bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Analysis of Stain-Free Fourier Ptychographic Microscopy and Traditional Histopathological Light Microscopy in Renal Membranous Nephropathy
Authors: Valentino Marika , Bianco Vittorio , D’Ambrosio Gioacchino , Paulli Marco , Smaldone Giovanni , Brancato Valentina , Miccio Lisa , Salvatore Marco , Gambacorta Marcello , Ferraro Pietro 
Published: September 2024

AbstractBackgroundHistology remains a cornerstone in the diagnosis and prognosis of renal diseases, with histopathological analysis of kidney tissue being crucial for understanding renal pathophysiology. The availability of multiple stained sections is essential for conducting a comprehensive histopathological analysis and achieving an accurate diagnosis. Recently, Fourier Ptychographic Microscopy (FPM) earned a spot among the most promising microscopy techniques. The ability to provide high-resolution, quantitative phase-contrast images over a wide area, particularly in a stain-free mode, makes FPM highly appealing to experts in histopathology. Since renal pathologies are characterized by subtle morphological changes encoded in tissue slides, phase maps obtained using FPM are well-suited for providing detailed, high-contrast images of tissue structures. Thus, FPM provides a quantitative imaging tool that can be descriptive of the sample and/or expressive of the disease.MethodsIn this study, we explore FPM capability to image pathological kidney tissue, enabling pathologists to select regions of interest within the intricate architecture of renal tissue and zoom in to observe minute submicron structures, ranging from overall tissue organization and glomeruli distribution to individual cell membranes. Attention is focused on membranous glomerulonephritis since it is a nephropathy highly dependent on histological examination.ResultsThe comparative analysis between FPM and traditional light microscopy showed a difference in thickness of glomerular basal membranes between healthy kidney tissues and those affected by membranous glomerulonephritis (MG). Moreover, the results reported in our investigation revealed better glomerular membranes contrast in FPM images with respect to the H&E-stained images.ConclusionsOur study shows the broad potential of FPM in characterizing hallmarks of MG disease even in stain-free tissue slides.
Stabilization of fluctuating population dynamics via the evolution of dormancy
Authors: Miller Zachary R. , Vasseur David , Hull Pincelli M. 
Published: September 2024

AbstractDormancy is usually understood as a strategy for coping with extrinsically variable environments, but intrinsic population fluctuations also create conditions where dormancy is adaptive. By analyzing simple population models, we show that, very generally, population fluctuations favor the evolution of dormancy, but dormancy stabilizes population dynamics. This sets up a feedback loop that can enable the coexistence of alternative dormancy strategies. Over longer timescales, we show that evolution of dormancy to an evolutionary stable state can drive populations to the edge of stability, where dynamics are only weakly stabilized. We briefly consider how these conclusions are likely to apply in more complex community contexts. Our results suggest that chaos and high-amplitude population cycles are highly vulnerable to invasion and subsequent stabilization by dormancy, potentially explaining their rarity. At the same time, the propensity of ecological dynamics to fluctuate may be an underappreciated driver of the evolution of dormancy.
De novoRNA base editing in plant organelles with engineered synthetic P-type PPR editing factors
Authors: Mathieu Sébastien , Lesch Elena , Garcia Shahinez , Stéfanie Graindorge , Schallenberg-Rüdinger Mareike , Hammani Kamel 
Published: September 2024

ABSTRACTIn plant mitochondria and chloroplasts, cytidine-to-uridine RNA editing plays a crucial role in regulating gene expression. While natural PLS-type PPR proteins are specialized in this process, synthetic PPR proteins offer significant potential for targeted RNA editing. In this study, we engineered chimeric editing factors by fusing synthetic P-type PPR guides with the DYW cytidine deaminase domain of a moss mitochondrial editing factor, PPR56. These designer PPR editors (dPPRe) elicited efficient and precisede novoRNA editing inEscherichia coli, and inNicotiana benthamianachloroplasts and mitochondria. Chloroplast transcriptome-wide analysis of the most efficient dPPRe revealed minimal off-target effects, with only three non-target C sites edited due to sequence similarity with the intended target. This study introduces a novel and precise method for RNA base editing in plant organelles, paving the way for new approaches in gene regulation applicable to plants and potentially other organisms.
Coexistence of bacteria with a competition-colonization tradeoff on a dynamic coral host
Authors: Gibbs Theo L. , Dahlin Kyle J.-M. , Brennan Joe , Silveira Cynthia B. , McManus Lisa C. 
Published: September 2024

