bluuebunny/crossref_metadata_2025 huggingface dataset:
Transposable elements are prevalent vectors of transgenerational epigenetic inheritance in nature
Authors: Baduel Pierre , De Oliveira Louna , Caillieux Erwann , Bohl-Viallefond Grégoire , El Messaoudi Mounia , Xu Ciana , Barois Matteo , Singh Vipin , Sarazin Alexis , Boccara Martine , Gilbault Elodie , de France Antoine , Quadrana Leandro , Loudet Olivier , Colot Vincent
Published: September 2024

Transgenerational epigenetic inheritance (TEI) mediated by transposable elements (TEs) is well established in plants. However, the molecular determinants and functional impact of this additional system of inheritance are poorly characterized. Through comprehensive analyses of severe DNA methylation loss over TEs in an experimental population and in >700 natural strains ofArabidopsis thaliana, we uncovered hundreds of TE epivariants in nature, most of which can be inherited independently of DNA sequence changes and thus are true epialleles. Furthermore, natural epivariants are enriched near genes and we uncovered a novel role for the Paf1 complex as a major facilitator of their prevalence. Conversely, related TE copies limit epiallelic variation, by producing the small RNAs that guide DNA methylation intrans. Crucially, natural epivariants mainly affect stress-responsive genes, making them unique targets for selection. Our findings therefore demonstrate that TEs are important mediators of transgenerational epigenetic variation in nature, with singular properties for plant adaptation.
The molecular arsenal of the key coastal bioturbatorHediste diversicolorfaced with changing oceans
Authors: Beine Kaylee , Feugere Lauric , Fletcher Nichola , Power Megan L. , Connell Liam J. , Bates Adam , Li Jiao , Winter Michael R. , Sellers Graham S. , Mincarelli Luana Fiorella , Vámos Sofia , James Jennifer , Ohnstad Hannah , Bartels-Hardege Helga , Parsons Daniel , Sanders Trystan , Parker Ruth , Bolam Stefan G. , Garcia Clement , Solan Martin , Hardege Jörg , Godbold Jasmin A. , Wollenberg Valero Katharina C.
Published: September 2024

The importance of infaunal bioturbators for the functioning of marine ecosystems cannot be overstated. Inhabitants of estuarine and coastal habitats are expected to show resilience to fluctuations in seawater temperature and pH, which adds complexity to our understanding of the effects of global change drivers. Further, stress responses may be propagated through chemical cues within and across species, which may amplify the costs of life and alter species interactions. Research into the molecular mechanisms underlying this resilience has been limited by a lack of annotated genomes and associated molecular tools. In this study, we present the first chromosome-level, annotated draft genome of the marine ragwormHediste diversicolor, specifically mapping genes important for chemical communication, sensing and pH homeostasis. Using these resources, we then evaluate the transcriptomic and behavioural responses of two distinct populations — one field-sampled from Portugal (Ria Formosa) and one laboratory-acclimated and -bred from the United Kingdom (Humber) — to changes in seawater pH, temperature, and odour cues from a low pH-stressed predator. Both populations displayed adaptive responses to future oceanic conditions, with targeted acid-base regulation in the Ria Formosa population experiment, and broader changes in metabolism and growth genes in the Humber population experiment. Chemical cues from stressed fish predators induced genes related to Schreckstoff biosynthesis in ragworms. Additionally, under future ocean conditions including increased temperature, the Humber population exhibited signs of cellular stress and damage. Our findings using the new annotated genome offer novel insights into the molecular arsenal of acid-base regulation which aids in predicting the impacts of an increasingly acidified and unstable ocean, and to transfer this knowledge to investigate these mechanisms in species with less tolerance.
De novoassembly and annotation of theEmpoasca fabaemitochondrial genome
Authors: Molligan Joshua , Jacques Jordanne , Mukhopadhyay Soham , Perez-Lopez Edel
Published: September 2024

This study presents the assembly and annotation of the full-length mitochondrial genome for the leafhopper speciesEmpoasca fabaeHarris, 1841. The mitogenome was obtained from a contig-level assembly with the identified mitochondrial genome being 14,873 bp in length. The base composition was A (38.8%), T (39.1%), C (11.7%), and G (10.4%). The mitogenome comprised 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and showed a unique, non-AT-rich D-loop region. Nearly all PCGs being with an ATN start codon, while two begin with TCG and GTG. Phylogenetic analysis confirmed the placement ofE. fabaewithin the subfamily Typhlocybinae, clustering with other species in theEmpoascagenus.
Independent avian epigenetic clocks for aging and development
Authors: Haller Ayke , Risse Judith , Sepers Bernice , van Oers Kees
Published: September 2024

