bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in nucleus accumbens core translatome accompanying incubation of cocaine craving
Authors: Kawa Alex B. , Hashimoto Joel G. , Beutler Madelyn M. , Guizzetti Marina , Wolf Marina E.
Published: September 2024

In the ‘incubation of cocaine craving’ model of relapse, rats exhibit progressive intensification (incubation) of cue-induced craving over several weeks of forced abstinence from cocaine self-administration. The expression of incubated craving depends on plasticity of excitatory synaptic transmission in nucleus accumbens core (NAcC) medium spiny neurons (MSN). Previously, we found that the maintenance of this plasticity and the expression of incubation depends on ongoing protein translation, and the regulation of translation is altered after incubation of cocaine craving. Here we used male and female rats that express Cre recombinase in either dopamine D1 receptor- or adenosine 2a (A2a) receptor-expressing MSN to express a GFP-tagged ribosomal protein in a cell-type specific manner, enabling us to use Translating Ribosome Affinity Purification (TRAP) to isolate actively translating mRNAs from both MSN subtypes for analysis by RNA-seq. We compared rats that self-administered saline or cocaine. Saline rats were assessed on abstinence day (AD) 1, while cocaine rats were assessed on AD1 or AD40-50. For both D1-MSN and A2a-MSN, there were few differentially translated genes between saline and cocaine AD1 groups. In contrast, pronounced differences in the translatome were observed between cocaine rats on AD1 and AD40-50, and this was far more robust in D1-MSN. Notably, all comparisons revealed sex differences in translating mRNAs. Sequencing results were validated by qRT-PCR for several genes of interest. This study, the first to combine TRAP-seq, transgenic rats, and a cocaine self-administration paradigm, identifies translating mRNAs linked to incubation of cocaine craving in D1-MSN and A2a-MSN of the NAcC.
Vocal processing networks in the human and marmoset brain
Authors: Dureux Audrey , Zanini Alessandro , Menon Ravi S. , Everling Stefan
Published: September 2024

Understanding the brain circuitry involved in vocal processing across species is crucial for unraveling the evolutionary roots of human communication. While previous research has pinpointed voice-sensitive regions in primates, direct cross-species comparisons using standardized protocols are limited. This study utilizes ultra-high field fMRI to explore vocal processing mechanisms in humans and marmosets. By employing voice-sensitive regions of interest (ROIs) identified via auditory localizers, we analyzed response time courses to species-specific vocalizations and non-vocal sounds using a dynamic auditory-stimulation paradigm. This approach gradually introduced sounds into white noise over 33 seconds. Results revealed that both species have responsive areas in the temporal, frontal, and cingulate cortices, with a distinct preference for vocalizations. Significant differences were found in the response time courses between vocal and non-vocal sounds, with humans displaying faster responses to vocalizations than marmosets. We also identified a shared antero-ventral auditory pathway in both species for vocal processing, originating from the superior temporal gyrus. Conversely, a posterior-dorsal pathway was more prominent in humans, whereas in marmosets, this pathway processed both sound types similarly. This comparative study sheds light on both conserved and divergent auditory pathways in primates, providing new insights into conspecific vocalization processing.
Embryonic exposure to valproic acid and neonicotinoid deteriorates the developmental GABA switch and impairs long-term potentiation in the local circuit of intermediate medial mesopallium of chick telencephalon
Authors: Matsushima Toshiya , Toji Noriyuki , Wada Kazuhiro , Shikanai Hiroki , Izumi Takeshi
Published: September 2024

Embryonic exposure to valproic acid (VPA) and imidacloprid (IMI, a neonicotinoid insecticide) impairs filial imprinting in hatchlings, and the deteriorating effects of VPA are mitigated by post-hatch injection of bumetanide, a blocker of the chloride intruder NKCC1. Here, we report that these exposures depolarized the reversal potential of local GABAergic transmission in the neurons of the intermediate medial mesopallium (IMM), the pallial region critical for imprinting. Furthermore, exposure increased field excitatory post-synaptic potentials in pre-tetanus recordings (fEPSPs) and impaired long-term potentiation by low-frequency tetanic stimulation (LTP). Bath-applied bumetanide rescued the impaired LTP in the VPA slices, whereas VU0463271, a blocker of the chloride extruder KCC2, suppressed LTP in the control slices, suggesting that hyperpolarizing GABA action is necessary for the potentiation of excitatory synaptic transmission. However, the transcriptional profiles of IMM slices did not support the expected increase in the NKCC1/KCC2 ratio, suggesting a potential modification of post-transcriptional processes. Instead, exposure to both VPA and IMI downregulated several transcriptional regulators (FOS, NR4A1, and NR4A2) and upregulated the RNA component of signal recognition particles (RN7SL1). As a limited set of response genes were shared, VPA and IMI could cause common neuronal malfunctions via distinct molecular cascades.
Novel naphthyridones targeting Pannexin 1 for colitis management
Authors: Hsueh Wen-Yun , Wu Yi-Ling , Weng Meng-Tzu , Liu Shin-Yun , Santavanond Jascinta P , Liu Yi-Chung , Lin Ching-I , Lai Cheng-Nong , Lu Yi-Ru , Hsu Jing Yin , Gao Hong-Yu , Lee Jinq-Chyi , Wei Shu-Chen , Lyu Ping-Chiang , Poon Ivan K H , Hsieh Hsing-Pang , Chiu Yu-Hsin
Published: September 2024

Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 is proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, we performed hit-to-lead optimization and identified a naphthyridone, compound12, as a new PANX1 inhibitor with an IC50of 0.73 μM that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, we revealed that compound12directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, we found that compound12markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, identify the binding site for future drug design, and present a targeted strategy for treating IBD.

Teaser

A specific PANX1 inhibitor presents a proof-of-concept treatment for inflammatory bowel disease.
An accessible platform to quantify oxygen diffusion in cell-laden hydrogels and its application to alginate-immobilized pancreatic beta cells
Authors: Champion Kurtis S. , Ebrahimi Orimi Hamid , Gauvin Laurier , Brassard Jonathan A. , Strand Berit L. , Leask Richard L. , Hoesli Corinne A.
Published: September 2024

Hydrogels are commonly used to immobilize mammalian cells, serving various purposes such as providing mechanical cues in three-dimensional cultures and acting as barriers for immunoprotection in transplantation. For instance, islet encapsulation holds promise in delivering insulin-producing cells for diabetes cellular therapy. Cell immobilization, by creating a barrier to bulk fluid motion, leads to diffusion-limited molecular transport and concentration gradients of nutrients such as oxygen being consumed by the immobilized cells. Oxygen mass transport models aid in designing immobilization strategies but rely on input parameters like oxygen diffusivity, often assumed rather than experimentally measured due to limited resources or expertise. We propose an accessible, cost-effective, and easy to operate system to experimentally determine the diffusion coefficient of cell-laden hydrogels, with application tested to alginate-immobilized pancreatic beta cell (MIN6). As compared to water, the oxygen diffusion coefficient was significantly reduced in alginate gels. The oxygen diffusion coefficient was inversely correlated with the dynamic loss modulus for gels with similar chemical composition, and significantly reduced when the alginate concentration was increased from 2% to 5%. The viability of immobilized MIN6 cells was highly dependent both on gel concentration and cell density, as predicted by Thiele modulus and effectiveness factor values calculated from measured oxygen diffusion coefficients. The proposed platform, combining a simple experimental setup and the use of dimensionless numbers, offers a straightforward means to predict maximal diffusion distances in cell immobilization strategies. This platform can be implemented in the rational design of cell encapsulation, immobilized cell culture, and tissue engineering strategies.
Extensive intrachromosomal duplications in a virulence-associated fungal accessory chromosome
Authors: Dijkstra Jelmer , van Westerhoven Anouk C. , Gómez-Gil Lucía , Aguilera-Galvez Carolina , Nakasato-Tagami Giuliana , Garnier Sebastien D. , Yamazaki Masaya , Arie Tsutomu , Kamakura Takashi , Arazoe Takayuki , Pietro Antonio Di , Seidl Michael F. , Kema Gert H.J.
Published: September 2024

Filamentous fungi have evolved compartmentalized genomes consisting of conserved core regions and dynamic accessory regions, which aid the adaptation to changing environments including the interaction with host organisms. In theFusarium oxysporumspecies complex, accessory regions play an important role during infection and it has been reported that these regions undergo extensive duplications, however, it is currently unknown how such duplications shape accessory regions. Moreover, the function of accessory regions apart from encoding virulence effectors is not completely understood. Here we determined the karyotype ofF. oxysporumTropical Race 4 (TR4), which causes the ongoing pandemic of Fusarium wilt of banana (FWB). We show that the single accessory chromosome of TR4 isolate II5 has undergone extensive intrachromosomal duplications, resulting in triplication of the chromosome size compared to other closely related TR4 strains. By obtaining mutant strains that have lost the accessory chromosome, we demonstrate that this chromosome is dispensable for vegetative growth but is required for full virulence on banana. Lastly, we found that the loss of chromosome 12 co-occurs with structural rearrangements of core chromosomes, which are generally co-linear between members of theF. oxysporumspecies complex. Together, our results provide new insights into the chromosome dynamics of the banana infecting TR4 lineage of theF. oxysporumspecies complex.

