bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the association between cannabis and opioid use among adults in Washington State: Estimates from a Cross-Sectional Survey
Authors: Abousamra Eslam , Andres Gabriel , Litman Alyson J
Published: November 2023

Introduction

Cannabis and opioids are commonly used for pain management. However, studies examining the association between use of both substances conflict. Furthermore, disruptions to healthcare services and access due to COVID-19 may have affected opioid use in favor of cannabis because of accessibility. Our objective was to examine associations between cannabis and opioid use in Washington State (WA), COVID-19’s impact on these associations, and the association between frequency of cannabis use and misuse of opioids.

Methods

We pooled cross-sectional data from 2019 and 2021 WA Behavior Risk Factors Surveillance Systems surveys to examine associations between cannabis use in the past 30 days and prescription or non-prescription opioid use and misuse during the past 12 months among adults 18 and older. Survey-weighted adjusted prevalence ratios were estimated using multivariable Poisson regression. A proportion test and adjusted trend test were used to examine trends between cannabis use frequency (no use, 1-5 days, 6-9 days, 10-29 days, and 30 days) and opioid misuse among those reported opioid use.

Results

Among 25,540 participants, the prevalence of opioid use was 19.2% among those who used cannabis and 13.8% among those who did not use cannabis (aPR=1.32; 95%CI: 1.20,1.46). COVID-19 did not modify the association between cannabis and opioid use. Among those who used opioids (n=2,168), daily cannabis use was associated with higher opioid misuse prevalence (aPR=2.64; 95% CI: 1.71,4.10), though less than daily use was not.

Conclusion

Cannabis and opioid use were positively associated. Our findings emphasize the need for cautious policy decisions on cannabis regulations. Promoting cannabis use may not correlate with a reduction in other substance misuse. Further research is warranted to explore patterns of cannabis and opioid misuse.
Spatial analysis of Hofbauer cell transcriptome, distribution and morphology in placentas exposed toPlasmodium falciparum
Authors: Ataide Ricardo , Harding Rebecca , Dharmaratne Malindrie , Chen Yunshun , Fielding Katherine , Whitehead Lachlan , Rogers Kelly L. , Anttila Casey , Ling Ling , Hickey Peter , Amann-Zalcenstein Daniela , Moya Ernest , Mhango Gomezghani , Kamiza Steve , Randall Louise , Bennett Cavan , Mzembe Glory , Mwangi Martin N. , Braat Sabine , Phiri Kamija , Pasricha Sant-Rayn
Published: November 2023

Placental infection remains a significant health burden for mothers and their babies in low-income countries, especially in sub-Saharan Africa, where malaria transmission is intense. An increase in inflammatory biomarkers and poor vascularisation are characteristics of placentas infected with malaria. Hofbauer cells (HBCs) – placental villous macrophages of fetal origin – are one of the most abundant immune cells in the placenta. HBCs are thought to have roles in angiogenic processes and have been linked with the pathophysiology of several infections and inflammatory conditions during pregnancy, including malaria (caused byPlasmodium falciparum). However, there is limitedin situdata on the transcriptional, proteomic or morphologic profile of these cells either during or following clearance ofP. falciparuminfection. We leveraged placental samples prospectively collected at delivery from 610 Malawian women enduring a high burden of malaria and other infections and nutritional deficiencies. We profiled placentas through spatial transcriptomic and proteomic platforms to discernin situHBC features that could distinguish placentas with or without evidence of past malaria. In this cohort, past placental infection was common and was associated with lower birth weight babies (adjusted effect [95% confidence interval], −80.9 [−165.9, −3.7] g, P= 0.040). However, at term, HBC numbers, abundance, and transcriptional profiles from placentas with evidence of past infection were similar to those of placentas without malaria. HBCs may recover post-infection back to a basal state or may be replaced in the tissue over the course of pregnancy. Placentas with evidence of past malaria did show evidence of reduced fetal vessel development (mean area difference: −22.8% [−37.6, −7.9], P=0.003). Reduced vascular development following infection early in pregnancy may reflect disturbances to the normal vasculogenic and angiogenic processes, of which HBCs are an integral part.
Mechanical loading rescues mechanoresponsiveness in a human osteoarthritis explant model despite Wnt activation
Authors: Castro-Viñuelas R , Viudes-Sarrión N , Rojo-García AV , Monteagudo S , Lories RJ , Jonkers I
Published: November 2023

Objectives

Optimizing rehabilitation strategies for osteoarthritis necessitates a comprehensive understanding of chondrocytes’ mechanoresponse in both health and disease, especially in the context of the interplay between loading and key pathways involved in osteoarthritis development, like canonical Wnt signaling. This study aims to elucidate the role of Wnt signaling in the mechanoresponsiveness of healthy and osteoarthritic human cartilage.

