bluuebunny/crossref_metadata_2025 huggingface dataset:
Proximity Labeling Expansion Microscopy (PL-ExM) resolves structure of the interactome
Authors: Park Sohyeon , Wang Xiaorong , Li Xiangpeng , Huang Xiao , Fong Katie C. , Yu Clinton , Tran Arthur A. , Scipioni Lorenzo , Dai Zhipeng , Huang Lan , Shi Xiaoyu
Published: November 2023

Elucidating the spatial relationships within the protein interactome is pivotal to understanding the organization and regulation of protein-protein interactions. However, capturing the 3D architecture of the interactome presents a dual challenge: precise interactome labeling and super-resolution imaging. To bridge this gap, we present the Proximity Labeling Expansion Microscopy (PL-ExM). This innovation combines proximity labeling (PL) to spatially biotinylate interacting proteins with expansion microscopy (ExM) to increase imaging resolution by physically enlarging cells. PL-ExM unveils intricate details of the 3D interactome’s spatial layout in cells using standard microscopes, including confocal and Airyscan. Multiplexing PL-ExM imaging was achieved by pairing the PL with immunofluorescence staining. These multicolor images directly visualize how interactome structures position specific proteins in the protein-protein interaction network. Furthermore, PL-ExM stands out as an assessment method to gauge the labeling radius and efficiency of different PL techniques. The accuracy of PL-ExM is validated by our proteomic results from PL mass spectrometry. Thus, PL-ExM is an accessible solution for 3D mapping of the interactome structure and an accurate tool to access PL quality.
Viral vector eluting lenses for single-step targeted expression of genetically-encoded activity sensors for in vivo microendoscopic calcium imaging
Authors: Jons Carolyn K. , Cheng David , Dong Changxin , Meany Emily L. , Nassi Jonathan J. , Appel Eric A.
Published: November 2023

Optical methods for studying the brain offer powerful approaches for understanding how neural activity underlies complex behavior. These methods typically rely on genetically encoded sensors and actuators to monitor and control neural activity. For microendoscopic calcium imaging, injection of a virus followed by implantation of a lens probe is required to express a calcium sensor and enable optical access to the target brain region. This two-step process poses several challenges, chief among them being the risks associated with mistargeting and/or misalignment between virus expression zone, lens probe and target brain region. Here, we engineer an adeno-associated virus (AAV)-eluting polymer coating for gradient refractive index (GRIN) lenses enabling expression of a genetically encoded calcium indicator (GCaMP) directly within the brain region of interest upon implantation of the lens. This approach requires only one surgical step and guarantees alignment between GCaMP expression and lens in the brain. Additionally, the slow virus release from these coatings increases the working time for surgical implantation, expanding the brain regions and species amenable to this approach. These enhanced capabilities should accelerate neuroscience research utilizing optical methods and advance our understanding of the neural circuit mechanisms underlying brain function and behavior in health and disease.
A NRF2/β3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress
Authors: Michel Lauriane Y. M. , Esfahani Hrag , Verdoy Roxane , de Mulder Delphine , Ambroise Jérôme , Roelants Véronique , Bouchard Bertrand , Savary Jérôme , Dewulf Joseph P. , Doumont Thomas , Bouzin Caroline , Haufroid Vincent , Luiken Joost J.F.P. , Nabben Miranda , Singleton Michael L. , Bertrand Luc , Ruiz Matthieu , Des Rosiers Christine , Balligand Jean-Luc
Published: November 2023

Background

Cardiac β3-adrenergic receptors (β3AR) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect from myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. The underlying mechanisms, however, remain elusive.

Methods

To dissect functional, transcriptional and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a humanADRB3transgene (β3AR-Tg) and subjected to transverse aortic constriction (TAC) were assessed using echocardiography, RNAseq, PET scan, metabolomics, seahorse and metabolic flux analysis. Subsequently, signaling and metabolic pathways were investigated furtherin vivoin β3AR-Tg andin vitroin neonatal rat ventricular myocytes adenovirally infected to express β3AR and subjected to neurohormonal stress. These results were completed with an analysis of single nucleus RNAseq data from human cardiac myocytes from heart failure patients.

Results

Compared with WT littermate, β3AR-Tg mice were protected from hypertrophy after transaortic constriction (TAC), while systolic function was preserved. β3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the Pentose-Phosphate Pathway (PPP) in β3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the PPP, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, while downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in β3AR-Tg post-TAC compared to WT, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as upstream transcription factor which was functionally verified in β3AR-expressing cardiac myocytes where its translocation and nuclear activity was dependent on β3AR activation of nitric-oxide synthase (NOS) NO production.