Information on individual age is a fundamental aspect in many ecological and evolutionary studies. However, accurate and non-lethal methods that can be applied to estimate the age of wild animals are often absent. Furthermore, since the process of ageing is accompanied by a physical decline and the deterioration of biological functions, the biological age often deviates from the chronological age. Epigenetic marks are widely suggested to be associated with this age-related physical decline, and especially changes in DNA methylation are suggested to be reliable age-predictive biomarkers. Here, we developed separate epigenetic clocks for ageing for development in a small passerine bird, the great tit (Parus major). The ageing clock was constructed and evaluated using erythrocyte DNA methylation data of 122 post-fledging individuals, and the developmental clock using 67 pre-fledging individuals from a wild population. Using a leave-one-out cross validation approach, we were able to accurately predict the ages of individuals with mediation absolute deviations of 0.40 years for the ageing and 1.06 days for the development clock. Moreover, using existing data from a brood-size manipulation we show that nestlings from reduced broods are estimated to be biologically older compared to control nestlings, while they are expected to have higher fitness. These epigenetic clocks provide further evidence that, as observed in mammals, changes in DNA methylation of certain CpG sites are highly correlated with chronological age in birds and open up new avenues for broad applications in behavioural and evolutionary ecology.
Neural substrates for saccadic modulation of visual representations in mouse superior colliculus
Authors: Hunt Joshua B. , Buteau Anna , Hanson Spencer , Poleg-Polsky Alon , Felsen Gidon
Published: September 2024

How do sensory systems account for stimuli generated by natural behavior? We addressed this question by examining how an ethologically relevant class of saccades modulates visual representations in the mouse superior colliculus (SC), a key region for sensorimotor integration. We quantified saccadic modulation by recording SC responses to visual probes presented at stochastic saccade-probe latencies. Saccades significantly impacted population representations of the probes, with early enhancement that began prior to saccades and pronounced suppression for several hundred milliseconds following saccades, independent of units’ visual response properties or directional tuning. To determine the cause of saccadic modulation, we presented fictive saccades that simulated the visual experience during saccades without motor output. Some units exhibited similar modulation by fictive and real saccades, suggesting a sensory-driven origin of saccadic modulation, while others had dissimilar modulation, indicating a motor contribution. These findings advance our understanding of the neural basis of natural visual coding.
Computational Modeling of the Anti-Inflammatory Complexes of IL37
Authors: Sardag Inci , Duvenci Zeynep Sevval , Belkaya Serkan , Timucin Emel
Published: September 2024

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, particularly through interfering with the IL18 signaling, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. Although the structural homology between IL37 and IL18 suggests a common binding mechanism with the primary members of IL18 signaling, the structures of IL37 complexes have not been experimentally resolvet yet. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations, revealing the structural underpinnings of its modulatory effects on the IL18 signaling pathway. All IL37 protein-protein complexes, including both receptor-dependent and receptor-independent pairs, were modeled using a range of methods from homology modeling to AlphaFold2 multimer predictions. The models that successfully captured experimental features were subjected to molecular dynamics simulations. As positive controls, binary and ternary PDB complexes of IL18 were also included. The comparative look on the IL37 and IL18 complexes revealed a highly dynamic nature for the IL37 complexes. Repeated simulations of IL37-IL18Rα showed altered receptor conformations capable of accommodating IL37 in its dimeric form without clashes, providing a structural basis for the failure of IL18Rβ to be recruited to the IL37-IL18Rα complex. Simulations of receptor complexes involving various mature forms of IL37 revealed that the N-terminal loop of IL37 is pivotal in modulating receptor dynamics. Additionally, the glycosyl chains on the primary receptor residue N297 act as a steric block against the IL37's N-terminal loop. The interactions between IL37 and IL18BP were also investigated, and our dynamical models indicated that a homologous binding mode was unlikely, suggesting an alternative mechanism by which IL37 functions as an anti-inflammatory cytokine upon binding to IL18BP. Altogether this study accesses to the structure and dynamics of IL37 complexes, offering molecular insights into IL37's inhibitory function within the IL18 signaling pathway and informing future experimental research.
Phosphorylation regulated conformational diversity and topological dynamics of an intrinsically disordered nuclear receptor
Authors: Akulov Vasily , Panizo Alba Jiménez , Estébanez-Perpiñá Eva , van Noort John , Mashaghi Alireza
Published: September 2024

Site-specific phosphorylation of disordered proteins is often considered as a marker of protein activity, yet it is unclear how phosphorylation alters conformational dynamics of disordered protein chains, such as those in the nuclear receptor superfamily. In the case of disordered human glucocorticoid receptor N-terminal domain (GR NTD), a negatively charged region known as core activation function 1 (AF1c) features three phosphorylation sites, regulating its function and intracellular localization. Deletion of this sequence reduces GR transcriptional activation ability dramatically in cell experiments. By developing a circuit topology-based fold analysis approach, combined with atomistic simulations, we reveal that site-specific phosphorylation facilitates formation of non-local contacts, leading to the emergence of disordered compact topologies with significant entanglement, which are distinct from solvent exposed topologies. While we observe that the topological buildup of solvent-exposed states is similar in different phosphovariants, it depends on the exact phosphorylation site for the disordered compact states. This study thus reveals the complex regulatory role of the GR phosphorylation and introduces a unique analysis framework that can be broadly applied to studying topological dynamics of disordered proteins.
Decoding Protein Dynamics: ProFlex as a Linguistic Bridge in Normal Mode Analysis
Authors: Magill Damian J. , Skvortsov Timofey A.
Published: September 2024