AbstractMany macroscopic organisms enter into tightly linked symbiosis with microbial communities. Although experimental work has demonstrated the importance of these symbioses, a theoretical understanding of stable, multi-scale coexistence remains underdeveloped. Here, we explored how the competition-colonization tradeoff, a classic coexistence mechanism, operates when bacterial species compete for a dynamic biological host. Specifically, we introduce a model where corals are colonized by fast-growing mutualists and slow-growing pathogens. We found that the vital rates of the host coral influenced coexistence outcomes between bacterial types. Notably, pathogen-induced host death expanded the region of parameter space where coexistence was stable for all three species and mutualistic bacteria enabled coexistence in systems that would have otherwise collapsed. These findings provide new insights into the interplay between microbial interactions and macroscopic processes. Our work illustrates how host-microbe interactions can shape ecosystem stability, providing a theoretical framework applicable to a wide range of symbiotic systems.
Rapid adaptation to a globally introduced virulent pathogen in a keystone species
Authors: Cassin-Sackett Loren , Tsuchiya Mirian TN , Dikow Rebecca B. 
Published: September 2024

AbstractEmerging infectious diseases are one of the foremost contemporary threats to biodiversity conservation. Outbreaks of novel pathogens can lead to extinction of host populations, loss of gene flow due to extirpation, and bottlenecks in host populations with surviving individuals. In outbreaks with survivors, pathogens can exert strong selection on hosts, in some cases leading to the evolution of resistance or tolerance in the host population. The pathogen causing sylvatic plague,Yersinia pestis, was introduced to North America in the early 20thcentury and caused rapid population declines in prairie dogs (genusCynomys), which experience >95% mortality during epizootics. Recently, survival from plague has been documented in a small number of black-tailed prairie dogs (C. ludovicianus) in natural populations in Colorado (USA). We performed whole-genome sequencing on 7 individuals from 3 colonies that survived infection with plague and 7 individuals from the same colonies that likely died during a plague epizootic. Using genome-wide association tests, FSToutlier tests, and other inferences of selection, we detected SNPs on 5 scaffolds that were strongly associated with survivorship from plague in the wild. Some genes associated with these scaffolds also differ in humans that survived versus died in the plague pandemic in London, UK, suggesting conservation of gene function across taxonomically diverse lineages. Understanding the genetic basis of immunity can enable genetically-informed management actions such as targeted relocation to protect prairie dogs and the species that rely on them. More generally, understanding how rapid adaptation to pathogens occurs can help us predict the time frame and spatial scale at which adaptation may occur, during which other interventions are needed.Significance StatementEmerging infectious diseases are one of the foremost threats to global biodiversity, causing extinctions and population crashes on all continents. Introduced pathogens can exert strong selection on hosts for the evolution of tolerance or resistance, yet these evolutionary events are rare and it remains challenging to identify and sample both immune and susceptible individuals during an epizootic. This study leverages one of the only documented examples of prairie dogs surviving infection from introduced sylvatic plague in nature and compares their genomes to those of individuals that perished. We find strong signatures of selection in a small number of immune and non-immune genes, one of which has been implicated in survival from plague in humans. These findings suggest that adaptation to novel pathogens may occur via a combination of conserved genes and the co-opting of genes outside of classical immune pathways. Finally, it provides evidence that in native species with sufficient standing genetic variation, there is potential for adaptation to introduced pathogens.
Real-space heterogeneous reconstruction, refinement, and disentanglement of CryoEM conformational states with HetSIREN
Authors: Herreros D. , Mata C.P. , Noddings C. , Irene D. , Krieger J. , Agard D.A. , Tsai M.-D. , Sorzano C.O.S. , Carazo J.M. 
Published: September 2024

AbstractSingle-particle analysis by Cryo-electron microscopy (CryoEM) provides direct access to the conformation of each macromolecule. However, the image’s signal-to-noise ratio is low, and some form of classification is usually performed at the image processing level to allow structural modeling. Classical classification methods imply the existence of a discrete number of structural conformations. However, new heterogeneity algorithms introduce a novel reconstruction paradigm, where every state is represented by a lower number of particles, potentially just one, allowing the estimation of conformational landscapes representing the different structural states a biomolecule explores. In this work, we present a novel deep learning-based method called HetSIREN. HetSIREN can fully reconstruct or refine a CryoEM volume in real space based on the structural information summarized in a conformational latent space. The unique characteristics that set HetSIREN apart start with the definition of the approach as a real space-based only method, a fact that allows spatially focused analysis, but also the introduction of a novel network architecture specifically designed to make use of meta-sinusoidal activations, with proven high analytics capacities. Continuing with innovations, HetSIREN can also refine the pose parameters of the images at the same time that it conditions the network with prior information/constraints on the maps, such as Total Variation andL1denoising, ultimately yielding cleaner volumes with high-quality structural features. Finally, but very importantly, HetSIREN addresses one of the most confusing issues in heterogeneity analysis, as it is the fact that real structural heterogeneity estimation is entangled with pose estimation (and to a lesser extent with CTF estimation), in this way, HetSIREN introduces a novel encoding architecture able to decouple pose and CTF information from the conformational landscape, resulting in more accurate and interpretable conformational latent spaces. We present results on computer-simulated data, public data from EMPIAR, and data from experimental systems currently being studied in our laboratories. An important finding is the sensitivity of the structure and dynamics of the SARS-CoV-2 Spike protein on the storage temperature.
Successful stimulation of myocardial ganglionic plexuses by TAU 20 in the absence of cardiac damage
Authors: Li Shengzhe , Kay Jamie A , Agha-Jaffar Danya , Gao Cindy S Y , Perkins Justin , Koutsoftidis Simos , Drakakis Emm Mic , Cantwell Chris , Wang Liliang , Kanagaratnam Prapa , Chowdhury Rasheda A 
Published: September 2024