Conclusion

Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts antioxidant effects through activation of the PPP and NRF2 pathway, thereby preserving myocardial oxidative metabolism, function and integrity under pathophysiological stress.
Assessing the capacity of high-resolution commercial satellite imagery for grapevine downy mildew detection and surveillance in New York state
Authors: Kanaley Kathleen , Combs David B. , Paul Angela , Jiang Yu , Bates Terry , Gold Kaitlin M.
Published: November 2023

Grapevine downy mildew (GDM), caused by the oomycetePlasmopara viticola,can cause 100% yield loss and vine death under conducive conditions. Growers currently rely on frequent fungicide applications for control, but this practice has led to widespread resistance. Rapid remote detection and surveillance of GDM outbreaks would enable precision pesticide applications to target effective but resistance-prone fungicides where and when most needed, while relying on less resistance-prone protectants elsewhere. High resolution commercial satellite platforms offer the opportunity to track rapidly spreading diseases like GDM over large, heterogeneous fields. Here, we investigate the capacity of PlanetScope (3 m) and SkySat (50 cm) imagery for season-long GDM detection and surveillance. A team of trained scouts rated GDM severity and incidence in two acres of Chardonnay grapevines in Geneva, NY, USA in June-August of 2020, 2021, and 2022. Satellite imagery acquired within 72 hours of scouting was processed to extract single-band reflectance and vegetation indices (VIs). Random forest models trained on spectral bands and VIs derived from both image datasets could classify areas of high and low GDM incidence and severity with maximum accuracies of 0.88 (SkySat) and 0.94 (PlanetScope). However, we do not observe significant differences between VIs of high and low damage classes until late July-early August. We identify cloud cover, image co-registration, and low spectral resolution as key challenges to operationalizing satellite-based GDM surveillance. This work establishes the capacity of spaceborne multispectral sensors to detect late-stage GDM and outlines steps towards incorporating satellite remote sensing in grapevine disease surveillance systems.
PriOmics: integration of high-throughput proteomic data with complementary omics layers using mixed graphical modeling with group priors
Authors: Kosch Robin , Limm Katharina , Staiger Annette M. , Kurz Nadine S. , Seifert Nicole , Oláh Bence , Solbrig Stefan , Ziepert Marita , Chteinberg Emil , Spang Rainer , Siebert Reiner , Zacharias Helena U. , Ott German , Oefner Peter J. , Altenbuchinger Michael
Published: November 2023

Mass spectrometry (MS)-based high-throughput proteomics data cover abundances of 1,000s of proteins and facilitate the study of co- and post-translational modifications (CTMs/PTMs) such as acetylation, ubiquitination, and phosphorylation. Yet, it remains an open question how to holistically explore such data and their relationship to complementary omics layers or phenotypical information. Network inference methods aim for a holistic analysis of data to reveal relationships between molecular variables and to resolve underlying regulatory mechanisms. Among those, graphical models have received increased attention as they can distinguish direct from indirect relationships, aside from their generalizability to diverse data types. We propose PriOmics as a graphical modeling approach to integrate proteomics data with complementary omics layers and pheno- and genotypical information. PriOmics models intensities of individual peptides and incorporates their protein affiliation as prior knowledge in order to resolve statistical relationships between proteins and CTMs/PTMs. We show in simulation studies that PriOmics improves the recovery of statistical associations compared to the state of the art and demonstrate that it can disentangle regulatory effects of protein modifications from those of respective protein abundances. These findings are substantiated in a dataset of Diffuse Large B-Cell Lymphomas (DLBCLs) where we integrate SWATH-MS-based proteomics data with transcriptomic and phenotypic information.

GRAPHICAL ABSTRACT
Characterization and Phylogenetic Insights into the First Viral Major Vault Proteins (MVPs), Identified in Bacteriophages from the Human Gut
Authors: Santos Thiago M. , Galvão Emerson , Gomes Helena , Del-Bem Luiz-Eduardo
Published: November 2023

