large-scale mutant analysis and genome-scale modelling.
mRNA nuclear clustering leads to a difference in mutant huntingtin mRNA and protein silencing by siRNAsin vivo
Authors: Allen Sarah , O’Reilly Daniel , Miller Rachael , Sapp Ellen , Summers Ashley , Paquette Joseph , Moreno Dimas Echeverria , Bramato Brianna , McHugh Nicholas , Yamada Ken , Aronin Neil , DiFiglia Marian , Khvorova Anastasia
Published: April 2024

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the first exon of the huntingtin gene (HTT). Oligonucleotide therapeutics, such as short interfering RNA (siRNA), reduce levels of huntingtin mRNA and proteinin vivoand are considered a viable therapeutic strategy. However, the extent to which they silence HTT mRNA in the nucleus is not established. We synthesized siRNA cross-reactive to mouse (wild-type)Httand human (mutant)HTTin a di-valent scaffold and delivered to two mouse models of HD. In both models, di-valent siRNA sustained lowering of wild-typeHtt, but not mutantHTTmRNA expression in striatum and cortex. Near-complete silencing of both mutant HTT protein and wild-type Htt protein was observed in both models. Subsequent fluorescent in situ hybridization (FISH) analysis shows that di-valent siRNA acts predominantly on cytoplasmic mutantHTTtranscripts, leaving clustered mutantHTTtranscripts in the nucleus largely intact in treated HD mouse brains. The observed differences between mRNA and protein levels, exaggerated in the case of extended repeats, might apply to other repeat-associated neurological disorders.
HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults
Authors: Becker Amanda , Filipp Mallory , Lantz Connor , Glinton Kristofor , Thorp Edward B.
Published: April 2024

The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent onhypoxia inducible transcription factor-1α(HIF-1α).In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age andHIF-1αdependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.
Group composition and its ontogenetic changes in marine pelagic fishes
Authors: Furuichi Sho , Suzuki Masahiro , Kamimura Yasuhiro , Yukami Ryuji
Published: April 2024

Group living is a widespread phenomenon among animals and an important trait in fishes. Understanding group composition and its dynamics is fundamental for elucidating ecological and evolutionary processes in natural populations of gregarious animal species, including fishes, but our knowledge of group composition in marine fishes is limited. Here, we examined group composition and its ontogenetic change in two marine fishes, Japanese sardine (Sardinops melanostictus) and chub mackerel (Scomber japonicus). We found that, at the juvenile stage, groups were composed of individuals with similar body length, age, and growth history. At the sub-adult stage, although body length within a group remained similar, the within-group similarity in age and growth history decreased, approaching the level expected when groups were randomly composed. Therefore, during the early life history, individuals form groups with those spawned at approximately the same time and place (i.e., those from the same batch). As they develop, however, individuals of various origins intermingle and selectively form groups with others exhibiting similar phenotypes. We further found that environmental and geographical factors were also related to the body size and age of individuals distributed. This indicates that Japanese sardine and chub mackerel exhibit phenotype-specific and growth-stage-specific habitat use, which also contributes to the formation and maintenance of structured groups. Our findings provide valuable information on group composition, its ontogenetic change, and its underlying mechanisms in marine fishes, for which the information is limited. These insights may help to clarify ecological and evolutionary processes such as population dynamics, density-dependent phenomena, and the evolution of grouping behaviour in small pelagic fishes.
Identification of high sugar diet-induced dysregulated metabolic pathways in muscle using tissue-specific metabolic models in Drosophila
Authors: Moon Sun Jin , Hu Yanhui , Dzieciatkowska Monika , Kim Ah-Ram , Chen Po-Lin , Asara John M. , D'Alessandro Angelo , Perrimon Norbert
Published: April 2024

Individual tissues perform highly specialized metabolic functions to maintain whole-body homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, a lack of tissue-specific metabolic models makes it challenging to quantitatively assess the metabolic processes of individual tissues and disease models in this organism. To address this issue, we reconstructed 32 tissue-specific genome-scale metabolic models (GEMs) using pseudo-bulk single cell transcriptomics data, revealing distinct metabolic network structures across tissues. Leveraging enzyme kinetics and flux analyses, we predicted tissue-dependent metabolic pathway activities, recapitulating known tissue functions and identifying tissue-specific metabolic signatures, as supported by metabolite profiling. Moreover, to demonstrate the utility of tissue-specific GEMs in a disease context, we examined the effect of a high sugar diet (HSD) on muscle metabolism. Together with 13C-glucose isotopic tracer studies, we identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a rate-limiting enzyme in glycolysis in response to HSD. Decreased GAPDH activity was linked to increased NADH/NAD+ ratio and oxidation of GAPDH. Furthermore, we introduced a pathway flux index to predict and validate additionally perturbed pathways, including fructose and butanoate metabolism. Altogether, our results represent a significant advance in generating quantitative tissue-specific GEMs and flux analyses in Drosophila, highlighting their use for identifying dysregulated metabolic pathways in a human disease model.
Involvement of neurons in the non-human primate anterior striatum in proactive inhibition
Authors: Yoshida Atsushi , Hikosaka Okihide
Published: April 2024

