bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Alternative Splicing During Mammalian Brain Development Reveals the Magnitude of Isoform Diversity and its Effects on Protein Conformational Changes
Authors: Alieh Leila Haj Abdullah , Cardoso de Toledo Beatriz , Hadarovich Anna , Toth-Petroczy Agnes , Calegari Federico
Published: October 2023

Regulation of gene expression is critical for fate commitment of stem and progenitor cells during tissue formation. In the context of mammalian brain development, a plethora of studies have described how changes in the expression of individual genes characterize cell types across ontogeny and phylogeny. However, little attention was paid to the fact that different transcripts can arise from any given gene through alternative splicing (AS). Considered a key mechanism expanding transcriptome diversity during evolution, assessing the full potential of AS on isoform diversity and protein function has been notoriously difficult. Here we capitalize on the use of a validated reporter mouse line to isolate neural stem cells, neurogenic progenitors and neurons during corticogenesis and combine the use of short- and long-read sequencing to reconstruct the full transcriptome diversity characterizing neurogenic commitment. Extending available transcriptional profiles of the mammalian brain by nearly 50,000 new isoforms, we found that neurogenic commitment is characterized by a progressive increase in exon inclusion resulting in the profound remodeling of the transcriptional profile of specific cortical cell types. Most importantly, we computationally infer the biological significance of AS on protein structure by using AlphaFold2 and revealing how radical protein conformational changes can arise from subtle changes in isoforms sequence. Together, our study reveals that AS has a greater potential to impact protein diversity and function than previously thought independently from changes in gene expression.
Regulatory T cells limit age-associated retinal inflammation and neurodegeneration
Authors: Llorián-Salvador María , de Fuente Alerie G , McMurran Christopher E. , Penalva Rosana , Dombrowski Yvonne , Stitt Alan W. , Fitzgerald Denise C
Published: October 2023

Aging is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology, and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. This study reveals a previously unknown protective role of regulatory T cells in maintaining aged retinal homeostasis.
Regulation of Hepatic Xenosensor Function by HNF4alpha
Authors: Kotulkar Manasi , Cabrera Diego Paine , Robarts Dakota , Apte Udayan
Published: October 2023

Nuclear receptors including Aryl hydrocarbon Receptor (AhR), Constitutive Androstane Receptor (CAR), Pregnane X Receptor (PXR), and Peroxisome Proliferator-Activated Receptor-alpha (PPARα) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4α) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4α is essential for function of these four major xenosensors.

Wild-type (WT) and hepatocyte-specific HNF4α knockout (HNF4α-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 µg/kg), CAR (TCPOBOP, 2.5 µg/g), PXR, (PCN, 100 µg/g), and PPARα (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study nuclear receptor activation.

TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4α-KO mice. Further, TCDD activated AhR in both WT and HNF4-KO mice, confirmed by increase in expression of its target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4α-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4α-KO mice however, it failed to induce PXR target genes in HNF4 KO mice. The treatment of WY-14643 (PPARα agonist) increased LW/BW ratio and PPARα target gene expression in WT mice but not in HNF4α-KO mice.

Together, these data indicate that the function of CAR, PXR, and PPARα but not of AhR was disrupted in HNF4α-KO mice. These results demonstrate that HNF4α function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.
Assembly and annotation of two high-quality columbid reference genomes from sequencing of aColumba liviaxColumba guineaF1hybrid
Authors: Maclary Emily T. , Holt Carson , Concepcion Gregory T. , Sović Ivan , Vickrey Anna I. , Yandell Mark , Kronenberg Zev , Shapiro Michael D.
Published: October 2023

Pigeons and doves (family Columbidae) are one of the most diverse extant avian lineages, and many species have served as key models for evolutionary genomics, developmental biology, physiology, and behavioral studies. Building genomic resources for colubids is essential to further many of these studies. Here, we present high-quality genome assemblies and annotations for two columbid species,Columba liviaandC. guinea. We simultaneously assembledC. liviaandC. guineagenomes from long-read sequencing of a single F1hybrid individual. The newC. liviagenome assembly (Cliv_3) shows improved completeness and contiguity relative to Cliv_2.1, with an annotation incorporating long-read IsoSeq data for more accurate gene models. Intensive selective breeding ofC. liviahas given rise to hundreds of breeds with diverse morphological and behavioral characteristics, and Cliv_3 offers improved tools for mapping the genomic architecture of interesting traits. TheC. guineagenome assembly is the first for this species and is a new resource for avian comparative genomics. Together, these assemblies and annotations provide improved resources for functional studies of columbids and avian comparative genomics in general.