The Major Vault Protein (MVP) is the principal component of the enigmatic vault complex, dome-shaped cytoplasmic ribonucleoproteins found in eukaryotes. Although vaults have been associated with several minor functions, including amino acid storage and cargo transport, their overall function remains to be fully understood. While MVPs are widely distributed among most higher eukaryotes and have homologs in prokaryotes, no similar protein have been reported in viral species until now. In this study, we explored the NCBI viral protein database for MVP homologs and identified two putative MVPs from distinct tailed bacteriophage isolates from the ClassCaudoviricetes, ctOa11 and ctRi15, of human gut metagenomic samples. Furtherin silicoanalysis were conducted to describe and characterize these unprecedent phage proteins. Phylogenetic topologies indicate that viral MVPs are closely related to bacterial MVP homologs. Tridimensional protein models of viral MVPs were generated to perform protein structure comparisons with eukaryotic and prokaryotic MVPs, indicating a significant similarity to bacterial proteins. For the functional significance of MVPs in phage infectivity, we suggest that they may have an unknown metabolic role enhancing phage fitness. While this work provides new insights into the genetic phage diversity and phylogenetic distribution of MVPs, complementary functional studies are necessary to fully elucidate their function in viral and bacterial species.
S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice
Authors: Gruel Roxane , Bijnens Baukje , Van Den Daele Johanna , Thys Sofie , Willems Roland , Wuyts Dirk , Van Dam Debby , Verstraelen Peter , Verboven Rosanne , Roels Jana , Vandamme Niels , Mancuso Renzo , Pita-Almenar Juan Diego , De Vos Winnok H.
Published: November 2023

Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (senescence accelerated mouse prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genesS100a8andS100a9. In 9-months-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction.

Graphical abstract
eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers
Authors: Waldron Joseph A. , Kanellos Georgios , Smith Rachael C. L. , Knight John R. P. , Munro June , Alexandrou Constantinos , Vlahov Nikola , Pardo-Fernandez Luis , Moore Madeleine , Gillen Sarah L. , Strathdee Douglas , Stevenson David , Warrander Fiona C. , Gilroy Kathryn , Nixon Colin , Cadden Barbara , Powley Ian , Officer-Jones Leah , Ballantyne Fiona , Hay Jennifer , Pennel Kathryn , Edwards Joanne , Campbell Andrew D. , Ridgway Rachel A. , Coffelt Seth B. , Norman Jim , Quesne John Le , Bushell Martin , Sansom Owen J.
Published: November 2023

Dysregulated translation is a hallmark of cancer. Targeting the translational machinery represents a therapeutic avenue which is being actively explored. eIF4A inhibitors target both eIF4A1, which promotes translation as part of the eIF4F complex, and eIF4A2, which can repress translation via the CCR4–NOT complex. While high eIF4A1 expression is associated with poor patient outcome, the role of eIF4A2 in cancer remains unclear. Furthermore, the on-target toxicity of targeting specific eIF4A paralogues in healthy tissue is under-explored. We show that while loss of either paralogue is tolerated in the wild-type intestine, eIF4A1 is specifically required to support the translational demands of oncogenic Wnt signalling. Intestinal tumourigenesis is suppressed in colorectal cancer models following loss of eIF4A1 but accelerated following loss of eIF4A2, while eIF4A inhibition with eFT226 mimics loss of eIF4A1 in these models.
Disruption of IL-17 signaling in the respiratory mucosa results in invasive streptococcal infection
Authors: Mills Jamie-Lee , Lepletier Ailin , Ozberk Victoria , Dooley Jessica , Kaden Jacqualine , Calcutt Ainslie , Huo Yongbao , Hicks Allan , Zaid Ali , Good Michael F. , Pandey Manisha
Published: November 2023

Streptococcus pyogenesinfection of the upper respiratory tract and skin can lead to severe invasive streptococcal disease (ISD). Previous studies have demonstrated that the deficiency of IL-17 in mice (IL-17-/-) reduces mucosal immunity againstS. pyogenes. However, the impact of IL-17 deficiency on the development of ISD is unknown. Here, we model single or repeated non-lethal, intranasal (IN)S. pyogenesM1 strain infections in immunocompetent and IL-17-/-mice to assess bacterial dissemination following a final IN or skin challenge. Immunocompetent mice that received a singleS. pyogenesIN infection displayed long-lasting mucosal immunity and no systemic infection. However, in the absence of IL-17, a single IN infection resulted in the dissemination ofS. pyogenesto the spleens, which was further exacerbated by repeated IN infections. Interestingly, immunity following skin challenge did not show a correlation with IL-17 and was instead associated with the activation of germinal center responses and the accumulation of neutrophils in the spleen. Our results highlight the critical role of IL-17 in preventing ISD followingS. pyogenesinfection of the respiratory mucosa.
Tonic dopamine and biases in value learning linked through a biologically inspired reinforcement learning model
Authors: Romero Pinto Sandra , Uchida Naoshige
Published: November 2023