Methods

We used an ex-vivo model involving short-term physiological mechanical loading of human cartilage explants. First, the loading protocol for subsequent experiments was determined. Next, loading was applied to non-OA explants with or without Wnt activation with CHIR99021. Molecular read-outs of anabolic, pericellular matrix and matrix remodeling markers were used to assess the effect of Wnt on cartilage mechanoresponse. Finally, the same set-up was used to study the effect of loading in cartilage from patients with established OA.

Results

Our results confirm that physiological loading maintains expression of anabolic genes in non-OA cartilage, but indicate a deleterious effect of Wnt activation in the chondrogenic mechanoresponsiveness. This suggests that loading-induced regulation of cartilage markers occurs downstream of canonical Wnt signaling. Interestingly, our study highlighted contrasting mechanoresponsiveness in the model of Wnt activation and the established OA samples, with established OA cartilage maintaining its mechanoresponsiveness, and mechanical loading rescuing the chondrogenic phenotype.

Conclusion

This study provides insights into the mechanoresponsiveness of human cartilage in both non-OA and OA conditions. These findings hold the potential to contribute to the development of strategies that optimize the effect of dynamic compression by correcting OA pathological cell signaling.
Tokenizing Foldable Protein Structures with Machine-Learned Artificial Amino-Acid Vocabulary
Authors: Lin Xiaohan , Chen Zhenyu , Li Yanheng , Ma Zicheng , Fan Chuanliu , Cao Ziqiang , Feng Shihao , Gao Yi Qin , Zhang Jun
Published: November 2023

Understanding functions of proteins and designing proteins committed to specific functionsin silicoare highly valuable for science, industry and therapeutics. However, there is a long-standing divergence in how to present function-related protein structures to the machine learning models: Although the 1-dimensional (1D) representation of proteins via Anfinsen’s tokens (i.e., amino acids) is sufficient in principle and more machine-friendly, it is less successful in structure-oriented protein design compared to symmetry-constrained 3D representation (i.e., atom coordinates). Aiming to bridge the gap between 1D and 3D protein representations and harvest the advantages of the two, we developprobabilistic tokenization theoryfor metastable protein structures. We present an unsupervised learning strategy, which conjugates inverse folding with structure prediction, to encode protein structures into artificial amino-acid tokens (ProTokens) and decode them back to atom coordinates. We show that tokenizing protein structuresvariationallycan lead to compact and informative representations. Compared to amino acids — the Anfinsen’s tokens — ProTokens are easier to detokenize and more descriptive of finer conformational ensembles. Therefore, protein structures can be efficiently compressed, stored, aligned and compared in the form of ProTokens. By unifying the discrete and continuous representations of protein structures, ProTokens also enable all-atom protein structure design via various generative models without the concern of symmetry or modality mismatch, and allows scalable foundation models to perceive, process and explore the microscopic structures of biomolecules effectively.
Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth
Authors: Shapeti Apeksha , Barrasa-Fano Jorge , Fattah Abdel Rahman Abdel , de Jong Janne , Sanz-Herrera José Antonio , Pezet Mylène , Assou Said , de Vet Emilie , Elahi Seyed Ali , Ranga Adrian , Faurobert Eva , Van Oosterwyck Hans
Published: November 2023

Force-driven cellular interactions are known to play a critical role in cancer cell invasion, but have remained largely unexplored in the context of vascular abnormalities, partly due to a lack of suitable genetic and cellular models. One such vascular abnormality, cerebral cavernous malformation (CCM) is characterized by leaky, tumor-like vessels in the brain, where CCM mutant cells recruit wild-type cells from the surrounding endothelium to form mosaic lesions and promote lesion growth; however the mechanisms underlying this recruitment remain poorly understood. Here, we use 3D traction force microscopy in a in-vitro model of early angiogenic invasion to reveal that hyper-angiogenic CCM2-silenced endothelial cells enhance angiogenic invasion of neighboring wild-type cells through force and extracellular matrix-guided mechanisms. We show that mechanically hyperactive CCM2-silenced tips guide wild-type cells by exerting and transmitting pulling forces and by leaving degraded paths in the matrix as cues promoting invasion in a ROCKs-dependent manner. This transmission of forces is associated with a reinforcement of β1 integrin-dependent adhesive sites and actin cytoskeleton in the wild-type followers. We also show that during this process wild-type cells are reprogrammed into stalk cells through activation of matrisome and DNA replication programs, eventually leading to cell proliferation. These observations unveil a novel vascular lesion growth mechanism where CCM2 mutants hijack the function of wild-type cells to fuel CCM lesion growth. By integrating biophysical computational methodologies to quantify cellular forces with advanced molecular techniques, we provide new insights in the etiology of vascular malformations, and open up avenues to study the role of cell mechanics in tissue heterogeneity and disease progression.
Joint subject-identification and task-decoding from inferred functional brain graphs via a multi-task neural network
Authors: Balcioglu Elif Sema , Döner Berkay , Sareen Ekansh , Van De Ville Dimitri , Behjat Hamid
Published: November 2023