Artificial intelligence has revolutionized structural bioinformatics, with AlphaFold being arguably the most impactful development to date. The structural atlases generated by these methods present significant opportunities for unraveling biological mysteries, but also pose challenges in leveraging such massive datasets effectively. In this work, we explore the dynamic landscape of hundreds of thousands of AlphaFold-predicted structures using normal mode analysis. The resulting data is used to define an alphabet summarizing relative protein flexibility, termed ProFlex. We believe that refining and further applying ProFlex-like approaches offers novel opportunities for understanding protein function and enhancing other methods.
Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import
Authors: Sudaryo Valentino , Carvalho Dayanne R. , Lee J. Michelle , Carozza Jacqueline A. , Cao Xujun , Cordova Anthony F. , Li Lingyin
Published: September 2024

STING agonists are promising innate immune therapies and can synergize with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. An important class of STING agonists are analogs of the endogenous STING agonist, cGAMP, and while transporters for these small molecules are known in some cell types, how they enter and kill T cells remains unknown. Here, we identify the cationic amino acid transporter SLC7A1 as the dominant transporter of cGAMP and its analogs in activated primary mouse and human T cells. T cells upregulate this transporter upon activation and rapid proliferation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. To circumvent the essentiality of SLC7A1 to proliferating T cells, we found that the residues responsible for cGAMP transport are separate from the arginine binding pocket allowing us to perturb cGAMP transport and STING-activation mediated killing without impacting arginine transport. These results suggest that SLC7A1 is a potential target for alleviating T cell toxicity associated with cGAMP and its analogs.
Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype
Authors: Arcuschin Camila D , Kahrizi Kamin , Sayaman Rosalyn W , DiBenedetto Carolina , Shen Yizhuo , Salaberry Pedro J , Zakroui Ons , Schwarzer Cecilia , Scapozza Alessandro , Betancur Paola , Saba Julie D , Coppé Jean-Philippe , Barcellos-Hoff Mary-Helen , Kappes Dietmar , van ‘t Veer Laura , Schor Ignacio E , Muñoz Denise P
Published: September 2024

Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identifiedT-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK,ZBTB7B), a CD4+cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.
Pollinator visitation pattern and differential reproductive compatibilities contribute to the unequal morph abundances in a nocturnal ginger from Western Ghats, India
Authors: Shrotri Saket , Gowda Vinita
Published: September 2024

Polymorphism, the presence of discrete floral morphs within a population, is often maintained by pollinator-mediated or frequency-dependent selection. While pollinators often act on visual displays, this study investigates hawkmoth-mediated selection in the nocturnalCurcuma caulina(Zingiberaceae), where visual cues play a minimal role. We explore the impact of non-visual traits, such as morph abundance, nectar rewards, and reproductive compatibility, on the maintenance of bract color polymorphism.

We measured floral traits, nectar rewards, and abundance of morphs in the natural population, and quantified reproductive compatibility using hand pollination treatments. We next used path analysis to test the effect of morph abundance on reproductive fitness via floral and ecological traits.

We identified tri-modal morph abundance with two common morphs and one rare morph. Morphs differed in nectar traits and reproductive compatibility but not in floral morphologies. Rare morphs had high-energy nectar, higher pollinator revisits and self-pollination, and lower seed output, while common morphs had low-energy nectar, lower revisits, higher outcrossing and fitness.

Morph abundance inC. caulinais shaped by an interplay between nectar rewards, pollinator attraction, and compatibility. We conclude that in perennial rhizomatic species understanding historical selection regimes and both abiotic and biotic factors are necessary to characterize floral polymorphism.
Excitatory and Inhibitory Effects of Saphenous Nerve Stimulation on Two Different Bladder Conditons: Underactivity and Overactivity
Authors: Li Chen , Zhou Zhonghan , Liao Limin , Li Xing
Published: September 2024

Background

This study aimed at exploring the effects of saphenous nerve stimulation (SNS) on treating both overactive bladder (OAB) and underactive bladder (UAB).

Method

In 6 α-chloralose anesthetized cats, bipolar nerve cuff electrodes were implanted on the saphenous nerve and pudendal nerve. UAB was induced by pudendal nerve stimulation (PNS) at 5Hz, 2 threshold (T) and OAB was induced by infusion of 0.25% acetic acid (AA). Multiple cystometrograms (CMGs) were performed to investigate the effects of SNS on pathological bladder at 1Hz and 20Hz, respectively.