ARTICLE SUMMARY

Pigeons and doves are important models for evolutionary genomics, developmental biology, physiology, and behavioral studies. Here, we present high-quality reference genome assemblies and annotations for two pigeon species, the domestic rock pigeon (Columba livia) and the African speckled pigeon (C. guinea). These assemblies and annotations provide improved resources for both comparative genomics and functional studies.
A 5’ UTR Language Model for Decoding Untranslated Regions of mRNA and Function Predictions
Authors: Chu Yanyi , Yu Dan , Li Yupeng , Huang Kaixuan , Shen Yue , Cong Le , Zhang Jason , Wang Mengdi
Published: October 2023

The 5’ UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5’ UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5’ UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best-known benchmark by up to 42% for predicting the Mean Ribosome Loading, and by up to 60% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5’ UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5’ UTR optimized for therapeutics.
Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin
Authors: Xu Yang , Cohen Erez , Johnson Craig N. , Parent Carole A. , Coulombe Pierre A.
Published: October 2023

Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated inex vivoculture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKCα activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKCα activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.
Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169
Authors: Kuzikov Maria , Morasso Stefano , Reinshagen Jeanette , Wolf Markus , Monaco Vittoria , Cozzolino Flora , Grdadolnik Simona Golič , Šket Primož , Plavec Janez , Iaconis Daniela , Summa Vincenzo , Esposito Francesca , Tramontano Enzo , Monti Maria , Beccari Andrea R. , Windshügel Björn , Gribbon Philip , Storici Paola , Zaliani Andrea
Published: October 2023

The SARS CoV-2 Papain-Like protease has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its capacity to antagonize host immune response. Targeting PLpro function is recognized as a promising mechanism to modulate viral replication whilst supporting host immune responses. However, development of PLpro specific inhibitors remains challenging. Upcoming studies revealed the limitation of reported inhibitors by profiling them through a pipeline of enzymatic, binding and cellular activity assays showing unspecific activity. GRL-0617 remained the only validated molecule with demonstrated anti-viral activity in cells. In this study we refer to the pitfalls of redox-sensitivity of PLpro. Using a screening-based approach to identify inhibitors of PLpro proteolytic activity, we made extensive efforts to validate the active compounds over a range of conditions and readouts, emphasising the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound CPI-169, showed to compete with GRL-0617 in NMR-based experiments, suggesting to share a similar binding mode, opening novel design opportunities for further developments as antiviral agents.

Author summary

The increasing knowledge about SARS-CoV-2 allowed the development of multiple strategies to contain the spread of COVID-19 infection. Nevertheless, effective antiviral pharmacological treatments are still rare and viral evolution allowed a fast adaptation and escape from available containment methods. The papain like protease (PLpro) has now become the next most promising SARS-CoV-2 therapeutic due to its multiple functions in virus replication cycle and antagonization of host immune response. However, due to inherent flexibility and sensitivity of this enzyme specific inhibitors are rare. Here we report on a screening strategy using repurposing of known drugs that takes into account PLpro characteristics to identify new inhibitors, showing the success of the approach by identifying CPI-169 that competitive targets the well described GRL-0617 inhibitor binding pocket of PLpro and helping to design further antiviral agents.
Partial information transfer from peripheral visual streams to foveal visual streams is mediated through local primary visual circuits
Authors: Costantino Andrea I. , Turner Benjamin O. , Williams Mark A. , Crossley Matthew J.
Published: October 2023