Significance

Fusarium oxysporumis a major fungal plant pathogen that causes vascular wilt disease on a wide variety of agronomically important crops. A current epidemic of Fusarium wilt of banana (FWB), caused by tropical race 4 (TR4), poses a major threat to global banana production and threatens food security in tropical and subtropical regions where banana is an important staple crop. Controlling TR4 requires a better understanding of the molecular mechanisms underlying pathogenicity, including the evolution of pathogenicity-related accessory regions. Here we demonstrate that intrachromosomal duplications are a key mechanism of accessory chromosome evolution in theF. oxysporumspecies complex. We identified a single accessory chromosome and show that TR4 mutants that lost this accessory chromosome display significantly reduced virulence on banana plants. Our results provide insight into the evolution of accessory chromosomes in theF. oxysporumspecies complex, underscore their importance in pathogenicity, and provide new clues for the development of resistant banana plants.
Ipsilateral stimulation shows somatotopy of thumb and shoulder auricular points on the left primary somatosensory cortex using high-density fNIRS
Authors: Okorie Ernest C. , Santosa Hendrik , Alter Benedict J. , Chelly Jacques E. , Vogt Keith M. , Huppert Theodore J.
Published: September 2024

Significance

Auriculotherapy is a technique based on stimulation applied to specific ear points. Its mechanism of active and clinical efficacy remain to be established. This study aims to assess the role that primary somatosensory cortex may play to validate auriculotherapy mechanisms.

Aim

This study examined whether tactile stimulation at specific auricular points is correlated with distinct cortical activation in the primary somatosensory cortex.

Approach

Seventeen healthy adults participated in the study. Tactile stimuli were delivered to the thumb, shoulder, and skin master points on the ear using von Frey filaments. Functional near-infrared spectroscopy was used to measure and spatially map cortical responses.

Results

This study revealed distinct hemodynamic activity patterns in response to ear point stimulation, consistent with the classic homunculus model of somatotopic organization. Ipsilateral stimulation showed specific cortical activations for the thumb and shoulder points, while contralateral stimulation showed less significant activity. Functional near-infrared spectroscopy effectively captured localized cortical responses to ear tactile stimuli, supporting the somatotopic mapping hypothesis.

Conclusion

These findings enhance the understanding of sensory processing with auricular stimulation and supports the concepts of auricular cartography that underpins some schools of auriculotherapy practice. Future research should explore bilateral cortical mapping and the integration of other neuroimaging techniques.
High-throughput amino acid-level characterization of the interactions of plasminogen activator inhibitor-1 with variably divergent proteases
Authors: Haynes Laura M , Holding Matthew L , DiGiovanni Hannah , Siemieniak David , Ginsburg David
Published: September 2024

While members of large paralogous protein families share structural features, their functional niches often diverge significantly. Serine protease inhibitors (SERPINs), whose members typically function as covalent inhibitors of serine proteases, are one such family. Plasminogen activator inhibitor-1 (PAI-1) is a prototypic SERPIN, which canonically inhibits tissue-and urokinase-type plasminogen activators (tPA and uPA) to regulate fibrinolysis. PAI-1 has been shown to also inhibit other serine proteases, including coagulation factor XIIa (FXIIa) and transmembrane serine protease 2 (TMPRSS2). The structural determinants of PAI-1 inhibitory function toward these non-canonical protease targets, and the biological significance of these functions, are unknown. We applied deep mutational scanning (DMS) to assess the effects of ∼80% of all possible single amino acid substitutions in PAI-1 on its ability to inhibit three putative serine protease targets (uPA, FXIIa, and TMPRSS2). Selection with each target protease generated a unique PAI-1 mutational landscape, with the determinants of protease specificity distributed throughout PAI-1’s primary sequence. Next, we conducted a comparative analysis of extant orthologous sequences, demonstrating that key residues modulating PAI-1 inhibition of uPA and FXIIa, but not TMPRSS2, are maintained by purifying selection. PAI-1’s activity toward FXIIa may reflect how protease evolutionary relationships predict SERPIN functional divergence, which we support via a cophylogenetic analysis of all secreted SERPINs and their cognate serine proteases. This work provides insight into the functional diversification of SERPINs and lays the framework for extending these studies to other proteases and their regulators.
Muscle fiber proteomics reveals sex- and fiber type-specific adaptations to resistance training
Authors: Moesgaard Lukas , Moreno-Justicia Roger , Schmalbruch Johann , Jessen Søren , Stocks Ben , Bangsbo Jens , Deshmukh Atul S. , Hostrup Morten
Published: September 2024

Skeletal muscle hypertrophy is a hallmark of resistance training that positively impacts health and longevity. However, despite physiological differences between sexes and fiber types, the underlying proteome changes with resistance training have not been studied in a sex- and fiber type-specific manner. Herein, we show sex differences in the fiber type-specific proteome, predominantly in type II fibers. Following 8 weeks of resistance training, substantial remodeling of the human skeletal muscle proteome occurred in a sex- and fiber type-specific manner. Notably, type II fibers exhibited much greater adaptations across both sexes, whereas the main sex-difference was a greater remodeling of intermediate filaments in females. In addition, baseline abundance of proteins involved in translation was highly correlated with fiber hypertrophy, and differed between sexes and fiber types. Thus, translational capacity may partially explain differences in resistance training-induced hypertrophy. Our findings demonstrate key aspects of sex- and fiber type differences in muscle physiology and their contributions to resistance training-induced adaptions.
Commitment to cytokinetic furrowing requires the coordinate activity of microtubules and Plk1
Authors: Day Charles A. , Langfald Alyssa , Lukes Tana , Middlebrook Hanna , Vaughan Kevin T. , Daniels David , Hinchcliffe Edward H.
Published: September 2024