Results

Application of PNS (5Hz, 2T) induced UAB by significantly increasing the bladder capacity (BC) to 156.3%±9.8% of control level, while combination of PNS and SNS (1Hz, 2T) applied during CMGs normalized the bladder underactivity by significantly reducing the BC to 93.6%±9.5% (P =0.026). Moreover, the BC was reduced to 64.1%±5.4% of control after infusion of AA, and SNS at 20Hz, 6T significantly increased the BC back to 93.4%±6.3% (P =0.005). No post-stimulation effect of SNS was detected at both 1Hz and 20Hz. However, there were no significant changes of contraction amplitude and duration during stimulation.

Conclusion

In this study, we confirmed the frequency-dependence of SNS in regulating pathological bladder in cats. It provided experimental evidence for treating both OAB and UAB using SNS in clinic.
Improving the accuracy of pose prediction by incorporating symmetry-related molecules
Authors: Hima Sree , Remya Chandran , Dileep K.V.
Published: September 2024

Accurate prediction of biologically relevant binding poses is crucial for the success of computer-aided drug development. In this study, we describe a general strategy to enhance the precision of pose prediction in molecular docking by incorporating symmetry-related molecules (SRMs). Our objective was to demonstrate the significant impact of SRMs on the accuracy of pose prediction. To achieve this, we evaluated our method on high-quality protein-ligand complex structures, focusing on the presence and absence of SRMs during molecular docking studies. We have extracted the co-crystal ligands from the selected crystal structure and were redocked in presence and absence of SRM to assess their influence. Additionally, we calculated the free energy of the docked poses using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method, comparing the results in the presence and absence of SRMs. The findings revealed that redocking performed in the presence of SRMs significantly improved the prediction of biologically significant/crystallographically relevant poses. Consequently, our proposed strategy offers a robust method for enhancing pose prediction in current molecular docking programs, potentially leading to more effective and reliable drug development processes.
Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders
Authors: Sidiropoulos Dimitrios N. , Shin Sarah M. , Wetzel Meredith , Girgis Alexander A. , Bergman Daniel , Danilova Ludmila , Perikala Susheel , Shu Daniel H. , Montagne Janelle M. , Deshpande Atul , Leatherman James , Dequiedt Lucie , Jacobs Victoria , Ogurtsova Aleksandra , Mo Guanglan , Yuan Xuan , Lvovs Dmitrijs , Stein-O’Brien Genevieve , Yarchoan Mark , Zhu Qingfeng , Harper Elizabeth I. , Weeraratna Ashani T. , Kiemen Ashley L. , Jaffee Elizabeth M. , Zheng Lei , Ho Won Jin , Anders Robert A. , Fertig Elana J. , Kagohara Luciane T.
Published: September 2024

Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Integrated multi-modal spatial profiling of human PDAC tumors from neoadjuvant immunotherapy clinical trials reveal diverse spatial niches enriched in TLS.

TLS maturity is influenced by tumor location and the cellular neighborhoods in which TLS immune cells are recruited.

Unsupervised machine learning of genome-wide signatures on spatial transcriptomics data characterizes the TLS-enriched TME and associates TLS transcriptomes with survival outcomes in PDAC.

Interactions of spatially variable gene expression patterns showed TLS maturation is coupled with immunoglobulin distribution and ECM remodeling in pathologic responders.

Intratumoral plasma cell and immunoglobin gene expression spatial dynamics demonstrate trafficking of TLS-driven humoral immunity in the PDAC TME.

Significance

We report a spatial multi-omics atlas of PDAC tumors from a series of immunotherapy neoadjuvant clinical trials. Intratumorally, pathologic responders exhibit mature TLS that propagate plasma cells into malignant niches. Our findings offer insights on the role of TLS-associated humoral immunity and stromal remodeling during immunotherapy treatment.
PhysiofUS : a tissue-motion based method for heart and breathing rate assessment in neurofunctional ultrasound imaging
Authors: Zucker Nicolas , Le Meur-Diebolt Samuel , Pereira Felipe Cybis , Baranger Jerome , Hurvitz Isabella , Demené Charlie , Osmanski Bruno , Ialy-Radio Nathalie , Biran Valérie , Baud Olivier , Pezet Sophie , Deffieux Thomas , Tanter Mickael
Published: September 2024

Recent studies have shown growing evidence that brain function is closely synchronised with global physiological parameters. Heart rate is linked to various cognitive processes and previous research has also demonstrated a strong correlation between neuronal activity and breathing. These findings highlight the significance of monitoring these key physiological parameters during neuroimaging as they provide valuable insights into the overall brain function. Today, in neuroimaging, assessing these parameters required additional cumbersome devices or implanted electrodes.

In this work, we performed ultrafast ultrasound imaging both in rodents and human neonates, and we extracted heart and breathing rates from local tissue motion assessed by raw ultrasound data processing. Such ‘PhysiofUS’ automatically select two specific and optimal brain regions with pulsatile tissue signals to monitor such parameters.

We validated the correspondence of these periodic signals with heart and breathing rates assessed using gold-standard electrodes in various conditions in rodents. We also validated Physio-fUS imaging in a clinical environment using conventional ECG.