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which one showed obviously increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond mere saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.
Morphology and synapse topography optimize linear encoding of synapse numbers inDrosophilalooming responsive descending neurons
Authors: Moreno-Sanchez Anthony , Vasserman Alexander N. , Jang HyoJong , Hina Bryce W. , von Reyn Catherine R. , Ausborn Jessica
Published: April 2024

Synapses are often precisely organized on dendritic arbors, yet the role of synaptic topography in dendritic integration remains poorly understood. Utilizing electron microscopy (EM) connectomics we investigate synaptic topography inDrosophila melanogasterlooming circuits, focusing on retinotopically tuned visual projection neurons (VPNs) that synapse onto descending neurons (DNs). Synapses of a given VPN type project to non-overlapping regions on DN dendrites. Within these spatially constrained clusters, synapses are not retinotopically organized, but instead adopt near random distributions. To investigate how this organization strategy impacts DN integration, we developed multicompartment models of DNs fitted to experimental data and using precise EM morphologies and synapse locations. We find that DN dendrite morphologies normalize EPSP amplitudes of individual synaptic inputs and that near random distributions of synapses ensure linear encoding of synapse numbers from individual VPNs. These findings illuminate how synaptic topography influences dendritic integration and suggest that linear encoding of synapse numbers may be a default strategy established through connectivity and passive neuron properties, upon which active properties and plasticity can then tune as needed.
Comparison of therapeutic effects between pulsed field ablation and cryoballoon ablation in the treatment of atrial fibrillation: a systematic review and meta-analysis
Authors: Wan Yun , Zeng Shuting , Liu FuWei , Gao Xin , Li Weidong , Liu Kaifeng , He Jie , Ji Jianqing , Luo Jun
Published: April 2024

Background

Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation surgery. Cryoballoon ablation (CBA), a conventional thermal ablation technique, enjoys widespread clinical application. In contrast, Pulsed field ablation (PFA) is a novel non thermal ablation technique for the treatment of atrial fibrillation (AF) patients, with safety comparable to traditional thermal ablation surgery. The present study aims to evaluate and compare the procedural efficiency and safety profiles of PFA and CBA in the management of AF.

Method

We performed a systematic search across PubMed, the Cochrane Library, and Embase databases, encompassing the literature up to February 2024, to inform our systematic review and meta-analysis. When assessing outcome indicators, the risk ratio (RR) and its corresponding 95% confidence interval (CI) were calculated for dichotomous variables. For continuous variables, the mean difference (MD) and the associated 95% CI were determined. In this context, an RR less than 1 and an MD less than 0 were considered advantageous for the PFA group.

Result

In this analysis, nine observational studies encompassing 2,875 patients with AF were included. Among these, 38% (n=1105) were treated with PFA, while 62% (n=1,770) received CBA. The results indicated that PFA was associated with a significantly shorter surgical duration compared to CBA, with a mean difference (MD) of -10.49 minutes (95% CI [-15.50, -5.49];p<0.0001). Additionally, the PFA group exhibited a reduced risk of perioperative complications relative to the CBA group, with a risk ratio (RR) of 0.52 (95% CI 0.30-0.89;p=0.02). Nevertheless, no statistically significant differences were observed when comparing the two treatment cohorts concerning fluorescence irradiation time (MD 0.71; 95% CI [-0.45, 1.86];p=0.23) and the recurrence of atrial arrhythmias during follow-up (RR 0.95; 95% CI 0.78-1.14;p=0.57).

Conclusion

The outcomes of this investigation reveal that PFA holds a relative advantage over CBA in certain respects, notably by reducing both surgical duration and the incidence of perioperative complications. However, no significant distinction was identified between the two modalities concerning the duration of fluorescence irradiation or the rate of atrial arrhythmia recurrence. To enhance the robustness of these estimates, further research is needed, especially by incorporating additional randomized controlled trials.
Angelica keiskeileaves extract attenuates psychosocial stress in overcrowding-subjected rats
Authors: Siswanto Ferbian Milas
Published: April 2024