A classic view holds that visual object recognition is driven through thewhatpathway in which perceptual features of increasing abstractness are computed in a sequence of different visual cortical regions. The cortical origin of this pathway, the primary visual cortex (V1), has a retinotopic organization such that neurons have receptive fields tuned to specific regions of the visual field. That is, a neuron that responds to a stimulus in the center of the visual field will not respond to a stimulus in the periphery of the visual field, and vice versa. However, despite this fundamental design feature, the overall processing of stimuli in the periphery – while clearly dependent on processing by neurons in the peripheral regions of V1 – can be clearly altered by the processing of neurons in the fovea region of V1. For instance, it has been shown that task-relevant, non-retinotopic feedback information about peripherally presented stimuli can be decoded in the unstimulated foveal cortex, and that the disruption of this feedback – through Transcranial Magnetic Stimulation or behavioral masking paradigms – has detrimental effects on same/different discrimination behavior. Here, we used fMRI multivariate decoding techniques and functional connectivity analyses to assess the nature of the information that is encoded in the periphery-to-fovea feedback projection and to gain insight into how it may be anatomically implemented. Participants performed a same/different discrimination task on images of real-world stimuli (motorbikes, cars, female and male faces) displayed peripherally. We were able to decode only a subset of these categories from the activity measured in peripheral V1, and a further reduced subset from the activity measured in foveal V1, indicating that the feedback from periphery to fovea may be subject to information loss. Functional connectivity analysis revealed that foveal V1 was functionally connected only to the peripheral V1 and not to later-stage visual areas, indicating that the feedback from peripheral to foveal V1 is likely implemented by neural circuits local to V1.
Finding regulatory modules of chemical reaction systems
Authors: Yamauchi Yuhei , Hishida Atsuki , Okada Takashi , Mochizuki Atsushi
Published: October 2023

Within a cell, numerous chemical reactions form chemical reaction networks (CRNs), which are the origins of cellular functions. We previously developed a theoretical method called structural sensitivity analysis (SSA) [1], which enables us to determine, solely from the network structure, the qualitative changes in the steady-state concentrations of chemicals resulting from the perturbations to a parameter. Notably, if a subnetwork satisfies specific topological conditions, it is referred to as a buffering structure, and the effects of perturbations to the parameter within the subnetwork are localized to the subnetwork (the law of localization) [2, 3]. A buffering structure can be the origin of modularity in the regulation of cellular functions generated from CRNs. However, an efficient method to search for buffering structures in a large CRN has not yet been established. In this study, we proved the “inverse theorem” of the law of localization, which states that a certain subnetwork exhibiting a confined response range is always a buffering structure. In other words, we are able to identify buffering structures in terms of sensitivities rather than the topological conditions. By leveraging this property, we developed an algorithm to enumerate all buffering structures for a given network by calculating the sensitivity. In addition, using the inverse theorem, we demonstrated that the hierarchy among nonzero responses is equivalent to the hierarchy of buffering structures. Our method will be a powerful tool for understanding the regulation of cellular functions generated from CRNs.
Hidden evolutionary constraints dictate the retention of coronavirus accessory genes
Authors: Goldstein Stephen A. , Feeley Teagan M. , Babler Kristina M. , Hilbert Zoë A. , Downhour Diane M. , Moshiri Niema , Elde Nels C.
Published: October 2023

Coronaviruses exhibit many mechanisms of genetic innovation, including the acquisition of accessory genes that originate by capture of cellular genes or through duplication of existing viral genes. Accessory genes influence viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) encoding a cellular AKAP7 phosphodiesterase and an inactive native phosphodiesterase, NS2 to model the evolutionary fate of accessory genes. After courses of serial infection, the gene encoding inactive NS2, ORF2, unexpectedly remained intact, suggesting it is under cryptic constraint uncoupled from the function of NS2. In contrast, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. Experimental evolution also led to altered viral replication in a cell type-specific manner and changed the relative proportions of subgenomic viral RNA in plaque-purified viral isolates, revealing additional mechanisms of adaptation. Guided by the retention of ORF2 and similar patterns in related betacoronaviruses, we analyzed ORF8 of SARS-CoV-2, which arose via gene duplication and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution, challenging assumptions on the dynamics of gene loss in virus genomes and extending these findings to viruses currently adapting to humans.
Adaptive genomic variation is linked to a climatic gradient in a social wasp
Authors: Cook Hannah L. , Miller Sara E. , Giri Gilbert , Loope Kevin J. , Sheehan Michael J. , Uy Floria M.K.
Published: October 2023