Functional connectivity (FC) between brain regions as manifested via fMRI entails signatures that can be used to differentiate individuals and decode cognitive tasks. In this work, we use methods from graph structure inference to estimate FC, which is in contrast to the conventional approach of deriving FC via correlation. Moreover, we infer FC graphs from seed-based co-activation patterns instead of raw fMRI data. We also propose a multi-task neural network architecture to jointly perform subject-identification and task-decoding from inferred functional brain graphs. We validate the developed model on data from the Human Connectome Project across eight fMRI tasks. Most importantly, our results show the superior task-decoding performance of FC graphs inferred from seed-based activity maps over graphs inferred from raw fMRI data. Furthermore, via gradient-based back-projection, we derive a significance score for inputs to the neural network, and present results showing the differential role of brain connections in subject-identification and task-decoding.
Phosphoproteomics identifies targets of Mos-MAPK regulating translation and spindle organization in oocyte meiosis
Authors: Avilov Ivan , Horokhovskyi Yehor , Cai Mingfang , Orzechowski Aleksander , Welp Luisa , Urlaub Henning , Liepe Juliane , Lenart Peter
Published: November 2023

The Mos kinase is a constitutive activator of the ERK/MAPK pathway exclusively expressed during oocyte meiosis, mediating key meiotic functions across animal species. While a few of its downstream effectors have been studied in some detail, molecular targets under the control of Mos-MAPK have not yet been identified systematically. Here, we combined live-cell microscopy of starfish oocytes to characterize the cellular phenotypes caused by Mos-MAPK inhibition with phosphoproteomic analysis of synchronous oocyte populations at key transitions. This revealed a large set of proteins involved in regulation of translation through the CPE-element binding protein CPEB to be controlled by Mos-MAPK. Our data indicate that cyclin B is the main target of this regulation to drive the second meiotic division. A second large group of phospho-proteins we found to be controlled by Mos-MAPK are regulators of the actin and microtubule cytoskeleton, in particular regulators of centrosomal microtubule nucleation. Indeed, we show that Mos-MAPK inhibition increases the size of microtubule asters and promotes separation of spindle poles in meiotic anaphase, i.e turning meiotic spindles mitotic-like. Together, here we identified core molecular modules controlled by Mos-MAPK driving key meiotic functions, haploidization and the asymmetric polar body divisions. These molecular modules are highly conserved and are thus likely to be involved in reproductive processes across species including humans. In addition, our work may help understand disease mechanisms when Mos is expressed erroneously, acting as an oncogene.
Modulation of human kinase activity through direct interaction with SARS-CoV-2 proteins
Authors: Halwachs Bettina , Moesslacher Christina S. , Kohlmayr Johanna M. , Fasching Sandra , Masser Sarah , Choteau Sébastien A. , Zanzoni Andreas , Kunowska Natalia , Stelzl Ulrich
Published: November 2023

The dysregulation of cellular signaling upon SARS-CoV-2 infection is mediated via direct protein interactions, with the human protein kinases constituting the major impact nodes in the signaling networks. Here, we employed a targeted yeast two-hybrid matrix approach to identify direct SARS-CoV-2 protein interactions with an extensive set of human kinases. We discovered 51 interactions involving 14 SARS-CoV-2 proteins and 29 human kinases, including many of the CAMK and CMGC kinase family members, as well as non-receptor tyrosine kinases. By integrating the interactions identified in our screen with transcriptomics and phospho-proteomics data, we revealed connections between SARS-CoV-2 protein interactions, kinase activity changes, and the cellular phospho-response to infection and identified altered activity patterns in infected cells for AURKB, CDK2, CDK4, CDK7, ABL2, PIM2, PLK1, NEK2, TRIB3, RIPK2, MAPK13, and MAPK14. Finally, we demonstrated direct inhibition of the FER human tyrosine kinase by the SARS-CoV-2 auxiliary protein ORF6, hinting at pressures underlying ORF6 changes observed in recent SARS-CoV-2 strains. Our study expands the SARS-CoV-2 – host interaction knowledge, illuminating the critical role of dysregulated kinase signaling during SARS-CoV-2 infection.
Can changes in ploidy drive the evolution to allogamy in a selfing species complex?
Authors: García-Muñoz Ana , Ferrón Camilo , Vaca-Benito Celia , Martínez-Gómez María Nazaret , Castro Sílvia , Castro Mariana , Loureiro João , Muñoz-Pajares A. Jesús , Abdelaziz Mohamed
Published: November 2023

The evolution of mating systems in plants is central for understanding the rise of their diversity on Earth. The transition towards self-fertilization is a well-known example of convergent evolution although the opposite direction is expected to be forbidden according to evolutionary theories. We suggest that the ploidy level could promote changes in the reproductive strategies through its effect on traits related to pollination.