Angelica keiskeiis currently used as a popular functional food with various beneficial effects, including antioxidant, anti-obesity, anti-tumor, anti-diabetic, and anti-bacterial. A recentin vitrostudy reported thatA. keiskeiinhibits monoamine oxidases (MAOs), suggesting the antidepressant property ofA. keiskei. However,in vivostudies on laboratory animals subjected to psychosocial stress have not been conducted. In this study, the effects of anA. keiskeileaves extract (AKE) on rats undergoing chronic social overcrowding stress were explored. Six-month-old male and female Wistar rats were housed in groups of three in 12 × 12 × 18 cm cages (overcrowding) for twenty-eight days. Both male and female rats were divided into two groups (N = 10); control group received oral distilled water, whilst the other group (treatment group) received 20 mg/kgBW/day of AKE supplementation. The results showed that AKE-treated rats exhibited lower anxiety- and depressive-related behaviors than that of control stressed rats. AKE significantly decreased corticosterone and increased testosterone and estrogen levels in stressed rats. Additionally, brain tissue MDA and TNF-alpha levels were reduced, while brain neurotransmitter 5-HT and antioxidant SOD levels were elevated by the AKE. These findings suggest, for the first time, that AKE could alleviate overcrowding stress-induced behavioral, neuroendocrine, antioxidant, and inflammatory dysfunctions.A. keiskeileaves extract could potentially be used as an agonist to reduce stress and depression.

GRAPHICAL ABSTRACT
Complementary benefits of multivariate and hierarchical models for identifying individual differences in cognitive control
Authors: Freund Michael C , Chen Ruiqi , Chen Gang , Braver Todd S
Published: April 2024

Understanding individual differences in cognitive control is a central goal in psychology and neuroscience. Reliably measuring these differences, however, has proven extremely challenging, at least when using standard measures in cognitive neuroscience such as response times or task-based fMRI activity. While prior work has pinpointed the source of the issue -- the vast amount of cross-trial variability within these measures -- solutions remain elusive. Here, we propose one potential way forward: an analytic framework that combines hierarchical Bayesian modeling with multivariate decoding of trial-level fMRI data. Using this framework and longitudinal data from the Dual Mechanisms of Cognitive Control project, we estimated individuals' neural responses associated with cognitive control within a color-word Stroop task, then assessed the reliability of these individuals' responses across a time interval of several months. We show that in many prefrontal and parietal brain regions, test--retest reliability was near maximal, and that only hierarchical models were able to reveal this state of affairs. Further, when compared to traditional univariate contrasts, multivariate decoding enabled individual-level correlations to be estimated with significantly greater precision. We specifically link these improvements in precision to the optimized suppression of cross-trial variability in decoding. Together, these findings not only indicate that cognitive control-related neural responses individuate people in a highly stable manner across time, but also suggest that integrating hierarchical and multivariate models provides a powerful approach for investigating individual differences in cognitive control, one that can effectively address the issue of high-variability measures.
Developmental defects in ectodermal appendages caused by missense mutation inedaraddgene in thenfrmangrove killifish,Kryptolebias marmoratus
Authors: Saud Hussein A. , O’Neill Paul A. , Ring Brian C. , Kudoh Tetsuhiro
Published: April 2024

From an ENU-mutated mangrove killifish line R228, we have identified and isolated a novel mutant line, no-fin-ray/nfrin which fin ray development is largely reduced. Besides the reduction of the fin, thenfrmutant also exhibited other phenotype associated with ectodermal cell lineages including loss of scales, deformation in the gill structure such as decreasing the number of gill filaments, the reduction in the number of jaw teeth, pharyngeal teeth and gill rakers. Illumina RNAseq with 12 embryos each from mutants, siblings and the parental WT strain Hon9 identified a mutation in theedaraddin a highly conserved C-terminal death domain. Edaradd is known as a cytoplasmic accessory protein for the Ectodysplasin A (EDA) signalling pathway. To confirm the crucial role ofedaraddduring fin development, CRISPR RNAs were designed to knock out the gene in another killifish species, Arabian killifish. Indeed, Arabian killifishedaraddcrispants showed a potent reduction of the fin development with 100% frequency. Furthermore,EDAcrispants also showed identical phenotypes to that ofedaraddcrispants, confirming the fin defect in the mutants/crispants is caused by the signalling pathway of theEDAin the killifish species. These data demonstrate a powerful genetic approach using isogenic self-fertilising mangrove killifish as a tool for identifying mutants and their mutation, and revealed the crucial role ofedaraddin the fish fin development and other ectoderm derived epithelial tissues.
Causal Debiasing for Unknown Bias in Histopathology - A Colon Cancer Use Case
Authors: Correa-Medero Ramón , Pai Rish , Ebare Kingsley , Buchanan Daniel , Jenkins Mark A , Phipps Amanda I. , Newcomb Polly A. , Gallinger Steven , Grant Robert , Le marchand Loic , Banerjee Imon
Published: April 2024