At anaphase, spindle microtubules (MTs) position the cleavage furrow and trigger actomyosin assembly by localizing the small GTPase RhoA and the scaffolding protein anillin to a narrow band along the equatorial cortex [1–6]. Using vertebrate somatic cells we examined the temporal control of furrow assembly. Although its positioning commences at anaphase onset, furrow maturation is not complete until ∼10-11 min later. The maintenance of the RhoA/anillin scaffold initially requires continuous signaling from the spindle; loss of either MTs or polo-like kinase 1 (Plk1) activity prevents proper RhoA/anillin localization to the equator, thereby disrupting furrowing. However, we find that at ∼6 min post-anaphase, the cortex becomes “committed to furrowing”; loss of either MTs or Plk1 after this stage does not prevent eventual furrowing, even though at this point the contractile apparatus has not fully matured. Also at this stage, the RhoA/anillin scaffold at the equator becomes permanent. Surprisingly, concurrent loss of both MTs and Plk1 activity following the “commitment to furrowing” stage results in persistent, asymmetric “half-furrows”, with only one cortical hemisphere retaining RhoA/anillin, and undergoing ingression. This phenotype is reminiscent of asymmetric furrows caused by a physical block between spindle and cortex [7–9], or by acentric spindle positioning [10–12]. The formation of these persistent “half-furrows” suggests a potential feedback mechanism between the spindle and the cortex that maintains cortical competency along the presumptive equatorial region prior to the “commitment to furrowing” stage of cytokinesis, thereby ensuring the eventual ingression of a symmetric cleavage furrow.
Noisy hemoglobin consumption by erythrocyticPlasmodium falciparumparasites: origins and possible implications
Authors: Perko Joseph R. , Singh Abhyudai , Lopez Secilia I. , Luckhart Shirley , Vasdekis Andreas E.
Published: September 2024

Non-genetic cell-to-cell phenotypic differences can significantly impact pathogen physiol-ogy and virulence, leading to unexpected phenomena such as antibiotic persistence. Here, we introduce the role of such non-genetic phenotypic differences in the host, with a focus on hemoglobin consumption byPlasmodium falciparumduring the erythrocytic stage of parasite development. Through imaging, we quantified the substantial variability in hemoglobin (Hb) concentration among uninfected red blood cells (RBCs), and subse-quently measured the rate of Hb consumption by parasites at different stages of their life cycle. This revealed a similarly significant variability among different infected RBCs. By employing a mathematical model, we demonstrated that this variability in Hb consumption can be attributed to non-genetic differences in host RBCs, marking the first evidence of this phenomenon in malaria parasite physiology. These findings underscore the im-portance of incorporating non-genetic host variability into models of disease progression and treatment strategies for malaria and potentially other pathogen-related diseases.
Untargeted and Semi-Targeted Metabolomics Approach for Profiling Small Intestinal and Fecal Metabolome Using High-Resolution Mass Spectrometry
Authors: Tronel Alexandre , Roger-Margueritat Morgane , Plazy Caroline , Cunin Valérie , Mohanty Ipsita , Dorrestein Pieter C. , Soranzo Thomas , Le Gouellec Audrey
Published: September 2024

The gut microbiome is a complex ecosystem varying along different gut sections, consisting of metabolites from food, host, and microbes. Microbially-derived metabolites like bile acids and short-chain fatty acids interact with host physiology. Current studies often use fecal samples, which don’t fully represent the upper gut due to stratification. To sample the proximal gut microbiome, endoscopic methods or new non-invasive devices are used. We developed an approach combining untargeted and semi-targeted metabolomics using a Q-Exactive Plus Orbitrap mass spectrometer to profile gut metabolites. We initially selected 49 key metabolites based on specific criteria, validated them through repeatability tests, and created a compound database with TraceFinder software. Our workflow enables molecule annotation in untargeted studies while validating 37 metabolites in semitargeted analyses. This method, applied to clinical trial samples (NCT05477069), shows promise in discovering new gut metabolites.

Highlights

Innovative Combined Metabolomics Workflow:The study introduces a combined approach that integrates semi-targeted and untargeted metabolomics analyses to characterized small intestinal and fecal metabolomes. This method allows for the relative quantification of carefully selected metabolites and the reanalysis of these metabolites using evolving curated databases, enhancing the understanding of the gut microbiome-health axis.

Untargeted Metabolomics Strategy:The untargeted approach aims to determine the global metabolic profile of samples and discover new metabolites. This involves processing data through a detailed pipeline, statistical analysis, and feature annotation using tools like MZmine, MetaboAnalyst, and the GNPS platform.