A hallmark of various psychiatric disorders is biased future predictions. Here we examined the mechanisms for biased value learning using reinforcement learning models incorporating recent findings on synaptic plasticity and opponent circuit mechanisms in the basal ganglia. We show that variations in tonic dopamine can alter the balance between learning from positive and negative reward prediction errors, leading to biased value predictions. This bias arises from the sigmoidal shapes of the dose-occupancy curves and distinct affinities of D1- and D2-type dopamine receptors: changes in tonic dopamine differentially alters the slope of the dose-occupancy curves of these receptors, thus sensitivities, at baseline dopamine concentrations. We show that this mechanism can explain biased value learning in both mice and humans and may also contribute to symptoms observed in psychiatric disorders. Our model provides a foundation for understanding the basal ganglia circuit and underscores the significance of tonic dopamine in modulating learning processes.
Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer
Authors: Zhou Yufan , Li Tian , He Zhijing , Choppavarapu Lavanya , Hu Xiaohui , Cao Ruifeng , Leone Gustavo W. , Kahn Michael , Jin Victor X.
Published: November 2023

The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
Optical segmentation-based compressed readout of neuronal voltage dynamics
Authors: Kim Seonghoon , Ko Gwanho , Kang Iksung , Tian He , Fan Linlin Z. , Li Yixin , Cohen Adam E. , Wu Jiamin , Dai Qionghai , Choi Myunghwan
Published: November 2023

Functional imaging of biological dynamics generally begins with acquiring time-series images, followed by quantifying spatially averaged intensity traces for the regions of interest (ROIs). The conventional pipeline discards a substantial portion of the acquired data when quantifying intensity traces, indicative of inefficient data acquisition. Here we propose a conceptually novel acquisition pipeline that assigns each ROI to a single pixel in the detector, enabling optimally compressed acquisition of the intensity traces. As a proof-of-principle, we implemented a detection module composed of a pair of spatial light modulators and a microlens array, which segments the original image into multiple subimages by introducing distinct angular shifts to each ROI. Each subimage exclusively encodes the signal for the corresponding ROI, facilitating the compressed readout of its intensity trace using a single pixel. This spatial compression allowed for maximizing the temporal information without compromising the spatial information on ROIs. Harnessing our novel approach, we demonstrate the recording of circuit-scale neuronal voltage dynamics at over 5 kHz sampling rate, revealing the individual action potential waveforms within subcellular structures, as well as their submillisecond-scale temporal delays.
Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release
Authors: Bodt Skylar M. L. , Ge Jinghua , Ma Wen , Rasicci David V. , Desetty Rohini , McCammon J. Andrew , Yengo Christopher M.
Published: November 2023

Inherited mutations in human beta-cardiac myosin (M2β) can lead to severe forms of heart failure. The E525K mutation in M2β is associated with dilated cardiomyopathy (DCM) and was found to stabilize the interacting heads motif (IHM) and autoinhibited super-relaxed (SRX) state in dimeric heavy meromyosin. However, in monomeric M2β subfragment 1 (S1) we found that E525K enhances (3-fold) the maximum steady-state actin-activated ATPase activity (kcat) and decreases (6-fold) the actin concentration at which ATPase is one-half maximal (KATPase). We also found a 3 to 4-fold increase in the actin-activated power stroke and phosphate release rate constants at 30 μM actin, which overall enhanced the duty ratio 3-fold. Loaded motility assays revealed that the enhanced intrinsic motor activity translates to increased ensemble force in M2β S1. Glutamate 525, located near the actin binding region in the so-called activation loop, is highly conserved and predicted to form a salt-bridge with another conserved residue (lysine 484) in the relay helix. Enhanced sampling molecular dynamics simulations predict that the charge reversal mutation disrupts the E525-K484 salt-bridge, inducing conformations with a more flexible relay helix and a wide phosphate release tunnel. Our results highlight a highly conserved allosteric pathway associated with actin activation of the power stroke and phosphate release and suggest an important feature of the autoinhibited IHM is to prevent this region of myosin from interacting with actin. The ability of the E525K mutation to stabilize the IHM likely overrides the enhanced intrinsic motor properties, which may be key to triggering DCM pathogenesis.

Significance Statement

Heart disease can be caused by inherited mutations in beta-cardiac myosin, the molecular motor that powers systolic contraction in the ventricles of the heart. However, it remains unclear how these mutations lead to contractile dysfunction and pathogenic remodeling of the heart. We investigated a unique dilated cardiomyopathy mutation (E525K) that dramatically stabilizes the autoinhibited state while enhancing intrinsic motor function. Thus, we examined how this mutation impacts transient kinetic steps of the ATPase cycle, motile properties, and structural changes associated with the power stroke and phosphate release. Our results provide a kinetic and structural basis for how beta-cardiac myosin mutations may disrupt molecular-level contractile function in complex ways, which may inform the development of targeted therapeutics.
AAV-mediated gene therapy for Sialidosis
Authors: van de Vlekkert Diantha , Hu Huimin , Fremuth Leigh E. , Brown Scott A. , Weesner Jason A. , Gomero Elida , Campos Yvan , d’Azzo Alessandra
Published: November 2023

Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-oldNeu1−/−mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis inNeu1−/−mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.
The effects of mutation and recombination rate heterogeneity on the inference of demography and the distribution of fitness effects
Authors: Soni Vivak , Pfeifer Susanne P. , Jensen Jeffrey D.
Published: November 2023

Disentangling the effects of demography and selection has remained a focal point of population genetic analysis. Knowledge about mutation and recombination is essential in this endeavour; however, despite clear evidence that both mutation and recombination rates vary across genomes, it is common practice to model both rates as fixed. In this study, we quantify how this unaccounted for rate heterogeneity may impact inference using common approaches for inferring selection (DFE-alpha, Grapes, and polyDFE) and/or demography (fastsimcoal2 andδaδi). We demonstrate that, if not properly modelled, this heterogeneity can increase uncertainty in the estimation of demographic and selective parameters and in some scenarios may result in mis-leading inference. These results highlight the importance of quantifying the fundamental evolutionary parameters of mutation and recombination prior to utilizing population genomic data to quantify the effects of genetic drift (i.e., as modulated by demographic history) and selection; or, at the least, that the effects of uncertainty in these parameters can and should be directly modelled in downstream inference.

Significance Statement

Despite evidence from numerous species that mutation and recombination rates vary along the genome, both rates tend to be modelled as fixed when performing population genetic inference. The impact of failing to account for this rate heterogeneity on the estimation of demographic and selective parameters has yet to be well quantified; thus, we here study this effect by comparing inference under both fixed and variable rate scenarios. Our results demonstrate that unaccounted for rate heterogeneity can increase uncertainty and lead to mis-inference in certain scenarios. We highlight the importance of utilizing mutation and recombination rate maps where possible, and of modelling the uncertainty underlying these estimates.
A non-adaptive explanation for macroevolutionary patterns in the evolution of complex multicellularity
Authors: Bingham Emma P. , Ratcliff William C.
Published: November 2023

“Complex multicellularity”, conventionally defined as large organisms with many specialized cell types, has evolved five times independently in eukaryotes, but never within prokaryotes. A number hypotheses have been proposed to explain this phenomenon, most of which posit that eukaryotes evolved key traits (e.g., dynamic cytoskeletons, alternative mechanisms of gene regulation, or subcellular compartments) which were a necessary prerequisite for the evolution of complex multicellularity. Here we propose an alternative, non-adaptive hypothesis for this broad macroevolutionary pattern. By binning cells into groups with finite genetic bottlenecks between generations, the evolution of multicellularity greatly reduces the effective population size (Ne) of cellular populations, increasing the role of genetic drift in evolutionary change. While both prokaryotes and eukaryotes experience this phenomenon, they have opposite responses to drift: mutational biases in eukaryotes tend to drive genomic expansion, providing additional raw genetic material for subsequent multicellular innovation, while prokaryotes generally face genomic erosion. These effects become more severe as organisms evolve larger size and more stringent genetic bottlenecks between generations— both of which are hallmarks of complex multicellularity. Taken together, we hypothesize that it is these idiosyncratic lineagespecific mutational biases, rather than cell-biological innovations within eukaryotes, that underpins the long-term divergent evolution of complex multicellularity across the tree of life.
Xanthomonas rydalmerenesissp. nov., a novel plant bacteria isolated fromFragaria x ananassa
Authors: McKnight Daniel J E , Wong Johanna , Okoh Efenaide B , Snijders Fridtjof , Lidbetter Fiona , Webster John , Haughton Mathew , Darling Aaron E , Djordjevic Steven P , Bogema Daniel R , Chapman Toni
Published: November 2023

We describe five bacterial isolates that were isolated fromFragaria x ananassain 1976 in Rydalmere, Australia, during routine biosecurity surveillance. Initially, biochemical characterisation identified these isolates as members of theXanthomonasgenus. To determine their species, we conducted further analysis using both phenotypic and genotypic approaches. Phenotypic analysis involved using MALDI-TOF MS and BIOLOG GEN III microplates, which confirmed that the isolates belonged to theXanthomonasgenus but could not classify species. Genome relatedness indices and extensive phylogenetic analysis confirmed that the isolates belonged to theXanthomonasgenus and represented a new species. Based on the absence of virulence factors typically found inXanthomonasspp. genomes, we suggest that these isolates are non-pathogenic. This conclusion was supported by a pathogenicity assay. Based on these findings, we propose the nameXanthomonas rydalmerenesis, with DAR34855 = ICMP24941 as the type strain.
The mitochondrial deoxyguanosine kinase is required for female fertility in mice
Authors: Gao Yake , Dong Rui , Yan Jiacong , Chen Huicheng , Sang Lei , Yao Xinyi , Fan Die , Wang Xin , Zuo Xiaoyuan , Zhang Xu , Yang Shengyu , Wu Ze , Sun Jianwei
Published: November 2023

Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleoside in the mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells.Dguokloss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. We found thatDguokknockout results in female infertility. Mechanistically, the deficiency of DGUOK hinders ovarian development and oocyte maturation. Moreover,Dguokdeficiency in oocytes caused a significant reduction in mitochondrial DNA and abnormal mitochondrial dynamics, and impaired germinal vesicle breakdown. Only few DGUOK-deficient oocytes were able to extrude the first polar body duringin vitromaturation, and these oocytes showed irregular chromosome arrangement and different spindle lengths. In addition,Dguokdeficiency elevated reactive oxygen species and accelerated apoptosis in oocytes. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate that DGUOK is a potential marker for the diagnosis of female infertility.
Exercise intervention for the management of chemotherapy-induced peripheral neuropathy: A systematic review and network meta-analysis
Authors: Nakagawa Natsuki , Yamamoto Sena , Hanai Akiko , Oiwa Ayano , Arao Harue
Published: November 2023

1

Although exercise is recommended for cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN), the effective types of exercise for preventing and treating CIPN remain unclear. This systematic review and network meta-analysis (NMA) aimed to evaluate the comparative effects of exercise on CIPN. We included relevant randomized controlled trials (RCTs) identified in a 2019 systematic review that evaluated the effects of exercise on CIPN and conducted an additional search for RCTs published until 2023. We evaluated the risk of bias for each RCT; the comparative effectiveness of exercise on patient-reported quality of life (QOL) through an NMA; and the effectiveness of exercise on QOL scores, patient-reported CIPN symptoms, and pain through additional meta-analyses.Twelve studies (exercise, n=540; control, n=527) comparing 8 exercise interventions were included in the analysis. All studies were determined to have a high risk of bias. The meta-analyses showed significantly improved QOL (standard mean differences [SMD] 0.45; 95% confidence interval [CI] = 0.12 to 0.78) and CIPN symptoms (SMD 0.46; 95% CI = 0.11 to 0.82). No severe adverse events were reported. Pain tended to improve with exercise (SMD 0.84; 95% CI = −0.11 to 1.80). An NMA suggested that the interventions of combination of balance and strength training showed the significant improvement in QOL scores compared to the control. Exercise interventions are safe and effective in improving QOL. For exercise categories, the combination of balance and strength training would be the promising program. Patients with CIPN will benefit from frequent exercise focusing on the declined symptoms.
Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes
Authors: Du Zhaohui , Lessard Samuel , Iyyanki Tejaswi , Chao Michael ,   FinnGen, Hammond Timothy , Ofengeim Dimitry , Klinger Katherine , de Rinaldis Emanuele , Shameer Khader , Chatelain Clément
Published: November 2023

Objective

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related riskloci, genes and pathways.

Methods

To increase power, we first included all patients with a diagnosis of inflammatory polyneuropathy (IP) as cases. We performed a GWAS study using FinnGen R10 individual data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. The second GWAS focused on CIDP patients and a total of 516 CIDP cases and 403,545 controls were included in the analysis. Stratified analyses by gender were also performed for both IP and CIDP. We performed gene-level analyses using transcriptome-wide mendelian randomization (TWMR) analysis, colocalization analysis, transcriptome-wide association study (TWAS) using S-PrediXcan and MAGMA to identify genes associated with IP and CIDP. Gene-set analyses were conducted using MAGMA to identify pathways that are related to IP and CIDP.

Results

In GWAS study, we identified one genome-wide significant loci at 20q13.33 for CIDP risk among women; the top variant located at the intron region of geneCDH4. TWMR, colocalization and S-PrediXcan analyses identifiedDGKQ, GLDC, IDUA, SLAMF9andTMEM175as candidate pathogenic genes for IP; genesDIRAS1, GNG7, andSLC39A3for CIDP; genesDIRAS1, DCTN1, andME1for IP among males; and genes DIRAS1 andME1for IP among women. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP.

Conclusion

Our study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.
Automated quantitative evaluation of thymic involution and hyperplasia on plain chest CT
Authors: Okamura Yuki T. , Endo Katsuhiro , Toriihara Akira , Fukuda Issei , Isogai Jun , Sato Yasunori , Yasuoka Kenji , Kagami Shin-Ichiro
Published: November 2023

Objective

To establish an automatic method to quantify thymic involution and hyperplasia based on plain chest computed tomography (CT).