We show the potential of fUS imaging as an integrative tool for simultaneously monitoring physiological parameters during neurofunctional imaging. Beyond the technological improvement, this innovation could enhance our understanding of the link between breathing, heart rate and neurovascular activity both anesthetised in preclinincal research and clinical functional ultrasound imaging.
MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics
Authors: Robitaille Francis , Ben Hadj Aziz , Campbell Amy , Nadeau-Lachance Ludovic , Niaison Thierry , Choquette Thierry , Roucou Xavier , Angers Annie , Breton Sophie
Published: September 2024

Mitochondrial-derived peptides significantly expand the coding potential of the human mitochondrial genome. Here, we report the discovery of MTALTCO1, a 259 amino-acid protein encoded by a mitochondrial alternative open reading frame found in the +3 reading frame of the cytochrome oxidase 1 gene (CO1). Using a custom antibody, we confirmed the mitochondrial expression of MTALTCO1 in human cell lines. Sequence analysis revealed high arginine content and an elevated isoelectric point that were not contingent on CO1’s amino acid sequence, suggesting selective pressures might be acting on this protein. MTALTCO1 displays extensive fusion-fission dynamics at the interspecies level, yet produces a full-length protein throughout human mitochondrial lineages. Our findings highlight the importance of identifying novel mitochondrial-derived peptides and proteins in expanding our understanding of the mitochondrial proteome.
Shift from visceral to subcutaneous fat inCyp17a1knockout rats prevent the progression of metabolic syndrome
Authors: Jeon Beom-Jin , Lee Jeong-Hwa , Kwon Dong-Hyeok , Kim Hee-Kyoung , Jang Goo
Published: September 2024

In this study, we investigated the effects ofCyp17a1gene knockout (KO) on obesity and metabolic syndrome.Cyp17a1KO in rats using CRISPR-Cas9 resulted in sex dimorphism and obesity, and interestingly, idiopathic accumulation was found in subcutaneous adipose tissue. Surprisingly, an insulin tolerance test and oral glucose tolerance test did not show any issues with insulin sensitivity and secretion despite hyperglycemia. In addition,Cyp17a1KO rats showed normal plasma insulin and free fatty acid levels compared to wild-type rats, and blood biochemistry analysis revealed normal triglyceride, total cholesterol, high-density lipoprotein, and low-density lipoprotein levels.Cyp17a1KO adipose-tissue-derived stem cells from subcutaneous fat showed increased expression of KLF5, an early adipogenesis marker, which implies enhanced adipogenic potential in subcutaneous adipose tissue. When gene expression associated with lipid, glucose, and insulin metabolism as well as inflammation in adipose tissue was examined, a metabolic shift to subcutaneous adipose tissue was discovered in theCyp17a1KO group. In conclusion, in the Cyp17a1 KO rat models we generated for the first time, the phenotype promoted by obesity reflected health obesity hypothesis, but this did not result in metabolic syndrome due to enhanced metabolism in the subcutaneous fats.
Mechanistic model for epigenetic maintenance by methyl-CpG-binding domain proteins
Authors: Dai Liuhan , Johnson-Buck Alexander , Walter Nils G.
Published: September 2024

DNA methylation is a fundamental element of epigenetic regulation that is governed by the MBD protein superfamily, a group of “readers” that share a highly conserved methyl-CpG-binding domain (MBD) and mediate chromatin remodeler recruitment, transcription regulation, and coordination of DNA and histone modification. Previous work has characterized the binding affinity and sequence selectivity of MBD-containing proteins toward palindromes of 5-methylcytosine (5mC) containing 5mCpG dinucleotides, often referred to as single symmetrically methylated CpG sites. However, little is known about how MBD binding is influenced by the prototypical local clustering of methylated CpG sites and the presence of DNA structural motifs encountered, e.g., during DNA replication and transcription. Here, we use Single-Molecule Kinetics through Equilibrium Poisson Sampling (SiMKEPS) to measure precise binding and dissociation rate constants of the MBD of human protein MBD1 to DNAs with varying patterns of multiple methylated CpG sites and diverse structural motifs. MBD binding is promoted by two major properties of its DNA substrates: 1) tandem (consecutive) symmetrically methylated CpG sites in double-stranded DNA and secondary structures in single-stranded DNA; and 2) DNA forks. Based on our findings, we propose a mechanistic model for how MBD proteins contribute to epigenetic boundary maintenance between transcriptionally silenced and active genome regions.
Enhancing NosZ Activity to Reduce N2O Emissions from Biological Wastewater Treatment Systems
Authors: Zhou Xueyang , Manna Bharat , Lyu Boyu , Singhal Naresh
Published: September 2024