Proof of Concept on Clinical Samples:The combined approach was tested on clinical samples from a participant in a clinical trial, revealing distinct metabolomes between small intestinal content and fecal samples. This proof of concept demonstrated the method’s ability to identify and quantify metabolites, showing significant differences in metabolite abundance between the two sample types and highlighting the potential for discovering new bile acids through molecular networking.
Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye
Authors: Schoot Uiterkamp Florianne E. , Maes Margaret E. , Alamalhoda MohammadAmin , Firoozi Arsalan , Colombo Gloria , Siegert Sandra
Published: September 2024

Purpose

Optic nerve crush (ONC) is a model for studying optic nerve trauma. Unilateral ONC induces massive retinal ganglion cell (RGC) degeneration in the affected eye, leading to vision loss within a month. A common assumption has been that the non-injured contralateral eye is unaffected due to the minimal anatomical decussation of the RGC projections at the chiasm. Yet, recently, microglia, the brain-resident macrophages, have shown a responsive phenotype in the contralateral eye after ONC. Whether RGC loss accompanies this phenotype is still controversial.

Methods

Using the available RGCode algorithm and developing our own RGC-Quant deep-learning-based tool, we quantify RGC’s total number and density across the entire retina after ONC.

Results

We confirm a short-term microglia response in the contralateral eye after ONC, but this did not affect microglia number. Furthermore, we cannot confirm the previously reported RGC loss between naïve and contralateral retinas five weeks after ONC induction across the commonly used Cx3cr1creERT2and C57BL6/J mouse models. Neither sex nor the direct comparison of the RGC markers Brn3a and RBPMS, with Brn3a co-labeling, on average, 89% of the RBPMS+-cells, explained this discrepancy, suggesting that the early microglia-responsive phenotype does not have immediate consequences on the RGC number.

Conclusions

Our results corroborate that unilateral optic nerve injury elicits a microglial response in the uninjured contralateral eye but without RGC loss. Therefore, the contralateral eye should be treated separately and not as an ONC control.
Suppression of optokinesis in the reafferent direction during pursuit eye movements
Authors: Bachtoula Omar , Miraval Melanie Ellul , Serrano-Pedraza Ignacio , Souto David
Published: September 2024

When tracking with the eyes an object moving against a textured background, the background retinal image moves in the opposite direction to the smooth pursuit eye movement. Optokinetic responses, such as optokinetic nystagmus (OKN) or ocular tracking, to this reafferent signal must be suppressed to sustain pursuit of the object-of-interest. We varied the contrast of a brief background motion to tell apart two plausible accounts of the suppression of optokinesis during pursuit; a visuomotor gain modulation account, which predicts that ocular tracking of background motion is suppressed in the same proportion at irrespective of contrast, and a sensory attenuation account, which predicts that larger contrasts are needed to elicit the same response. Unexpectedly, neither account fits ocular tracking in the reafferent signal direction. The combination of contrast-dependent gating, with maximal suppression observed with higher contrasts, and visuomotor gain modulation, provides a good fit for most observers’ data. Contrast-dependent gating promotes visuomotor stability in response to most salient signals, as a likely adaptation to the statistics of the environment.

Significance statement

For humans to be able to track small moving objects, there is a need for a mechanism to cancel optokinesis, that is reflexive eye movements towards prevalent visual motion. We show that this cancellation is not a simple “volume-control” reduction of responses to motion signals, as expected. This suppression also involves contrast-dependent gating, meaning that most salient signals are not allowed to modify the ongoing movement. This additional component could have arisen from an adaptation to image statistics of motion signals prevalent in natural environments.
Integrated View of Baseline Protein Expression in Human Tissues using public Data Independent Acquisition datasets
Authors: Prakash Ananth , Collins Andrew , Vilmovsky Liora , Fexova Silvie , Jones Andrew R. , Vizcaino Juan Antonio
Published: September 2024

The PRIDE database is the largest public data repository of mass spectrometry-based proteomics data and currently stores more than 40,000 datasets covering a wide range of organisms, experimental techniques and biological conditions. During the past few years, PRIDE has seen a significant increase in the amount of submitted Data-Independent Acquisition (DIA) proteomics datasets. This provides an excellent opportunity for large scale data reanalysis and reuse.

We have reanalysed 15 public label-free DIA datasets across various healthy human tissues, to provide a state-of-the-art view of the human proteome in baseline conditions (without any perturbations). We computed baseline protein abundances and compared them across various tissues, samples and datasets. Our second aim was to compare protein abundances obtained here from the results of previous analyses using human baseline Data-Dependent Acquisition (DDA) datasets. We observed a good correlation across some tissues, especially in liver and colon but weak correlations were found in others, such as lung and pancreas. The reanalysed results including protein abundance values and curated metadata are made available to view and download from the resource Expression Atlas.