Species vary in their ability to adapt to rapid changes, with the presence of genetic variation often facilitating long-term evolutionary responses. Given the impending threat of climate change, it is critical to investigate how genetic variation facilitates persistence and possible range expansion in animals. Here, we combine genomic and climatic data to characterize the drivers of local adaptation in the widely distributed, social waspMischocyttarus mexicanus cubicola. Using whole genome sequence data, we show that adaptive genomic variation is linked to a climatic gradient across the broad distribution of this species. We found strong population structure, dividing the species into two genetic clusters that follow subtropical and temperate regions. Patterns of gene flow across the range deviate from those expected by isolation by distance alone with climatic differences resulting in reduced gene flow even between adjacent populations. Importantly, genotype-environment analyses reveal candidate single nucleotide polymorphism (SNPs) associated with temperature and rainfall, suggesting adaptation for thermal and desiccation tolerance. In particular, candidate SNPs in or near mitochondrial genesND5,CO1, andCOIIIare linked to cold tolerance and metabolism. Similarly, theGldnuclear gene shown to mediate cold hardiness and cuticle formation, shows two candidate SNPs with non-synonymous mutations unique to temperate populations. Together, our results reveal candidate SNPs consistent with local adaptation to distinct climatic conditions. Thus, the integration of genomic and climatic data can be a powerful approach to predict vulnerability and persistence of species under rapid climate change.
Storage cell proliferation during somatic growth establishes that tardigrades are not eutelic organisms
Authors: Quiroga-Artigas Gonzalo , Moriel-Carretero María
Published: October 2023

Tardigrades, microscopic ecdysozoans renowned for their resilience to extreme environments, have long been thought to maintain a constant cell number after completing embryonic development, a phenomenon known as eutely. However, sporadic reports of dividing cells have raised questions about this assumption. In this study, we investigated whether tardigrades truly exhibit a fixed cell number during somatic growth using the model speciesHypsibius exemplaris. Comparing hatchlings to adults, we observed an overall increase in the number of storage cells, a tardigrade cell type involved in nutrient storage. To assess cell proliferation, we monitored DNA replication via the incorporation of the thymidine analog 5-ethynyl-2’-deoxyuridine (EdU). A significantly higher number of storage cells incorporated EdU while animals were still growing. Starvation halted both animal growth and storage cell proliferation, linking the two processes. Additionally, we found that EdU incorporation in storage cells is associated with molting, a critical process in tardigrade post-embryonic development, since it involves cuticle renewal to enable further growth. Finally, we show that hydroxyurea, a drug that slows down DNA replication progression, strongly reduces the number of EdU+cells and results in molting-related fatalities. Our data not only provide a comprehensive picture of replication events during tardigrade growth but also highlight the critical role of proper DNA replication in tardigrade molting and survival. This study definitively challenges the notion of eutely in tardigrades, offering promising avenues for exploring cell cycle, replication stress, and DNA damage management in these remarkable creatures as genetic manipulation techniques emerge within the tardigrade research field.

SIGNIFICANCE

Tardigrades, microscopic invertebrate animals renowned for their resilience in extreme conditions, have traditionally been considered eutelic, implying little to no somatic cell proliferation during their growth. However, a few isolated reports challenged this notion. In this study, using the emerging modelHypsibius exemplaris, we provide unequivocal molecular evidence of DNA replication and proliferation in a specific tardigrade cell type called ‘storage cells’, primarily involved in nutrient storage, throughout the animal’s growth. Furthermore, we demonstrate that this proliferation is associated with the timing of cuticle molting, and we highlight the critical role of proper DNA replication in tardigrade molting and survival. Our research definitively resolves the long-standing controversy surrounding tardigrade eutely, opening up uncharted territories in tardigrade research.
IDENTIFICATION OF CANDIDATE GENES AND PATHWAYS LINKED TO THE TEMPERAMENT TRAIT IN SHEEP
Authors: Romaniuk Estefanía , Vera Brenda , Peraza Pablo , Ciappesoni Gabriel , Damián Juan Pablo , van Lier Elize
Published: October 2023