Nitrous oxide (N2O) emissions from wastewater treatment plants, with a warming potential 298 times that of CO2, pose a significant challenge to lowering their carbon footprint. Current mitigation strategies focus on limiting N2O formation during nitrification and denitrification but overlook microbial reduction mechanisms. This study examines the potential for enhancing nitrous oxide reductase (NosZ) activity to reduce N2O to N2. We hypothesize that strategic oxygen manipulation can enhance N2O destruction by continuous NosZ expression and enable NosZ activation in microorganisms with superior NosZ capabilities. We assess microbial community function and metabolic regulation using metagenomics and metaproteomics to clarify the effect of intermittent aeration regimes on N2O emission. Intermittent aeration with periodic anoxic exposure significantly reduced N2O emissions with 71% nitrogen removal by enhancing the metabolic activity ofHyphomicrobium. NosZ activity increased by 4- to 6.5-fold after system adaptation to oxygen modulations, compared to continuous oxic-anoxic cycling without the anoxic phase. The latter resulted in increased N2O emissions due to suppressed NosZ activity and higher N2O production fromMethylobacillus, which uses nitric oxide as an alternative electron acceptor. Our finding that strategic oxygen manipulation can energize N2O destruction lays the foundation for developing next-generation wastewater treatment technologies for mitigating N2O emissions.
The GeoTox Package: Open-source software for connecting spatiotemporal exposure to individual and population-level risk
Authors: Messier Kyle P , Reif David M , Marvel Skylar W
Published: September 2024

Background

Comprehensive environmental risk characterization, encompassing physical, chemical, social, ecological, and lifestyle stressors, necessitates innovative approaches to handle the escalating complexity. This is especially true when considering individual and population-level diversity, where the myriad combinations of real-world exposures magnify the combinatoric challenges. The GeoTox framework offers a tractable solution by integrating geospatial exposure data from source-to-outcome in a series of modular, interconnected steps.

Results

Here, we introduce theGeoToxopen-source R software package for characterizing the risk of perturbing molecular targets involved in adverse human health outcomes based on exposure to spatially-referenced stressor mixtures. We demonstrate its usage in building computational workflows that incorporate individual and population-level diversity. Our results demonstrate the applicability of GeoTox for individual and population-level risk assessment, highlighting its capacity to capture the complex interplay of environmental stressors on human health.

Conclusions

TheGeoToxpackage represents a significant advancement in environmental risk characterization, providing modular software to facilitate the application and further development of the GeoTox framework for quantifying the relationship between environmental exposures and health outcomes. By integrating geospatial methods with cutting-edge exposure and toxicological frameworks,GeoToxoffers a robust tool for assessing individual and population-level risks from environmental stressors.GeoToxis freely available athttps://niehs.github.io/GeoTox/.
Socio-economic patterns of diet, obesity, and biomarkers for cardiovascular disease among Indian adolescents
Authors: Kalita Neelam , Griffin Susan , Mazumdar Sumit
Published: September 2024

Background

The impact of socioeconomic (SES) factors, maternal education and household wealth on diet and consequently on a host of cardiovascular disease (CVD) biomarkers is rarely examined among Indian adolescents, who are in a critical development phase. This study examines the socio-economic patterning of dietary behaviour and its correlation with overweight/obesity and CVD biomarkers among Indian adolescents aged 10 to 19 years.

Methods

We use nationally representative data on dietary patterns and CVD biomarkers from the Comprehensive National Nutrition Dataset, a nationally representative survey of 35,830 adolescents conducted from 2016 to 2018. Dietary pattern is assessed using a summary indicator-Dietary Diversity Score based on 17 specific food groups. Overweight/obesity and the biomarkers, including the ratio of total cholesterol to high-density lipoprotein-cholesterol, serum triglycerides, hypertension, and pre-diabetic/diabetic, are analysed.

Results

Adolescents from higher SES have higher dietary diversity than those from lower SES. This socio-economic patterning is concentrated on higher daily consumption of certain foods such as fats and oil, sugar and jaggery and those high in fats, sugar, and salt (HFSS) comprising-junk food, fried food, sweets, and aerated drinks among those from high SES and urban areas. This, in turn, may explain the concentration of overweight/obesity in this cohort. The SES gradient in diet, overweight/obesity, and associated CVD biomarkers among Indian adolescents remains positive for the household wealth index (worse health for the more economically advantaged) and urban dwellers. However, it is starting to shift towards negative for maternal education, resulting in an inverted U shape (better health for the lowest and highest socially advantaged, worse health for those in the middle).

Conclusions

There is a clustering of overweight/obesity and CVD biomarkers among adolescents from urban and wealthier households that may be associated with increased consumption of HFSS in this cohort.
Morphometric variations of human mandible in Indian population: comparison between subjects having healthy and ankylosed temporomandibular joint
Authors: Chandra Girish , Ghosh Rajdeep , Kaur Kamalpreet , Roychoudhury Ajoy , Mukherjee Sudipto , Chawla Anoop , Mukherjee Kaushik
Published: September 2024