For TOC Only
Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors
Authors: Karatepe Kutay , Mafra de Faria Bruna , Zhang Jian , Chen Xinyue , Pinto Hugo , Fyodorov Dmitry , Sefik Esen , Willcockson Michael , Flavell Richard , Skoultchi Arthur , Guo Shangqin
Published: September 2024

Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factorHlfis located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0highHSPCs. Furthermore, H1.0 protein in HSPCs decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha (IFNα) signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.
Individual differences in decision-making shape how mesolimbic dopamine regulates choice confidence and change-of-mind
Authors: Kocharian Adrina , Redish A. David , Rothwell Patrick E.
Published: September 2024

Nucleus accumbens dopamine signaling is an important neural substrate for decision-making. Dominant theories generally discretize and homogenize decision-making, when it is in fact a continuous process, with evaluation and re-evaluation components that extend beyond simple outcome prediction into consideration of past and future value. Extensive work has examined mesolimbic dopamine in the context of reward prediction error, but major gaps persist in our understanding of how dopamine regulates volitional and self-guided decision-making. Moreover, there is little consideration of individual differences in value processing that may shape how dopamine regulates decision-making. Here, using an economic foraging task in mice, we found that dopamine dynamics in the nucleus accumbens core reflected decision confidence during evaluation of decisions, as well as both past and future value during re-evaluation and change-of-mind. Optogenetic manipulations of mesolimbic dopamine release selectively altered evaluation and re-evaluation of decisions in mice whose dopamine dynamics and behavior reflected future value.
Vocalisations indicate behavioural type inGlossophaginebats
Authors: Schabacker Theresa , Castiglione Raffaella , Snijders Lysanne , Knoernschild Mirjam
Published: September 2024

Vocalisations play a crucial role in the social systems of many animals, and may inadvertently reveal behavioural characteristics of the sender. Bats, the second largest mammalian order, rely extensively on vocalisations due to their nocturnal lifestyle and complex social systems, making them ideal for studying links between vocalisations and consistent behavioural traits. In this study, we developed a new testing regime to investigate if consistent individual vocalisation differences in nectarivorous bats are associated with specific behavioural types. We exposed 60 wild, maleGlossophaga soricina handleyibats to novel and risky stressors, and assessed their behavioural and vocal responses. Proactive, exploratory, and bold bats were more likely to produce social calls, and among the vocalising bats, more agitated bats produced higher numbers of social calls. We thus show that bat vocalisation behaviour can be indicative of a certain behavioural type, potentially allowing conspecifics to assess personalities from a distance, which in turn could impact subsequent social interactions, group dynamics, and reproductive success. Our results, in combination with previous findings in birds, suggest that advertent or inadvertent long-distance broadcasting of personality may be widespread, thus opening up new exciting questions about the links between vocalisations and sociality.
Updated science-wide author databases of standardized citation indicators including retraction data
Authors: Ioannidis John P. A. , Pezzullo Angelo Maria , Cristiano Antonio , Boccia Stefania , Baas Jeroen
Published: September 2024

Citation metrics are widely used in research appraisal, but they provide incomplete views of scientists’ impact and research track record. Other indicators of research practices should be linked to citation data. We have updated a Scopus-based database of highly-cited scientists (top-2% in each scientific subfield according to a composite citation indicator) to incorporate retraction data. Using data from the Retraction Watch database (RWDB), retraction records were linked to Scopus citation data. Of 55,237 items in RWDB as of August 15, 2024, we excluded non-retractions, retractions clearly not due to any author error, retractions where the paper had been republished, and items not linkable to Scopus records. Eventually 39,468 eligible retractions were linked to Scopus. Among 217,097 top-cited scientists in career-long impact and 223,152 in single recent year (2023) impact, 7,083 (3.3%) and 8,747 (4.0%), respectively, had at least one retraction. Scientists with retracted publications had younger publication age, higher self-citation rates, and larger publication volume than those without any retracted publications. Retractions were more common in the life sciences and rare or nonexistent in several other disciplines. In several developing countries, very high proportions of top-cited scientists had retractions (highest in Senegal (66.7%), Ecuador (28.6%) and Pakistan (27.8%) in career-long citation impact lists). Variability in retraction rates across fields and countries suggests differences in research practices, scrutiny, and ease of retraction. Addition of retraction data enhances the granularity of top-cited scientists’ profiles, aiding in responsible research evaluation. However, caution is needed when interpreting retractions, as they do not always signify misconduct; further analysis on a case-by-case basis is essential. The database should hopefully provide a resource for meta-research and deeper insights into scientific practices.
Application of novel 3D culture device for human omental adipocytes and macrophages derived from surgery
Authors: Shimoji Miyuki , Akabori Hiroya
Published: September 2024