We performed controlled crosses on several populations from the polyploidErysimum incanumspecies complex, described as predominantly selfing, to evaluate the inbreeding depression. Additionally, we measured mating traits such as floral size, herkogamy, anther exertion, the relative investment in male and female components (P:O ratio) and genetic diversity.

We described three ploidy levels in the complex – hexaploids were unknown until now. We found significant differences in the self-pollination success among ploidies and even among populations within the same ploidy. Inbreeding depression was present in higher ploidies, accompanied by bigger flowers with higher anther exposure, increased herkogamy and P:O and genetic diversity.

These findings suggest that ploidy could be promoting alternative reproductive strategies to selfing, driving mating system diversification within a selfing species, which has not been previously described in the wild.
Activatable prodrug for controlled release of an antimicrobial peptide via the proteases overexpressed inCandida albicansandPorphyromonas gingivalis
Authors: Amer Lubna , Retout Maurice , Jokerst Jesse V.
Published: November 2023

We report the controlled release of an antimicrobial peptide using enzyme-activatable prodrugs to treat and detectCandida albicansandPorphyromonas gingivalis. Our motivation lies in the prevalence of these microorganisms in the subgingival area where the frequency of fungal colonization increases with periodontal disease. This work is based on an antimicrobial peptide that is both therapeutic and induces a color change in a nanoparticle reporter. This antimicrobial peptide was then built into a zwitterionic prodrug that quenches its activity until activation by a protease inherent to these pathogens of interest: SAP9 or RgpB forC. albicansandP. gingivalis, respectively. We first confirmed that the intact zwitterionic prodrug has negligible toxicity to fungal, bacterial, and mammalian cells absent a protease trigger. Next, the therapeutic impact was assessed via disk diffusion and viability assays and showed a minimum inhibitory concentration of 3.1 – 16 µg/mL, which is comparable to the antimicrobial peptide alone (absent integration into prodrug). Finally, the zwitterionic design was exploited for colorimetric detection ofC. albicansandP. gingivalisproteases. When the prodrugs were cleaved, the plasmonic nanoparticles aggregated causing a color change with a limit of detection of 10 nM with gold nanoparticles and 3 nM with silver nanoparticles. This approach has value as a convenient and selective protease sensing and protease-induced treatment mechanism based on bioinspired antimicrobial peptides.

Abstract Figure
Olfactory system structure and function in newly hatched and adult locusts
Authors: Sun Kui , Ray Subhasis , Gupta Nitin , Aldworth Zane , Stopfer Mark
Published: November 2023

An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.
Discovering Secondary Protein Structures via Local Euler Curvature
Authors: Moreira Rodrigo A. , Braddell Roisin , Santos Fernando A. N. , Fülöp Tamàs , Desroches Mathieu , Ubarretxena-Belandia Iban , Rodrigues Serafim
Published: November 2023

Protein structure analysis and classification, which is fundamental for predicting protein function, still poses formidable challenges in the fields of molecular biology, mathematics, physics and computer science. In the present work we exploit recent advances in computational topology to define a new intrinsic unsupervised topological fingerprint for proteins. These fingerprints, computed via Local Euler Curvature (LECs), identify secondary protein structures, such as Helices and Sheets, by capturing their distinctive topological signatures. Using an extensive protein residue database, the proposed computational framework not only distinguishes between structural classes via unsupervised clustering but also achieves remarkable accuracy in classifying proteins structures through supervised machine learning classifier. We also show that the internal structure of LEC space embeds the information about the secondary structure of proteins. Beyond its immediate implications for the advancement of critical application areas such as drug design and biotechnology, our approach opens a fascinating avenue towards characterizing the multiscale structures of diverse biopolymers based solely on their geometric and topological attributes.
Aggressive mimicry lure polymorphisms in the parasitic musselLampsilis fasciolamodel fish or leech host prey and differ in morphology and pigmentation, but not in display behavior
Authors: Hewitt Trevor L. , Johnson Paul , Buntin Michael , Moore Talia , Foighil Diarmaid Ó
Published: November 2023