Temperament can be defined as the emotional variability among animals of the same species in response to the same stimulus, thus being able to group animals by reactivity as nervous, intermediate or calm. The main objective for this study was to identify genomic regions with the temperament phenotype measured by the Isolation Box Test (IBT) by single-step genome wide association studies (ssGWAS). The database used consisted of 4,317 animals with temperament records, and 1,697 genotyped animals with 38,268 effective SNP after quality control. We identified three genomic regions that explained the greatest percentage of the genetic variance, resulting in 25 SNP associated with candidate genes on chromosomes 6, 10 and 21. A total of nine candidate genes are reported for the temperament trait, which are:PYGM,SYVN1,CAPN1,FADS1,SYT7,GRID2,GPRIN3,EEF1A1andFRY, linked to energetic activity of the organism, synaptic transmission, meat tenderness and calcium associated activities. This is the first study to identify these genetic variants associated with temperament in sheep, leading the opportinuty to potential applications of these molecular markers in future behavioral research.
Low- and high-level information analyses of transcriptome connecting endometrial-decidua-placental origin of preeclampsia subtypes: A preliminary study
Authors: Sufriyana Herdiantri , Wu Yu-Wei , Su Emily Chia-Yu
Published: October 2023

Background

Existing proposed pathogenesis for preeclampsia (PE) was only applied for early onset subtype and did not consider pre-pregnancy and competing risks. We aimed to decipher PE subtypes by identifying related transcriptome that represents endometrial maturation and histologic chorioamnionitis.

Methods

We utilized eight arrays of mRNA expression for discovery (n=289), and other eight arrays for validation (n=352). Differentially expressed genes (DEGs) were overlapped between those of: (1) healthy samples from endometrium, decidua, and placenta, and placenta samples under histologic chorioamnionitis; and (2) placenta samples for each of the subtypes. They were all possible combinations based on four axes: (1) pregnancy-induced hypertension; (2) placental dysfunction-related diseases (e.g., fetal growth restriction [FGR]); (3) onset; and (4) severity.

Results

The DEGs of endometrium at late-secretory phase, but none of decidua, significantly overlapped with those of any subtypes with: (1) early onset (p-values ≤0.008); (2) severe hypertension and proteinuria (p-values ≤0.042); or (3) chronic hypertension and/or severe PE with FGR (p-values ≤0.042). Although sharing the same subtypes whose DEGs with which significantly overlap, the gene regulation was mostly counter-expressed in placenta under chorioamnionitis (n=13/18, 72.22%; odds ratio [OR] upper bounds ≤0.21) but co-expressed in late-secretory endometrium (n=3/9, 66.67%; OR lower bounds ≥1.17). Neither the placental DEGs at first-nor second-trimester under normotensive pregnancy significantly overlapped with those under late-onset, severe PE without FGR.

Conclusions

We identified the transcriptome of endometrial maturation in placental dysfunction that distinguished early- and late-onset PE, and indicated chorioamnionitis as a PE competing risk. This study implied a feasibility to develop and validate the pathogenesis models that include pre-pregnancy and competing risks to decide if it is needed to collect prospective data for PE starting from pre-pregnancy including chorioamnionitis information.
ACID: A Comprehensive Toolbox for Image Processing and Modeling of Brain, Spinal Cord, and Post-mortem Diffusion MRI Data
Authors: David Gergely , Fricke Björn , Oeschger Jan Malte , Ruthotto Lars , Fritz Francisco J. , Ohana Ora , Mordhorst Laurin , Sauvigny Thomas , Freund Patrick , Tabelow Karsten , Mohammadi Siawoosh
Published: October 2023

Diffusion MRI (dMRI) has become a crucial imaging technique in the field of neuroscience, with a growing number of clinical applications. Although most studies still focus on the brain, there is a growing interest in utilizing dMRI to investigate the healthy or injured spinal cord. The past decade has also seen the development of biophysical models that link MR-based diffusion measures to underlying microscopic tissue characteristics, which necessitates validation through ex vivo dMRI measurements. Building upon 13 years of research and development, we present an open-source, MATLAB-based academic software toolkit dubbed ACID: A Comprehensive Toolbox for Image Processing and Modeling of Brain, Spinal Cord, and Ex Vivo Diffusion MRI Data. ACID is an extension to the Statistical Parametric Mapping (SPM) software, designed to process and model dMRI data of the brain, spinal cord, and ex vivo specimens by incorporating state-of-the-art artifact correction tools, diffusion and kurtosis tensor imaging, and biophysical models that enable the estimation of microstructural properties in white matter. Additionally, the software includes an array of linear and non-linear fitting algorithms for accurate diffusion parameter estimation. By adhering to the Brain Imaging Data Structure (BIDS) data organization principles, ACID facilitates standardized analysis, ensures compatibility with other BIDS-compliant software, and aligns with the growing availability of large databases utilizing the BIDS format. Furthermore, being integrated into the popular SPM framework, ACID benefits from a wide range of segmentation, spatial processing, and statistical analysis tools as well as a large and growing number of SPM extensions. As such, this comprehensive toolbox covers the entire processing chain from raw DICOM data to group-level statistics, all within a single software package.
Valuing carbon sequestration by Antarctic krill faecal pellets
Authors: Cavan E. L. , Mackay N. , Hill S.L. , Atkinson A. , Belcher A. , Visser A.
Published: October 2023