Visceral adipose tissue plays a key role in the inflammation, inducing metabolic dysfunction. The culturing system of major components, adipocytes andadiposetissuemacrophages (ATM) have been improved up to date, for example, the ceiling culture system, three-dimensional collagen gels and membrane mature adipocyte aggregate cultures (MAAC). Here we applied for a novel 3D culture device, cellbed of human omental adipocytes with ATM derived from surgery and presented the first morphological report. The pilot study has the limitation of resolution due to the thickness, however, the simple method would be a convenient assay to detect their morphological alteration after surgery. In addition, the combination of cell morphological observation on the cellbed and adipocytokine secretion capability would give an insight into the mechanism of adipose tissue-derived inflammation after surgery. The cellbed composed of high-grade silica glass fiver has been already provided the morphological study with the critical signaling transduction in human oral cancer research. The novel simple 3D device will prevail to spread the practical diversity in the functional clinical research.
Capturing spatiotemporal variation in salt marsh belowground biomass, a key resilience metric, through geoinformatics
Authors: Runion Kyle D , Mishra Deepak R , Alber Merryl , Lever Mark A , O’Connell Jessica L
Published: September 2024

The Belowground Ecosystem Resiliency Model (BERM) is a geoinformatics tool that was developed to predict belowground biomass (BGB) ofSpartina alterniflorain salt marshes based on remote sensing of aboveground characteristics and other readily available hydrologic, climatic, and physical data. We sought to characterize variation inS. alternifloraBGB over both temporal and spatial gradients through extensive marsh field observations in coastal Georgia, USA, to quantify their relationship with a suite of predictor variables, and to use these results to improve performance and expand the parameter space of BERM. We conducted pairwise comparisons ofS. alternifloragrowth metrics measured at nine sites over three to eight years and found that BGB grouped by site differed in 69% of comparisons, while only in 21% when grouped by year. This suggests that BGB varies more spatially than temporally. We used the BERM machine learning algorithms to evaluate how variables relating to biological, climatic, hydrologic, and physical attributes covaried with these BGB observations. Flooding frequency and intensity were most influential in predicting BGB, with predictor variables related to hydrology composing 61% of the total feature importance in the BERM framework. When we used this expanded calibration dataset and associated predictors to advance BERM, model error was reduced from a normalized root mean square error of 13.0% to 9.4% in comparison to the original BERM formulation. This reflects both an improvement in predictive performance and an expansion in conditions for potential model application. Finally, we used regression commonality analysis to show that model estimates reflected the spatiotemporal structure of BGB variation observed in field measurements. These results can help guide future data collection efforts to describe landscape-scale BGB trends. The advanced BERM is a robust tool that can characterizeS. alternifloraproductivity and resilience over broad spatial and temporal scales.
Glycosite Mapping andin situMass Spectrometry Imaging of MUC2 Glycopeptides via On-slide Digestion with Mucinase StcE
Authors: Lowery Sarah C. , Tran Isabella P. , Grimsley Grace , Stubler Rachel , Mahoney Keira E. , Lucas Taryn M. , Charkoftaki Georgia , Santos-Neto Alvaro , Varki Nissi , Vasiliou Vasilis , Drake Richard R. , Malaker Stacy A.
Published: September 2024

Many cancers are characterized by altered mucin expression and glycosylation, although the mechanistic relationship between tumor glycosylation and disease progression is not well-defined. Herein, our goal was to map specific mucin glycoforms in diseased tissue, enabling correlation of the tumor glycan profile with malignant features. To this end, we developed a workflow implementing on-tissue digestion with mucinase StcE, followed by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and liquid chromatography coupled to mass spectrometry (LC-MS). To optimize our workflow, we analyzed four different mucinous carcinomas derived from colon, esophageal, and salivary gland tissue.

Using this technique, we deduced the spatial distribution of StcE-generated O-glycopeptides within mucinous tumors using MALDI-IMS. Subsequent LC-MS analyses revealed the identity of different species detected in imaging experiments, in addition to comprehensively characterizing the mucinome and proteome of each tissue. Our coupled MS approach unveiled a striking mucin 2 (MUC2) expression pattern in two colorectal mucinous adenocarcinomas, in which different glycoforms clearly stratified regions within the tumor. Notably, our LC-MS experiments obtained near-complete sequence coverage over the mucin domains of MUC2, enabling glycoproteomic mapping of this canonical mucin in unprecedented depth. MUC2 glycosylation was dominated by the T and Tn antigens, with surprisingly little sialylation detected. However, O-glycans containing mono- and di-O-acetylated sialic acid were detected in low abundance. Finally, we obtained spectral evidence for an endogenous O-acetylated GalNAc, an O-glycan structure not previously reported in the literature. Overall, this proof-of-concept work underscores the potential of this technique to generate new research avenues in oncology and beyond.