Unionoid freshwater mussels (Bivalvia: Unionidae) are free-living apart from a brief, obligately parasitic, larval stage that infects fish hosts and gravid female mussels have evolved a spectrum of strategies to infect fish hosts with their larvae. In many North American species, this involves displaying a mantle lure: a pigmented fleshy extension that acts as an aggressive mimic of a host fish prey, thereby eliciting a feeding response that results in host infection. The mantle lure ofLampsilis fasciolais of particular interest because it is apparently polymorphic, with two distinct primary lure phenotypes. One, described as “darter-like”, has “eyespots”, a mottled body coloration, prominent marginal extensions, and a distinct “tail”. The other, described as “worm-like”, lacks those features and has an orange and black coloration. We investigated this phenomenon to 1) confirm that it is a true polymorphism; 2) investigate its ecological persistence; 3) identify the range of putative model species targeted by this mimicry system within a river drainage; 4) determine whether the mantle lure polymorphism includes a behavioral component. Detection of within-brood lure variation and within-population phylogenomic (ddRAD-seq) analyses of individuals bearing different lures confirmed that this phenomenon is a true polymorphism. It appears stable over ecological timeframes: the ratio of the two lure phenotypes in a River Raisin (MI) population in 2017 was consistent with that of museum samples collected at the same site 6 decades earlier. Within the River Raisin, four main “darter-like” lure motifs visually approximated four co-occurring darter species (Etheostoma blennioides, E. exile, E. microperca,andPercina maculata) and the “worm-like” lure resembled a widespread common leech,Macrobdella decora. Darters and leeches are typical prey ofMicropterus dolomieui(smallmouth bass), the primary fish host ofL. fasciola.In situfield recordings were made of theL. fasciola“darter” and “leech” lure display behaviors, in addition to the non-polymorphic lure display of co-occurringL. cardium. Despite having putative models in distinct phyla, bothL. fasciolalure morphs have similar display behaviors that differ significantly from that of sympatricL. cardiumindividuals. We conclude that theL. fasciolamantle lure polymorphism does not include a behavioral component. Discovery of discrete within-brood inheritance of the lure polymorphism implies potential control by a single genetic locus and identifiesL. fasciolaas a promising study system to identify regulatory genes controlling a key adaptive trait of freshwater mussels.
Applying Super-Resolution and Tomography Concepts to Identify Receptive Field Subunits in the Retina
Authors: Krüppel Steffen , Khani Mohammad H. , Schreyer Helene M. , Sridhar Shashwat , Ramakrishna Varsha , Zapp Sören J. , Mietsch Matthias , Karamanlis Dimokratis , Gollisch Tim
Published: November 2023

Spatially nonlinear stimulus integration by retinal ganglion cells lies at the heart of various computations performed by the retina. It arises from the nonlinear transmission of signals that ganglion cells receive from bipolar cells, which thereby constitute functional subunits within a ganglion cell’s receptive field. Inferring these subunits from recorded ganglion cell activity promises a new avenue for studying the functional architecture of the retina. This calls for efficient methods, which leave sufficient experimental time to leverage the acquired knowledge. Here, we combine concepts from super-resolution microscopy and computed tomography and introduce super-resolved tomographic reconstruction (STR) as a technique to efficiently stimulate and locate receptive field subunits. Simulations demonstrate that this approach can reliably identify subunits across a wide range of model variations, and application in recordings of primate parasol ganglion cells validates the experimental feasibility. STR can potentially reveal comprehensive subunit layouts within less than an hour of recording time, making it ideal for online analysis and closed-loop investigations of receptive field substructure in retina recordings.
The epigenetics effects of transposable elements are context dependent and not restricted to gene silencing
Authors: Coronado-Zamora Marta , González Josefa
Published: November 2023

Transposable elements (TEs) represent a threat to genome integrity due to their proliferation capacity. Eukaryotic cells silence TEs through different epigenetic mechanisms, including the deposition of repressive histone marks. Previous studies have shown that repressive marks can spread to neighboring sequences. However, evidence for this spreading affecting nearby gene expression remains limited. Similarly, whether TEs induce changes in the enrichment of active histone marks genome-wide, and its potential impact on gene expression have not been widely studied. In this work, we performed a comprehensive study of the epigenetic effects of 2,235 TEs and their potential effects on nearby gene expression onD. melanogasterhead, gut and ovary. While most of the TEs (816) induce the enrichment of the H3K9me3 repressive mark, with stronger epigenetic effects in the ovary, a substantial number (345 TEs) induce the enrichment of the H3K27ac active mark, particularly in the gut. We found that 70% of the H3K9me3 enriched TEs induced gene down-regulation, and 50% of the H3K27ac enriched TEs induced gene up-regulation. These changes in expression affect specific regulatory networks in head and gut while in ovary, genes were not enriched for any biological functions. Furthermore, TE epigenetic effects on gene expression are genomic context dependent. Finally, we found that TEs also affect gene expression by disrupting regions enriched for histone marks. Overall, our results show that TEs do generate regulatory novelty through epigenetic changes, with these epigenetic effects not restricted to gene silencing and being context dependent.