Methods

We defined the thymic region for quantification (TRQ) as the target region. We manually segmented the TRQ in 135 CT studies, followed by construction of segmentation neural network (NN) models based on the data. We developed the estimator of thymic volume (ETV), a measure of the thymic tissue volume in the segmented TRQ. The Hounsfield unit (HU) value and volume of the TRQ were measured, and the ETV was calculated in each CT study from 853 healthy subjects. We investigated how these measures were related to the age and sex using quantile additive regression models. We defined the ETV z-score, an age- and sex-adjusted version of ETV, to distinguish between subjects with thymic hyperplasia (18 cases) and healthy subjects. A receiver operating characteristic (ROC) curve analysis was conducted.

Results

A significant correlation between the NN-segmented and manually segmented TRQ was seen for both the HU value and volume of the TRQ (r= 0.996 andr= 0.986 respectively). The ETV could detect age-related decline in the thymic tissue volume (p< 0.001). No statistically significant difference was detected between male and female subjects (p= 0.19). The ETV was significantly higher in the thymic hyperplasia group as compared with that in the healthy control group (p< 0.001). The ETV z-score could distinguish between subjects with thymic hyperplasia and healthy subjects, with the ROC curve analysis revealing an area under the curve (AUC) of 0.88 (95% CI: 0.75-1.0).

Conclusion

Our method enabled robust quantification of thymic involution and hyperplasia. The results were consistent with the trends found in previous studies.

Clinical Relevance Statement

Our method allows reliable and automatic measurement of thymic involution and hyperplasia on CT images. This may aid in the early detection and monitoring of pathologies related to the thymus, including autoimmune diseases.

Key Points

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We defined the thymic region for quantification (TRQ) to fully automate the evaluation of thymic involution and hyperplasia. The neural networks could identify the TRQ with sufficient accuracy.

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We developed the estimator of thymic volume (ETV) to quantify the thymic tissue in the TRQ. ETV captured age-related thymic involution and thymic hyperplasia.

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The ETV could prove useful in the management of pathologies associated with involution or hyperplasia of the thymus.
Somatic RIT1 indels identified in arteriovenous malformations hyperactivate RAS-MAPK signaling and are amenable to MEK inhibition
Authors: Kapp Friedrich G. , Bazgir Farhad , Mahammadzade Nagi , Vassella Erik , Döring Yvonne , Holm Annegret , Karow Axel , Seebauer Caroline , Batista da Silva Natascha Platz , Wohlgemuth Walter A. , Kröning Pia , Niemeyer Charlotte M. , Schanze Denny , Zenker Martin , Eng Whitney , Ahmadian Mohammad R. , Baumgartner Iris , Rössler Jochen
Published: November 2023

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. Treatment is often difficult and relapse after therapy is common. AVM are mainly caused by somatic mosaicism with pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep next generation sequencing we identified novel somaticRIT1indel variants in lesional tissue of three AVM patients.RIT1– not previously implicated in AVM development – encodes a RAS-like protein that can modulate RAS-MAPK signaling. For biochemical characterization, we expressedRIT1variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of theRIT1indels in zebrafish embryos induced AVM formation, highlighting the functional importance in vascular development. Both ERK1/2 hyperactivationin vitroand AVM formationin vivocould be suppressed by pharmacological MEK inhibition. Targeted treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings expand the genetic spectrum of AVM by identifyingRIT1as a novel gene involved in AVM formation and pave the way for targeted treatment and clinical trials in patients with AVM.
Genome-wide association study analysis of disease severity in Acne reveals novel biological insights
Authors: Du Zhaohui , Iyyanki Tejaswi , Lessard Samuel , Chao Michael ,   FinnGen, Asbrand Christian , Nassar Dany , Klinger Katherine , de Rinaldis Emanuele , Khader Shameer , Chatelain Clément
Published: November 2023

Acne vulgaris is a common skin disease that affects >85% of teenage young adults among which >8% develop severe lesions that leaves permanent scars. Genetic heritability studies of acne in twin cohorts have estimated that the heritability for acne is 80%. Previous genome-wide association studies (GWAS) have identified 50 geneticlociassociated with increased risk of developing acne when compared to healthy individuals. However only a few studies have investigated genetic association with disease severity. GWAS of disease progression may provide a more effective approach to unveil potential disease modifying therapeutic targets.