Significance Statement

Aberrant mucin expression and glycosylation are hallmarks of cancer, but how these changes promote malignant processes are not well understood. Solid tumors are highly heterogeneous in their cellular and molecular composition, and many advanced spatial techniques have emerged in recent years to study the tumor microenvironment (TME) for better understanding disease progression. Spatially resolved glycoprotein analyses typically detect either the protein or glycan components, but not both. We developed a workflow using a dual mass spectrometry approach to map the location of intact glycopeptides in mucinous tumors, enabled by on-tissue digestion with the mucin-specific protease StcE. Future applications of this method on larger patient cohorts will enhance our understanding of glycans in malignancy, identify disease biomarkers, and define therapeutic targets.
Microbiome and climate: Skin microbial diversity and community functions ofPolypedates megacephalus(Anura: Rhacophoridae) associated with bioclimate
Authors: Sun Dan , Liu Yewei , Zhou Shipeng , Meegaskumbura Madhava
Published: September 2024

The microbiome inhabiting animal skin plays a crucial role in host fitness by influencing both the composition and function of microbial communities. Environmental factors, including climate, significantly impact microbial diversity and the functional attributes of these communities. However, it remains unclear how specific climatic factors affect amphibian skin microbial composition, community function, and the relationship between these two aspects. Given that amphibians are poikilotherms, and thus more susceptible to temperature fluctuations, understanding these effects is particularly important. Here, we investigated the skin microbiome of the rhacophorid tree frogPolypedates megacephalusacross different climatic regimes using 16S rRNA gene sequencing. Skin swab samples were collected from nine populations ofP. megacephalusadults in the Guangxi region, China. The majority of the core microbiota were found to belong to the genusPseudomonas. Our findings indicate that microbial community diversity, composition, and function are associated with changes in climatic conditions. Specifically, the taxonomic and functional diversity of the skin microbiome increased in response to greater climate variability, particularly in temperature fluctuations. Additionally, the functional attributes of microbial communities changed in parallel with shifts in community diversity and composition, suggesting that environmental filtering driven by climate changes negatively impacts microbial community functional redundancy. These results highlight the critical influence of climatic factors on amphibian skin microbiomes and offer new insights into how microbial composition and function contribute to host adaptation in varying environmental conditions.

IMPORTANCE

This study is important in understanding the association between climate variability, microbial diversity, and host adaptation in amphibians, particularly vulnerable to environmental changes due to their poikilothermic nature. Amphibians rely on their skin microbiome for key functions like disease resistance, yet little is known about how climate fluctuations impact these microbial communities. By analyzing the microbiome ofPolypedates megacephalusacross different climatic regimes, our analysis reveals that while climate variability enhances microbial diversity, it reduces functional redundancy. These findings highlight the potential ecological consequences of climate change and emphasize the need to integrate microbiome health into amphibian conservation strategies.
Mapping the combinatorial coding between olfactory receptors and perception with deep learning
Authors: Chithrananda Seyone , Amores Judith , Yang Kevin K.
Published: September 2024

The sense of smell remains poorly understood, especially in contrast to visual and auditory coding. At the core of our sense of smell is the olfactory information flow, in which odorant molecules activate a subset of our olfactory receptors and combinations of unique receptor activations code for unique odors. Understanding this relationship is crucial for unraveling the mysteries of human olfaction and its potential therapeutic applications. Despite this, predicting molecule-OR interactions remains incredibly difficult. Here, we develop a novel, biologically-inspired approach that first maps odorant molecules to their respective OR activation profiles and subsequently predicts their odor percepts. Despite a lack of overlap between molecules with OR activation data and percept annotations, our joint model improves percept prediction by leveraging the OR activation profile of each odorant as auxiliary features in predicting its percepts. We extend this cross receptor-percept approach, showing that sets of molecules with very different structures but similar percepts, a common challenge for chemosensory prediction, have similar predicted OR activation profiles. Lastly, we further probe the odorant-OR model’s predictive ability, showing it can distinguish binding patterns across unique OR families, as well as between protein-coding genes or frequently occuring pseudogenes in the human olfactory subgenome. This work may aid in the potential discovery of novel odorant ligands targeting functions of orphan ORs, and in further characterizing the relationship between chemical structures and percepts. In doing so, we hope to advance our understanding of olfactory perception and the design of new odorants with desired perceptual qualities.
Deep learning-based predictions of gene perturbation effects do not yet outperform simple linear baselines
Authors: Ahlmann-Eltze Constantin , Huber Wolfgang , Anders Simon
Published: September 2024

Advanced deep-learning methods, such as foundation models, promise to learn representations of biology that can be employed to predictin silicothe outcome of unseen experiments, such as the effect of genetic perturbations on the transcriptomes of human cells. To see whether current models already reach this goal, we benchmarked five foundation models and two other deep learning models against deliberately simplistic linear baselines. For combinatorial perturbations of two genes for which only the individual single perturbations had been seen, we find that the deep learning-based approaches did not perform better than a simple additive model. For perturbations of genes that had not yet been seen, the deep learning-based approaches did not outper-form the baseline of predicting the mean across the training perturbations. We hypothesize that the poor performance is partially because the pre-training data is observational; we show that a simple linear model reliably outperforms all other models when pre-trained on another perturbation dataset. While the promise of deep neural networks for the representation of biological systems and prediction of experimental outcomes is plausible, our work highlights the need for clear setting of objectives and for critical benchmarking to direct research efforts.

Contact

constantin.ahlmann@embl.de