Significance statement

Transposable elements (TEs) are repetitive DNA sequences found in nearly all studied organisms that have the capacity to move within the genome. To prevent their proliferation, eukaryotic cells target TEs with repressive histone marks, an epigenetic signal that blocks their expression. While these repressive marks can spread to neighboring genes, the evidence of how this impacts gene expression is limited. Similarly, whether TEs also influence the enrichment and depletion of active histone marks and their genome-wide impact is not understood. In this work, we studied the histone mark enrichment of 2,235 polymorphic TEs across three body parts ofD. melanogaster. Our results provide evidence for the genome-wide role of TEs in the generation of regulatory novelty through epigenetic changes.
Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes
Authors: Dereli Ihsan , Telychko Vladyslav , Papanikos Frantzeskos , Raveendran Kavya , Xu Jiaqi , Boekhout Michiel , Stanzione Marcello , Neuditschko Benjamin , Imjeti Naga Sailaja , Selezneva Elizaveta , Erbasi Hasibe Tuncay , Demir Sevgican , Giannattasio Teresa , Gentzel Marc , Bondarieva Anastasiia , Stevense Michelle , Barchi Marco , Schnittger Arp , Weir John R. , Herzog Franz , Keeney Scott , Tóth Attila
Published: November 2023

Programmed DNA double-strand break (DSB) formation is a unique meiotic feature that initiates recombination-mediated linking of homologous chromosomes, thereby enabling chromosome number halving in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We discovered in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms, which are based on a DBF4-dependent kinase (DDK)–modulated interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.
Anti- and pro-inflammatory milieu differentially regulate differentiation and immune functions of oligodendrocyte progenitor cells
Authors: Zveik Omri , Rechtman Ariel , Brill Livnat , Vaknin-Dembinsky Adi
Published: November 2023

Oligodendrocyte progenitor cells (OPC) were regarded for years solely for their regenerative role; however, their immune-modulatory roles have gained much attention recently, particularly in the context of multiple sclerosis (MS). Despite extensive studies on OPCs, there are limited data elucidating the interactions between their intrinsic regenerative and immune functions, as well as their relationship with the inflamed central nervous system (CNS) environment, a key factor in MS pathology. We examined the effects of pro-inflammatory cytokines, represented by interferon (IFN)-γ and tumor necrosis factor (TNF)-α, as well as anti-inflammatory cytokines, represented by interleukin(IL)-4 and IL-10, on OPC differentiation and immune characteristics. Using primary cultures, ELISA, and immunofluorescence stainings, we assessed differentiation capacity, phagocytic activity, major histocompatibility complex (MHC)-II expression, and cytokine secretion. We observed that the anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-α led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, and cytokines secretion. Those effects were attributed to signaling via TNF-receptor-2 (TNFR2) and counteracted the detrimental effects of IFNγ on OPC differentiation. Our findings suggest that a pro-regenerative, permissive inflammatory environment is needed for OPCs to execute both regenerative and immune-modulatory functions.
Drivers of population dynamics of at-risk populations change with pathogen arrival
Authors: Grimaudo Alexander T. , Hoyt Joseph R. , King R. Andrew , Toomey Rickard S. , Simpson Chris , Holliday Cory , Silvis Alexander , Doyle Rick T. , Kath Joseph A. , Armstrong Mike P. , Brack Virgil , Reynolds Richard J. , Williamson Ryan H. , Turner Gregory G. , Kuczynska Vona , Meyer Jordan J. , Jansky Kyle , Herzog Carl J. , Hopkins Skylar R. , Langwig Kate E.
Published: November 2023

Successful wildlife conservation in an era of rapid global change requires understanding determinants of species population abundance and growth. However, when populations are faced with novel stressors, factors associated with healthy and growing populations can change, necessitating a shift in conservation strategies. For example, emerging infectious diseases can cause conditions previously beneficial or neutral to host populations to increase disease impacts. Here, we paired a population dataset of 265 colonies of the federally endangered Indiana bat (Myotis sodalis) with 50.7 logger-years of environmental data to explore factors that affected colony response to white-nose syndrome (WNS), an emerging fungal disease. We found wide variation in colony responses to WNS, ranging from extirpation to stabilization and persistence. Simulating future population dynamics suggests that most extirpations have already occurred, as the pathogen has been present for several years in most colonies, and that small colonies were more susceptible to extirpation than large ones. Further, while temperature and humidity conditions of hibernacula appeared unassociated with Indiana bat colony growth prior to WNS, extirpation risk following pathogen arrival was elevated in colonies that used colder and wetter hibernacula. Additionally, rates of decline were greater in colder hibernacula, opposite the association for a sympatric bat species. Overall, this study illustrates that emerging infectious diseases can change the factors associated with host population abundance and optimal growth, including through novel environmental associations, which can vary across host species. Consideration of these shifting associations and intrinsic differences between impacted host species will be essential to successful species conservation.
Loss of Myeloid Cell-Specific β2-Adrenergic Receptor Expression Ameliorates Cardiac Function and Remodeling after Acute Ischemia
Authors: Nayak Tapas K. , Bajpai Anamika , Patwa Viren , Carter Rhonda L. , Enjamuri Nitya , Gao Erhe , Xiang Yang K. , Tilley Douglas G.
Published: November 2023