ABSTRACTAtrial fibrillation (AF) is a major healthcare burden worldwide. For AF that is resistant to pharmacological intervention, the standard invasive treatment is a pulmonary vein isolation (PVI) procedure. Ganglionated plexuses (GP) ablation can be used as an adjunctive therapy to PVIs, together reducing the likelihood of AF recurrence. High-frequency stimulation (HFS) is a technique used to identify ectopy-triggering GP sites. However, to locate GP sites, sequential HFS must be delivered over the whole atria. Therefore, ensuring the safety of HFS delivery is integral to avoid causing irreversible damage from excessive pacing. We tested Tau-20 version 2 neural simulator, a prototype of a novel electrophysiological pacing and recording system that has the potential to guide intracardiac AF treatments. Using anex vivoporcine Langendorff model that closely resembles the anatomy and physiology of a human heart, we confirmed that HFS can successfully trigger AF, indicating that HFS-positive locations contain GP sites. Additionally, we found that the HFS delivered via Tau-20 version 2 did not cause any damage to the heart. These findings evidence that once fully optimised, the Tau-20 system could be suitable for use in clinical settings.
Humatch - fast, gene-specific joint humanisation of antibody heavy and light chains
Authors: Chinery Lewis , Jeliazkov Jeliazko R. , Deane Charlotte M. 
Published: September 2024

1AbstractAntibodies are a popular and powerful class of therapeutic due to their ability to exhibit high affinity and specificity to target proteins. However, the majority of antibody therapeutics are not genetically human, with initial therapeutic designs typically obtained from animal models. Humanisation of these precursors is essential to reduce immunogenic risks when administered to humans.Here, we present Humatch, a computational tool designed to offer experimental-like joint humanisation of heavy and light chains in seconds. Humatch consists of three lightweight Convolutional Neural Networks (CNNs) trained to identify human heavy V-genes, light V-genes, and well-paired antibody sequences with near-perfect accuracy. We show that these CNNs, alongside germline similarity, can be used for fast humanisation that aligns well with known experimental data. Throughout the humanisation process, a sequence is guided towards a specific target gene and away from others via multiclass CNN outputs and gene-specific germline data. This guidance ensures final humanised designs do not sit ‘between’ genes, a trait that is not naturally observed. Humatch’s optimisation towards specific genes and good VH/VL pairing increases the chances that final designs will be stable and express well and reduces the chances of immunogenic epitopes forming between the two chains. Humatch’s training data and source code are provided open-source.AvailabilitySource code is freely available at github.com/oxpig/Humatch. Data can be found at doi.org/10.5281/zenodo.13764770Contactdeane@stats.ox.ac.ukSupplementary informationSupplementary data are available atbioRxivonline.
A PROXIMITY LIGATION SCREEN IDENTIFIES SNAT2 AS A NOVEL TARGET OF THE MARCH1 E3 UBIQUITIN LIGASE
Authors: Balthazard Renaud , Mitchell William , Raymond Maxime , Vidal Arnau Ballestero , Roy Dominic G. , Zambrano Libia Cecilia Palma , Moulefera Mohamed Abdelwafi , Faubert Denis , Pasquin Sarah , Gauchat Jean-François , Thibodeau Jacques 
Published: September 2024