Marine life contribute to carbon stores helping lock carbon away from the atmosphere. Open-ocean pelagic ecosystems are vastly under-reported in terms of carbon sequestration conservation potential, compared to coastal vegetation ‘blue carbon’ systems. Here we show that a harvested organism, Antarctic krill, has similar carbon sequestration potential through its sinking faecal pellets as coastal blue carbon stores, namely seagrasses, mangroves and marshes. Building upon recent advances in krill abundance and faecal pellet carbon flux data, and combining these with an ocean circulation model, we show that from Austral spring to early autumn Antarctic krill sequester 20 Mt C into the deep ocean for at least 100 years. This equates to USD$ 4 - 46 billion per spring/summer season depending on the price of carbon. The footprint of remineralised krill pellet carbon has a global extent, with some reaching as far as the North Pacific. The vast area of ocean krill inhabit and their high abundance make their total carbon sequestered each year similar to that from coastal vegetated blue carbon stores. As Antarctic krill are being impacted by rapid polar climate change and they are harvested, both krill populations and their habitat warrant protection to preserve this valuable carbon sink.
Metamorphosis reverses the behavioural phenotype inRana arvalisalong a latitudinal gradient
Authors: Cortazar-Chinarro Maria , Corral-Lopez Alberto , Lüdtke Deike U. , Tegner Fredrik , Luquet Emilien , Laurila Anssi
Published: October 2023

Understanding how demographic processes and environmental conditions shape behavioural variation across populations is pivotal in evolutionary ecology. However, the role that such processes play in the link between behaviour and life-history traits across populations remains largely unclear.

The moor frog (Rana arvalis) has colonized Sweden via two distinct routes from south via Denmark and from north via Finland. We collectedR. arvaliseggs from multiple populations along a 1700 km latitudinal gradient across Northern Europe and raised tadpoles in a common garden experiment. We assessed developmental growth and proactivity levels in ca. 300 individuals at two key stages of anuran larval development: tadpoles (Gosner stage 32) and froglets (Gosner stage 46).

We found strong behavioural differences along the latitudinal gradient and between developmental stages. Tadpoles from northernmost populations were bolder (shorter times to leave a shelter) and showed higher activity levels in an open field test compared to those from southern populations.

However, these behavioural patterns reversed at the froglet stage, with individuals from northern populations showing reduced proactivity that those from southern populations. Further analyses indicated significant associations between developmental growth and boldness, with contrasting patterns across developmental stages and colonization routes.

In line with recent revisitations of the pace-of-life syndrome theory (POLS) for animal personality, our findings suggest a decoupling of correlations between behaviour and life history traits across ontogeny, likely reflecting adaptive responses to divergent ecological and demographic constraints along the latitudinal gradient.
Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition
Authors: Schepers Melissa , Hendrix Sven , Mussen Femke , van Breedam Elise , Ponsaerts Peter , Lemmens Stefanie , Hellings Niels , Ricciarelli Roberta , Fedele Ernesto , Bruno Olga , Brullo Chiara , Prickaerts Jos , Van Broeckhoven Jana , Vanmierlo Tim
Published: October 2023

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient’s quality of life. Two key strategies are currently being considered to improve clinical outcomes after SCI: modulation of the neuroinflammatory response, which exacerbates the primary injury, and stimulation of neuro-regenerative repair mechanisms to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.
Iterative convergent computation may not be a useful inductive bias for residual neural networks
Authors: Samuel Lippl , Benjamin Peters , Nikolaus Kriegeskorte
Published: October 2023