The temporomandibular joint (TMJ) helps to perform the functional activities of the oral cavity. Such activities often get affected by end-stage degenerative disorders such as TMJ ankylosis. Alloplastic reconstruction using TMJ implants helps to restore those activities. However, commercially available stock implants often suffer from fit discrepancies in Indian population. Therefore, this study is aimed to compare comparison between mandibular morphometry of subjects with healthy or normal TMJ joints (TMJN) and patients with TMJ ankylosis (TMJA) from the Indian population. Furthermore, the observed mandibular morphometry has also been compared with those of the other populations. In this study, the most useful anatomical parameters of mandible are measured from the CT-based reconstructed mandibles of 367 Indian subjects (199 healthy;168 ankylosis). Significant differences in ramus length (healthy males: 61.74±7.53 mm, ankylosis males: 46.81±10.35 mm; healthy females: 55.21±6.12 mm, ankylosis females: 41.77±8.57 mm) and condyle width (healthy males: 18.76±3.22 mm, ankylosis males: 22.67±5.56 mm; healthy females: 16.94±2.41 mm, ankylosis females: 21.31±4.65 mm) have been observed between mandibles of ankylosis and healthy subjects. Differences in ramus length (affected side: 43.87±9.51 mm; unaffected side: 55.34±7.12 mm) and condyle width (affected side: 23±4.68 mm; unaffected side: 17.99±2.81 mm) were also observed between affected and unaffected sides of mandibles for unilateral ankylosis patients. Ramus length in healthy subjects was found to be the most statistically significant parameter between mandibles of Indians and other populations.
Cell signaling facilitates apical constriction by basolaterally recruiting Arp2/3 via Rac and WAVE
Authors: Zhang Pu , Medwig-Kinney Taylor N. , Breiner Eleanor A. , Perez Jadyn M. , Song April N. , Goldstein Bob
Published: September 2024

Apical constriction is a critical cell shape change that bends tissues. How precisely-localized actomyosin regulators drive apical constriction remains poorly understood.C. elegansgastrulation provides a valuable model to address this question. The Arp2/3 complex is essential inC. elegansgastrulation. To understand how Arp2/3 is locally regulated, we imaged embryos with endogenously-tagged Arp2/3 and its nucleation-promoting factors (NPFs). The three NPFs – WAVE, WASP, and WASH – colocalized with Arp2/3 and controlled Arp2/3 localization at distinct subcellular locations. We exploited this finding to study distinct populations of Arp2/3 and found that only WAVE depletion caused penetrant gastrulation defects. WAVE localized basolaterally with Arp2/3 at cell-cell contacts, dependent on CED-10/Rac. Establishing ectopic cell contacts recruited WAVE and Arp2/3, identifying contact as a symmetry-breaking cue for localization of these proteins. These results suggest that cell-cell signaling via Rac activates WAVE and Arp2/3 basolaterally, and that basolateral Arp2/3 is important for apical constriction.
CLCC1 promotes membrane fusion during herpesvirus nuclear egress
Authors: Dai Bing , Polack Lucas , Sperl Adrian , Dame Haley , Huynh Tien , Deveney Chloe , Lee Chanyoung , Doench John G. , Heldwein Ekaterina E.
Published: September 2024

ABSTRACT/SUMMARY

Herpesviralesare an ancient viral order that infects species from mollusks to humans for life. During infection, these viruses translocate their large capsids from the nucleus to the cytoplasm independently from the canonical route through the nuclear pore. Instead, capsids dock at the inner nuclear membrane and bud into the perinuclear space. These perinuclear enveloped virions fuse with the outer nuclear membrane releasing the capsids into the cytoplasm for maturation into infectious virions. The budding stage is mediated by virally encoded proteins. But the mediator of the subsequent fusion stage is unknown. Here, using a whole-genome CRISPR screen with herpes simplex virus 1, we identified CLCC1 as an essential host factor for the fusion stage of nuclear egress. Loss of CLCC1 results in a defect in nuclear egress, accumulation of capsid-containing perinuclear vesicles, and a drop in viral titers. In uninfected cells, loss of CLCC1 causes a defect in nuclear pore complex insertion. Viral homologs of CLCC1 are present in herpesviruses that infect mollusks and fish. Our findings uncover an ancient cellular membrane fusion mechanism important for the fundamental cellular process of nuclear envelope morphogenesis that herpesviruses hijack for capsid transport.
A curated collection of transcriptome datasets to study the transcriptional response in blood and nasal samples following viral respiratory inoculation and vaccination
Authors: Lan Zheng , Zhang Tongli , Zhang Yu , Sun Xuejun , Liu Chuwen , Liu Pei , Tang Muyao , Fu Meng , Hagood James S. , Pickles Raymond J , Zou Fei , Zheng Xiaojing
Published: September 2024

Our understanding of the human immune system’s response to viral respiratory tract infections (VRTIs) and vaccines, including the molecular mechanisms and correlates of protection, remains incomplete. Extensive transcriptomic data from inoculation and vaccination studies have been deposited in publicly available databases. However, these studies are often separate and difficult to locate. We provide a curated compendium of public gene expression data repositories for researchers to reanalyze transcriptomes from human whole blood, peripheral blood mononuclear cells (PBMCs), and nasal swab samples. This enables the study of transcriptional responses to viral inoculation or vaccination. This collection includes 18 datasets from inoculation studies and 37 datasets from vaccination studies, sourced from the NCBI Gene Expression Omnibus (GEO), ImmPort Shared Data, and ArrayExpress.
A Comprehensive and Accessible Model for Co-Segregation Analysis inBRCA1, BRCA2, andPALB2Variant Classification
Authors: Moghadasi Setareh , Monajemi Ramin , Braspenning Merel E. , Vreeswijk Maaike P.G. , Rodríguez-Girondo Mar
Published: September 2024