Myeloid cells, including neutrophils, monocytes and macrophages, accumulate quickly after ischemic injury in the heart where they play integral roles in the regulation of inflammation and repair. We previously reported that deletion of β2-adrenergic receptor (β2AR) in all cells of hematopoietic origin resulted in generalized disruption of immune cell responsiveness to injury, but with unknown impact on myeloid cells specifically. To investigate this, we crossed floxed β2AR (F/F) mice with myeloid cell-expressing Cre (LysM-Cre) mice to generate myeloid cell-specific β2AR knockout mice (LB2) and subjected them to myocardial infarction (MI). Via echocardiography and immunohistochemical analyses, LB2 mice displayed better cardiac function and less fibrotic remodeling after MI than the control lines. Despite similar accumulation of myeloid cell subsets in the heart at 1-day post-MI, LB2 mice displayed reduced numbers of Nu by 4 days post-MI, suggesting LB2 hearts have enhanced capacity for Nu efferocytosis. Indeed, bone marrow-derived macrophage (BMDM)-mediated efferocytosis of Nu was enhanced in LB2-versus F/F-derived cells in vitro. Mechanistically, several pro-efferocytosis-related genes were increased in LB2 myeloid cells, with annexin A1 (Anxa1) in particular elevated in several myeloid cell types following MI. Accordingly, shRNA-mediated knockdown ofAnxa1in LB2 bone marrow prior to transplantation into irradiated LB2 mice reduced Mac-induced Nu efferocytosis in vitro and prevented the ameliorative effects of myeloid cell-specific β2AR deletion on cardiac function and fibrosis following MI in vivo. Altogether, our data reveal a previously unrecognized role for β2AR in the regulation of myeloid cell-dependent efferocytosis in the heart following injury.
Exploring Abstract Pattern Representation in The Brain and Non-symbolic Neural Networks
Authors: Avcu Enes , Gow David
Published: November 2023

Human cognitive and linguistic generativity depends on the ability to identify abstract relationships between perceptually dissimilar items. Marcus et al. (1999) found that human infants can rapidly discover and generalize patterns of syllable repetition (reduplication) that depend on the abstract property of identity, but simple recurrent neural networks (SRNs) could not. They interpreted these results as evidence that purely associative neural network models provide an inadequate framework for characterizing the fundamental generativity of human cognition. Here, we present a series of deep long short-term memory (LSTM) models that identify abstract syllable repetition patterns and words based on training with cochleagrams that represent auditory stimuli. We demonstrate that models trained to identify individual syllable trigram words and models trained to identify reduplication patterns discover representations that support classification of abstract repetition patterns. Simulations examined the effects of training categories (words vs. patterns) and pretraining to identify syllables, on the development of hidden node representations that support repetition pattern discrimination. Representational similarity analyses (RSA) comparing patterns of regional brain activity based on MRI-constrained MEG/EEG data to patterns of hidden node activation elicited by the same stimuli showed a significant correlation between brain activity localized in primarily posterior temporal regions and representations discovered by the models. These results suggest that associative mechanisms operating over discoverable representations that capture abstract stimulus properties account for a critical example of human cognitive generativity.
Ephaptic coupling between olfactory receptor neurons is sensitive to relative stimulus timing: Implications for odour source discrimination
Authors: Raiser Georg , Galizia C. Giovanni , Szyszka Paul
Published: November 2023

Insect olfactory receptor neurons (ORNs) are often co-localized within sensilla and exhibit non-synaptic reciprocal inhibition through ephaptic coupling. It has been postulated that this inhibition aids odour source discrimination, as synchronous arrival of different odour molecules (odorants) from a single source should increase ephaptic inhibition, whereas asynchronous arrival of odorants from different sources should decrease ephaptic inhibition. However, it was as yet unknown whether temporal arrival patterns of different odorants indeed modulate ephaptic inhibition, since past studies have focused on ephaptic inhibition of sustained ORN responses to prolonged and constant odour stimuli. However, most natural odour stimuli are not constant but rather transient and fluctuate as a result of dispersion in turbulent plumes in the air. To investigate the role of ephaptic inhibition in olfaction within turbulent environments, we recorded co-localized ORNs in the fruit flyDrosophila melanogasterexposed to dynamic odorant mixtures. We found that ephaptic inhibition does modulate transient ORN responses, and the strength of ephaptic inhibition decreases as the synchrony between arriving odorants decreases. These results support the hypothesis that ephaptic inhibition aids odour source discrimination.
Evidence for a Causal Dissociation of the McGurk Effect and Congruent Audiovisual Speech Perception via TMS
Authors: Ahn EunSeon , Majumdar Areti , Lee Taraz , Brang David
Published: November 2023