Recent work has suggested that feedforward residual neural networks (ResNets) approximate iterative recurrent computations. Iterative computations are useful in many domains, so they might provide good solutions for neural networks to learn. Here we quantify the degree to which ResNets learn iterative solutions and introduce a regularization approach that encourages learning of iterative solutions. Iterative methods are characterized by two properties: iteration and convergence. To quantify these properties, we define three indices of iterative convergence. Consistent with previous work, we show that, even though ResNets can express iterative solutions, they do not learn them when trained conventionally on computer vision tasks. We then introduce regularizations to encourage iterative convergent computation and test whether this provides a useful inductive bias. To make the networks more iterative, we manipulate the degree of weight sharing across layers using soft gradient coupling. This new method provides a form of recurrence regularization and can interpolate smoothly between an ordinary ResNet and a “recurrent” ResNet (i.e., one that uses identical weights across layers and thus could be physically implemented with a recurrent network computing the successive stages iteratively across time). To make the networks more convergent we impose a Lipschitz constraint on the residual functions using spectral normalization. The three indices of iterative convergence reveal that the gradient coupling and the Lipschitz constraint succeed at making the networks iterative and convergent, respectively. However, neither recurrence regularization nor spectral normalization improve classification accuracy on standard visual recognition tasks (MNIST, CIFAR-10, CIFAR-100) or on challenging recognition tasks with partial occlusions (Digitclutter). Iterative convergent computation, in these tasks, does not provide a useful inductive bias for ResNets.
Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function
Authors: Gourisankar S. , Wenderski W. , Paulo J. A. , Kim S.H. , Roepke K. , Ellis C. , Gygi S.P. , Crabtree G.R.
Published: October 2023

Genes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleteriousde novomutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known1,2. Synaptic activity in neurons is critical for learning and memory and proper neural development3. Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers4. While BAF is required for activity-dependent developmental processes such as dendritic outgrowth5–7, the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/Arid2, uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.
Widespread detoxifying NO reductases impart a distinct isotopic fingerprint on N2O under anoxia
Authors: Wang Renée Z. , Lonergan Zachery R. , Wilbert Steven A. , Eiler John M. , Newman Dianne K.
Published: October 2023

Nitrous oxide (N2O), a potent greenhouse gas, can be generated by compositionally complex microbial populations in diverse contexts. Accurately tracking the dominant biological sources of N2O has the potential to improve our understanding of N2O fluxes from soils as well as inform the diagnosis of human infections. Isotopic “Site Preference” (SP) values have been used towards this end, as bacterial and fungal nitric oxide reductases produce N2O with different isotopic fingerprints. Here we show that flavohemoglobin, a hitherto biogeochemically neglected yet widely distributed detoxifying bacterial NO reductase, imparts a distinct SP value onto N2O under anoxic conditions that correlates with typical environmental N2O SP measurements. We suggest a new framework to guide the attribution of N2O biological sources in nature and disease.

One-Sentence Summary

Detoxifying nitric oxide reductases impart a distinct isotopic biosignature on nitrous oxide.
Proteasome inhibition reprograms chromatin landscape in breast cancer
Authors: Kinyamu H Karimi , Bennett Brian D. , Ward James M. , Archer Trevor
Published: October 2023

The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNAPII transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic super enhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology.

Highlights

Proteasome inhibition uncoversde novoDifferential Open Chromatin Regions (DOCRs) in breast cancer cells.

Proteasome inhibitor sensitive promoters exhibit a distinctive chromatin architecture with discrete transcription initiation patterns.

Proteasome inhibition reprograms accessibility of super enhancers.

Proteasome inhibitor sensitive super enhancers distinguish basal from non-basal breast cancer subtypes.
Rtf1-dependent transcriptional pausing regulates cardiogenesis
Authors: Langenbacher Adam D. , Lu Fei , Tsang Luna , Huang Zi Yi Stephanie , Keer Benjamin , Tian Zhiyu , Eide Alette , Pellegrini Matteo , Nakano Haruko , Nakano Atsushi , Chen Jau-Nian
Published: October 2023