Advancement of AI has opened new possibility for accurate diagnosis and prognosis using digital histopathology slides which not only saves hours of expert effort but also makes the estimation more standardized and accurate. However, preserving the AI model performance on the external sites is an extremely challenging problem in the histopathology domain which is primarily due to the difference in data acquisition and/or sampling bias. Although, AI models can also learn spurious correlation, they provide unequal performance across validation population. While it is crucial to detect and remove the bias from the AI model before the clinical application, the cause of the bias is often unknown. We proposed a Causal Survival model that can reduce the effect of unknown bias by leveraging the causal reasoning framework. We use the model to predict recurrence-free survival for the colorectal cancer patients using quantitative histopathology features from seven geographically distributed sites and achieve equalized performance compared to the baseline traditional Cox Proportional Hazards and DeepSurvival model. Through ablation study, we demonstrated benefit of novel addition of latent probability adjustment and auxiliary losses. Although detection of cause of unknown bias is unsolved, we proposed a causal debiasing solution to reduce the bias and improve the AI model generalizibility on the histopathology domain across sites.
Paranormal believers are quicker but less accurate in rejecting the presence of the target in conjunction visual search compared to skeptics
Authors: Akbari Fatemeh , Asivandzadehchaharmahali Samaneh , Narmashiri Abdolvahed
Published: April 2024

Recent studies have shown that paranormal believers may exhibit cognitive dysfunctions, yet their performance in conjunction with visual search has not been understood. To address this issue, we examined the performance of both paranormal believers and skeptics in a conjunction visual search task, paying particular attention to their search time and accuracy across different set sizes in both target-present (TP) and target-absent (TA) trials. In our study, believers demonstrated a tendency toward speed but also displayed carelessness compared to skeptics when rejecting the presence of the target. Conversely, skeptics exhibited slower search times but demonstrated greater accuracy both in rejecting the presence of the target and in finding it. Overall, our findings suggest that believers were quicker and less accurate in rejecting the presence of the target in conjunction visual search compared to skeptics, highlighting potential differences in cognitive processing between skeptics and believers.

Significant statement

Our study investigates the performance of paranormal believers and skeptics in conjunction with visual search tasks, shedding light on potential differences in cognitive processing between the two groups. While believers demonstrate faster search times, they also display greater carelessness compared to skeptics when rejecting the target’s presence. In contrast, skeptics exhibit slower search times but higher accuracy in both rejecting and finding the target. These findings underscore the importance of considering individual belief systems in understanding cognitive performance in conjunction with visual tasks.
Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity
Authors: Cassioli Chiara , Capitani Nagaja , Staton Claire C. , Schirra Claudia , Finetti Francesca , Onnis Anna , Alawar Nadia , Tu Szu-Min , Lopresti Ludovica , Tatangelo Vanessa , Tangredi Carmela , Valvo Salvatore , Chang Hsin-Fang , Miccoli Annachiara , Compeer Ewaldus B. , Nicholls Jemma , Blazar Bruce , Marotta Giuseppe , Wood Matthew J. A. , Trentin Livio , Patrussi Laura , Dustin Michael L. , Becherer Ute , Baldari Cosima T.
Published: April 2024

Supramolecular Attack Particles (SMAPs) are particulate entities, characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a glycoproteic shell, released by CTLs and NK cells. Prior proteomic analysis identified thrombospondin-1 (TSP-1) and thrombospondin-4 (TSP-4) as putative components of SMAPs. While TSP-1 has been validated as a component of the SMAP shell and shown to contribute significantly to CTL-mediated killing, the expression and function of TSP-4 in CTLs, and its interplay with TSP-1 in SMAP biogenesis and function, has not been investigated as yet. Here we demonstrate that TSP-4 and TSP-1 have a complementary expression profile during in vitro human CD8+T cell differentiation to CTLs and sequentially localize to lytic granules (LG), with TSP-4 being required for TSP-1 association with LGs. Correlative light microscopy identified the TSP-enriched LGs as the SMAP-containing multicore granules. We show by STED microscopy a heterogeneity among TSP-enriched LGs, the most abundant population being positive for both TSP-4 and TSP-1. We also show that TSP-1 and TSP-4 are co-released in association with SMAPs at immune synapses formed on planar supported lipid bilayers, as assessed by dSTORM imaging. Finally, we provide evidence that TSP-4 is required for CTL- and SMAP-mediated cell killing. Of note, we found that chronic lymphocytic leukemia (CLL) cell supernatants, which suppress CTL mediated killing, also suppress expression of TSP-4 as well as of cytolytic effectors and impair SMAP biogenesis. These results identify TSP-4 as a key player in SMAP structure and activity and suggest that SMAPs may be a new target for immune suppression by CLL.