Congruent visual speech improves speech perception accuracy, particularly in noisy environments. Conversely, mismatched visual speech can alter what is heard, leading to an illusory percept known as the McGurk effect. This illusion has been widely used to study audiovisual speech integration, illustrating that auditory and visual cues are combined in the brain to generate a single coherent percept. While prior transcranial magnetic stimulation (TMS) and neuroimaging studies have identified the left posterior superior temporal sulcus (pSTS) as a causal region involved in the generation of the McGurk effect, it remains unclear whether this region is critical only for this illusion or also for the more general benefits of congruent visual speech (e.g., increased accuracy and faster reaction times). Indeed, recent correlative research suggests that the benefits of congruent visual speech and the McGurk effect reflect largely independent mechanisms. To better understand how these different features of audiovisual integration are causally generated by the left pSTS, we used single-pulse TMS to temporarily impair processing while subjects were presented with either incongruent (McGurk) or congruent audiovisual combinations. Consistent with past research, we observed that TMS to the left pSTS significantly reduced the strength of the McGurk effect. Importantly, however, left pSTS stimulation did not affect the positive benefits of congruent audiovisual speech (increased accuracy and faster reaction times), demonstrating a causal dissociation between the two processes. Our results are consistent with models proposing that the pSTS is but one of multiple critical areas supporting audiovisual speech interactions. Moreover, these data add to a growing body of evidence suggesting that the McGurk effect is an imperfect surrogate measure for more general and ecologically valid audiovisual speech behaviors.
Piezo1 stretch-activated channel activity differs between bone marrow-derived and cardiac tissue-resident macrophages
Authors: Simon-Chica A , Klesen A , Emig R , Chan A , Grün D , Lother A , Hilgendorf I , Ravens U , Kohl P , Schneider-Warme F , Peyronnet R
Published: November 2023

Macrophages (MΦ) play pivotal roles in tissue homeostasis and repair. Their mechanical environment recently emerged as a key modulator of various cell functions, and MΦ mechanosensitivity is likely to be critical for cellular activity in particular in a rhythmically contracting organ such as the heart. MΦ,in-vitro-differentiated from bone marrow (MΦBM), form a popular cell model for research. This study explores the activity of stretch-activated ion channels (SAC) in murine MΦBMand compares it to SAC activity in cardiac tissue-resident MΦ (MΦTR). Our main findings are: i) MΦBMand MΦTRhave stretch-induced currents, indicating expression of functional SAC at their plasma membrane; ii) the current profiles in MΦBMand in MΦTRshow characteristics of cation non-selective SAC; iii) unlike in MΦBM, Piezo1 ion channel activity at the plasma membrane of MΦTRis not detectable, neither by assessing electrophysiological activity using the patch clamp technique, nor by measuring cytosolic calcium concentration upon perfusion with Yoda1, a Piezo1 channel agonist. In mature scars after ventricular cryoablation, stretch-induced current characteristics of MΦTRare not significantly different compared to non-injured control tissue, even though scars are expected to contain a mix of pre-existing and circulation-recruited MΦ. This suggests that MΦ invading injured cardiac tissue either phenoconvert their mechanosensitivity from MΦBMto MΦTR, or that thein vitrodifferentiation protocols used to obtain MΦBMgenerate cells that differ from MΦ recruited from the circulation during tissue repairin vivo. Further investigations will explore SAC identity in lineage-traced MΦ in scar tissue, and compare mechanosensitivity of circulating monocytes with that of MΦBM.

Key points

MΦBMand MΦTRhave stretch-induced currents, indicating expression of functional SAC at their plasma membrane;

The current profiles in MΦBMand in MΦTRshow characteristics of cation non-selective SAC;

Unlike in MΦBM, Piezo1 ion channel activity at the plasma membrane of MΦTRis not detectable
Selective sweep probabilities in spatially expanding populations
Authors: Stein Alexander , Kizhuttil Ramanarayanan , Bak Maciej , Noble Robert
Published: November 2023

Evolution during range expansions shapes biological systems from microbial communities and tumours up to invasive species. A fundamental question is whether, when a beneficial mutation arises during a range expansion, it will evade clonal interference and sweep through the population to fixation. However, most theoretical investigations of range expansions have been confined to regimes in which selective sweeps are effectively impossible, while studies of selective sweeps have either assumed constant population size or have ignored spatial structure. Here we use mathematical modelling and analysis to investigate selective sweep probabilities in the alternative yet biologically relevant scenario in which mutants can outcompete and displace a slowly spreading wildtype. Assuming constant radial expansion speed, we derive probability distributions for the arrival time and location of the first surviving mutant and hence find surprisingly simple approximate and exact expressions for selective sweep probabilities in one, two and three dimensions, which are independent of mutation rate. Namely, the selective sweep probability is approximately (1− cwt/cm)d, wherecwtandcmare the wildtype and mutant radial expansion speeds, anddthe spatial dimension. Using agent-based simulations, we show that our analytical results accurately predict selective sweep frequencies in the two-dimensional spatial Moran process. We further compare our results with those obtained for alternative growth laws. Parameterizing our model for human tumours, we find that selective sweeps are predicted to be rare except during very early solid tumour growth, thus providing a general, pan-cancer explanation for findings from recent sequencing studies.