Here, we performed a multi-ethnic GWAS analysis to capture disease severity in acne patients by using individuals with normal acne as a control. Our cohort consists of a total of 2,956 participants, including 290 severe acne cases and 930 normal acne controls from FinnGen, and 522 cases and 1,214 controls from BioVU. We also performed mendelian randomization (MR), colocalization analyses and transcriptome-wide association study (TWAS) to identify putative causal genes. Lastly, we performed gene-set enrichment analysis using MAGMA to implicate biological pathways that drive disease severity in Acne.

We identified two new loci associated with acne severity at the genome-wide significance level, six novel associated genes by MR, colocalization and TWAS analyses, including genesCDC7, SLC7A1, ADAM23, TTLL10, CDK20andDNAJA4, and 5 novel pathways by MAGMA analyses. Our study suggests that the etiologies of acne susceptibility and severity have limited overlap, with only 26% of known acne risk loci presenting nominal association with acne severity and none of the novel severity associated genes reported as associated with acne risk in previous GWAS.
Effect of Sinotubular Junction Size on TAVR Leaflet Thrombosis: A Fluid-structure Interaction Analysis
Authors: Oks David , Reza Symon , Vázquez Mariano , Houzeaux Guillaume , Kovarovic Brandon , Samaniego Cristóbal , Bluestein Danny
Published: November 2023

Purpose

TAVR has emerged as a standard approach for treating severe aortic stenosis patients. However, it is associated with several clinical complications, including subclinical leaflet thrombosis characterized by Hypoattenuated Leaflet Thickening (HALT). A rigorous analysis of TAVR device thrombogenicity considering anatomical variations is essential for estimating this risk. Clinicians use the Sinotubular Junction (STJ) diameter for TAVR sizing, but there is a paucity of research on its influence on TAVR devices thrombogenicity.

Methods

A Medtronic Evolut® TAVR device was deployed in three patient models with varying STJ diameters (26, 30, and 34mm) to evaluate its impact on post-deployment hemodynamics and thrombogenicity, employing a novel computational framework combining prosthesis deployment and fluid- structure interaction analysis.

Results

The 30 mm STJ patient case exhibited the best hemodynamic performance: 5.94mmHgmean transvalvular pressure gradient (TPG), 2.64cm2mean geometric orifice area (GOA), and the lowest mean residence time (TR) - indicating a reduced thrombogenic risk; 26 mm STJ exhibited a 10 % reduction in GOA and a 35% increase in mean TPG compared to the 30 mm STJ; 34 mm STJ depicted hemodynamics comparable to the 30 mm STJ, but with a 6% increase in TRand elevated platelet stress accumulation.

Conclusion

A smaller STJ size impairs adequate expansion of the TAVR stent, which may lead to suboptimal hemodynamic performance. Conversely, a larger STJ size marginally enhances the hemodynamic performance but increases the risk of TAVR leaflet thrombosis. Such analysis can aid pre- procedural planning and minimize the risk of TAVR leaflet thrombosis.
Ability of calculated right adrenal vein aldosterone levels to identify the aldosterone-overproducing side in patients with primary aldosteronism undergoing adrenal venous sampling
Authors: Tuandam Lalita , Soonthornpun Supamai
Published: November 2023

Backgroud

Adrenal venous sampling (AVS) is a gold standard procedure to determine the dominant side of aldosterone secretion in patients with primary aldosteronism. Unsuccessful cannulation of right adrenal vein (RAV) is a common problem in performing AVS.

Objective

To use calculated aldosterone concentration in the RAV (cAldoRAV) for identifying the dominant side of aldosterone secretion.

Design

Retrospective study, 2011-2023.

Methods

Based on the assumption that cortisol production from both adrenal glands is equal, aldosterone concentration in the RAV was calculated by using the data from left adrenal vein (LAV) and inferior vena cava. The aldosterone concentration in the LAV (AldoLAV) compared to the cAldoRAV(AldoLAV:cAldoRAVratio) was then used to determine the dominant side of aldosterone secretion in patients with primary aldosteronism.

Results

Of 117 patients with successful AVS, 95 (81.2%) had concordant results between adrenal imaging and AVS study and were used as the gold standard for studying diagnostic performance. The AldoLAV:cAldoRAVratio with the cutoff values of ≥3 and ≤0.33 could identify unilateral diseases (left-sided and right-sided disease, respectively) with 93.8% sensitivity and 100% specificity. In 22 patients who had discordant results between adrenal imaging and standard AVS interpretation, 11 had concordant results when using the AldoLAV:cAldoRAVratio.

Conclusions

The AldoLAV:cAldoRAVratio can determine the dominant side of aldosterone secretion with high sensitivity and specificity. It can not only be used for patients with unsuccessful cannulation of RAV but also increase the concordance rate in those who have discordance between adrenal imaging and standard AVS interpretation.