Variants of uncertain significance (VUS) are genetic variations with unclear clinical implications, often complicating clinical management in genetic testing. The analysis of co-segregation of the variant with the disease in families has been shown to be a powerful tool for the classification of these variants. We present CAL-Leiden (Co-segregation Analysis via Likelihood ratio analysis-Leiden), a comprehensive co-segregation model facilitating the classification of variants inBRCA1, BRCA2andPALB2genes, which can be used as an important component of the ACMG/AMP classification guideline. CAL-Leiden includes an expanded range of cancer types, including pancreatic cancer, in addition to breast and ovarian cancer. It also considers contralateral breast cancer. The model integrates population incidence rates from the Netherlands and the United Kingdom, along with penetrance data from the latest literature. A web-based platform has been developed, making the model accessible and practical for use in diagnostic labs:https://bioexp.net/cosegregation/. We demonstrate the functionality of the tool with multiple pedigrees and compare its performance with alternative approaches. These features in CAL-Leiden collectively contribute to a more comprehensive and accurate assessment of variant pathogenicity, helping lab specialists in classification of the variants of uncertain significance.
Divergent selection and plasticity shape reproductive isolation at the onset of speciation
Authors: Jarrett Benjamin J. M. , Downing Philip A. , Svensson Erik I.
Published: September 2024

Reproductive isolation is a key process during speciation, but the factors that shape its evolution during the early stages of speciation remain largely unknown. Using a meta-analysis of 34 experimental speciation studies, we show that populations that experience divergent selection evolved stronger reproductive isolation compared to populations that evolved in similar environments, consistent with ecological speciation theory. However, and contrary to predictions, reproductive isolation did not increase with the number of generations. We present evidence that phenotypic plasticity could play a role in explaining these results, as divergent environments induce an increase in reproductive isolation in the first few generations. Our results highlight that adaptation to different environments in conjunction with plasticity can lead to a rapid increase in reproductive isolation at the beginning of speciation.
A minor impact of VGLUT1 expression level on quantal size revealed through the characterization of VGLUT1mEos2knock-down new mouse model
Authors: Zhang Xiao Min , François Urielle , Angelo Maria Florencia , Claverol Stéphane , Mondin Magali , Martin Christelle , Deshors Melissa , Humeau Yann , Lipstein Noa , Herzog Etienne
Published: September 2024

Synaptic vesicles (SVs) are small organelles secreting neurotransmitters at synapses. By fusing a photoactivated fluorescent protein to VGLUT1, we generated a VGLUT1mEos2knock-in mouse. VGLUT1mEos2knock-in mice are viable and healthy, but exhibit a severe reduction in VGLUT1 expression levels. Using VGLUT1mEos2expressing neurons, we established paradigms to trace individual SV mobility at the single-molecule level or via massive photoconversion. Hippocampal neurons with significantly diminished VGLUT1 expression maintain unaltered miniature glutamate release characteristics in terms of quantal size and frequency. We demonstrate that VGLUT1 expression level are not correlated in a linear fashion with the vesicular glutamate content. In conclusion, the VGLUT1mEos2mouse line serves as a powerful tool for exploring SV mobility properties and elucidating the contributions of VGLUT1 to excitatory neurotransmission and cognitive processes.
Accurate non-invasive quantification of astaxanthin content using hyperspectral images and machine learning
Authors: Calderini Marco L. , Pääkkönen Salli , Yli-Tuomola Aliisa , Timilsina Hemanta , Pulkkinen Katja , Pölönen Ilkka , Salmi Pauliina
Published: September 2024

Commercial cultivation of the microalgaeHaematococcus pluvialisto produce natural astaxanthin has gained significant traction due to the high antioxidant capacity of this pigment and its application in foods, feed, cosmetics and nutraceuticals. However, monitoring of astaxanthin content in cultures remains challenging and relies on invasive, time consuming and expensive approaches. In this study, we employed reflectance hyperspectral imaging (HSI) ofH. pluvialissuspensions within the visible spectrum, combined with a 1-dimensional convolutional neural network (CNN) to predict the astaxanthin content (μg mg−1) as quantified by high-performance liquid chromatography (HPLC). This approach had low average prediction error (5.9%) across a gradient of astaxanthin contents and was only unreliable at very low contents (<0.6 μg mg−1). In addition, our machine learning model outperformed single or dual wavelength linear regression models even when the spectral data was obtained with a spectrophotometer coupled with an integrating sphere. Overall, this study proposes the use of HSI in combination with a CNN for precise non-invasive quantification of astaxanthin in cell suspensions.