During heart development, a well-characterized network of transcription factors initiates cardiac gene expression and defines the precise timing and location of cardiac progenitor specification. However, our understanding of the post-initiation transcriptional events that regulate cardiac gene expression is still incomplete. The PAF1C component Rtf1 is a transcription regulatory protein that modulates pausing and elongation of RNA Pol II, as well as cotranscriptional histone modifications. Here we report that Rtf1 is essential for cardiogenesis in fish and mammals, and that in the absence of Rtf1 activity, cardiac progenitors arrest in an immature state. We found that Rtf1’s Plus3 domain, which confers interaction with the transcriptional pausing and elongation regulator Spt5, was necessary for cardiac progenitor formation. ChIP-seq analysis further revealed changes in the occupancy of RNA Pol II around the transcription start site (TSS) of cardiac genes inrtf1morphants reflecting a reduction in transcriptional pausing. Intriguingly, inhibition of pause release inrtf1morphants and mutants restored the formation of cardiac cells and improved Pol II occupancy at the TSS of key cardiac genes. Our findings highlight the crucial role that transcriptional pausing plays in promoting normal gene expression levels in a cardiac developmental context.
Transcriptional Regulation of the AlternativeSex Hormone-Binding GlobulinPromoter by KLF4
Authors: Meyers Warren M.
Published: October 2023

Abstract

In most mammals the major site of sex hormone-binding globulin (SHBG) synthesis is the liver wherefrom it is secreted into the bloodstream and is the primary determinant of sex steroid access to target tissues. The minor site of SHBG synthesis is the testis and in lower mammals testicular SHBG has long been known to be synthesized and secreted by Sertoli cells. However, human testicularSHBGis expressed in developing germ cells from an upstream alternative promoter (altP-SHBG). Transcripts arising from this region comprise an alternative first exon (1A) with the resultant protein confined to the acrosomal compartment of the mature spermatozoa. I have dissected the regulatory components of the alternativeSHBGpromoter and identified motifs that are required for optimal transcriptional activity from this region. Transcriptional activity is driven by two CACCC elements that appear to be functionally redundant. The transcription factor KLF4 interacts with promoter the region spanning these elementsin vivo. Knockdown ofKlf4results in decreased altP-SHBGactivity, whileKlf4overexpression relieves the effects of knockdown. Based on their shared patterns of expressionin vivo, I conclude that KLF4 is a transcriptional regulator ofSHBGin male germ cells.
Estimating body volumes and surface areas of animals from cross-sections
Authors: Zhao Ruizhe Jackevan
Published: October 2023

Body mass and surface area are among the most important biological properties, but such information are lacking for some extant organisms and all extinct species. Numerous methods have been developed for body size estimation for this reason. There are two main categories of mass-estimating methods: volumetric-density approaches and extant-scaling approaches. In this paper, a new 2D volumetric-density approach named cross-sectional method is presented. Cross-sectional method integrates biological cross-sections to obtain volume and surface area accurately. Unlike all previous 2D methods, cross-sectional method processes true cross-sectional profiles directly rather than approximating. Cross-sectional method also has the advantage over others that it can deal with objects with gradually changing cross-sections. It generates very accurate results, with errors always lower than 2% in all cases tested.
Inferring Viral Transmission Pathways from Within-Host Variation
Authors: Specht Ivan O. A. , Petros Brittany A. , Moreno Gage K. , Brock-Fisher Taylor , Krasilnikova Lydia A. , Schifferli Mark , Yang Katherine , Cronan Paul , Glennon Olivia , Schaffner Stephen F. , Park Daniel J. , MacInnis Bronwyn L. , Ozonoff Al , Fry Ben , Mitzenmacher Michael D. , Varilly Patrick , Sabeti Pardis C.
Published: October 2023

Genome sequencing can offer critical insight into pathogen spread in viral outbreaks, but existing transmission inference methods use simplistic evolutionary models and only incorporate a portion of available genetic data. Here, we develop a robust evolutionary model for transmission reconstruction that tracks the genetic composition of within-host viral populations over time and the lineages transmitted between hosts. We confirm that our model reliably describes within-host variant frequencies in a dataset of 134,682 SARS-CoV-2 deep-sequenced genomes from Massachusetts, USA. We then demonstrate that our reconstruction approach infers transmissions more accurately than two leading methods on synthetic data, as well as in a controlled outbreak of bovine respiratory syncytial virus and an epidemiologically-investigated SARS-CoV-2 outbreak in South Africa. Finally, we apply our transmission reconstruction tool to 5,692 outbreaks among the 134,682 Massachusetts genomes. Our methods and results demonstrate the utility of within-host variation for transmission inference of SARS-CoV-2 and other pathogens, and provide an adaptable mathematical framework for tracking within-host evolution.