ABSTRACTE3 ubiquitin ligases are part of various families of proteins and include hundreds of members, which play key roles in all aspects of cell biology. They generally regulate the half-life of other proteins but can also modulate their cellular localization and functions. The MARCH family of ubiquitin ligases is composed of 11 members and two closely related proteins, MARCH1 and MARCH8, share similar targets, while being active in different cell types. Although they appear to target principally immune cell components, such as MHC class II molecules and the co-stimulatory molecule CD86, the repertory of their targets remains to be fully documented. Here, to further define the MARCH1’s interactome, we adapted a proximity-dependent biotin identification (BioID)-based screening approach in live HEK293 cells. We transfected a fusion protein consisting of mouse MARCH1 linked to YFP at its N-terminus and to the biotin ligase ofAquifex aeolicusat its C-terminus. Upon transient overexpression of this construct in the presence of exogenous biotin, we could recover biotinylated proteins that are presumably found within 10nm of MARCH1. To help in the identification ofbona fidedown-regulated specific targets, we compared MARCH1’s interactome with the one obtained using a ubiquitination-deficient MARCH1 mutant (MARCH1W104A). CD98 and CD71, two previously described targets of MARCH1, were identified in this screen. Of 16 other biotinylated proteins identified by semi-quantitative mass spectrometry, 10 were tested directly by flow cytometry to monitor their expression in the presence or absence of transfected MARCH1. The protein levels of five of these endogenous targets, CD29, CD112, NKCC1, CD147 and SNAT2, confirmed their negative regulation by MARCH1 in this system. SNAT2 was particularly sensitive to the presence of MARCH1 and was found to be ubiquitinated on Western blots following immunoprecipitation. Thus, BioID2 is an effective mean of characterizing the interactome of MARCH1 and the identification of SNAT2 suggests a role of this ubiquitin ligase in cellular metabolism.
Structure-guided assembly of an influenza spike nanobicelle vaccine provides pan H1 intranasal protection
Authors: Myers Mallory L. , Gallagher John R. , Woolfork De’Marcus D. , Khorrami Noah D. , Park William B. , Maldonado-Puga Samantha , Bohrnsen Eric , Schwarz Benjamin H. , Alves Derron A. , Bock Kevin W. , Dearborn Altaira D. , Harris Audray K. 
Published: September 2024

AbstractDevelopment of intranasal vaccines for respiratory viruses has gained popularity. However, currently only a live-attenuated influenza vaccine is FDA-approved for intranasal administration. Here, we focused on influenza virus as it circulates seasonally, has pandemic potential, and has vaccine formulations that present hemagglutinin (HA) in different structural arrangements. These display differences have not been correlated with induction of pan-H1 antibodies or shown to provide intranasal protection. Using electron microscopy, biochemistry and animal studies, we identified HA complexes arranged as lipid discs with multiple trimeric HAs displayed along the perimeter, termed spike nanobicelles (SNB). We utilized a structure-guided approach to synthesize in vitro assembled spiked nanobicelles (IA-SNB) from a classical 1934 H1N1 influenza virus. IA-SNBs elicited pan-H1 antibodies and provided protection against antigenically divergent H1N1 viruses via intranasal immunizations. Viral glycoprotein spikes displayed as SNBs could aid in combating antigenic variation and provide innovative intranasal vaccines to aid universal influenza vaccine development.
From the Ground Up: Stakeholder Perspectives on Housing Interventions to Reduce Environmentally Mediated Infections
Authors: Acklin Matthias , Graham Jay P. , Benjamin-Chung Jade 
Published: September 2024

AbstractBackgroundHousing conditions are intrinsically linked to human health, with inadequate housing potentially increasing exposure to environmentally mediated pathogens. Housing interventions that aim to improve housing and reduce environmentally mediated infections, such as finished floors and housing upgrades for vector-borne diseases, remain relatively under-explored as health interventions. This study explored facilitators of and barriers to funding, implementing, and scaling up housing improvements as health interventions to reduce environmentally mediated infectious diseases.MethodsSixteen key informants (KIs) with direct experience in implementing or working within housing interventions and environmentally mediated infectious diseases in low- and middle-income countries were interviewed using a semi-structured interview format. KIs had diverse backgrounds, including academics researching housing interventions, housing policy advisors, and practitioners implementing housing interventions. A thematic analysis approach was used to identify key themes in interview transcripts, highlighting patterns, commonalities, and variations in participants’ responses.ResultsKIs emphasized the multi-dimensional impacts of housing interventions that are intrinsically linked to Sustainable Development Goals (SDGs), including physical and mental health, as well as environmental, social, and economic dimensions. Moreover, a pronounced shortage of funding and financial systems to address housing interventions was highlighted, alongside the urgent need for more rigorous evidence and cost-benefit analyses. Furthermore, the imperative to raise awareness of the significance of housing and the critical importance of strong collaboration across sectors and stakeholders were stressed. Emphasizing the necessity for project-based and context-specific housing policies, the interviews revealed that contextualizing interventions to their specific setting and fostering community involvement are essential for successful implementation and scale-up.ConclusionsHousing interventions play a pivotal role in mitigating environmentally mediated diseases. These interventions can complement existing strategies like water, sanitation, and hygiene (WASH) interventions, ensuring comprehensive approaches to healthy housing and sustainable development goals amidst climate change.
Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling
Authors: Piletic Klara , Kayvanjoo Amir H. , Richter Felix Clemens , Borsa Mariana , Lechuga-Vieco Ana V. , Popp Oliver , Grenet Sacha , Long Ko Jacky Ka , Zec Kristina , Kyriazi Maria , Koneva Lada , Sansom Stephen , Mertins Philipp , Powrie Fiona , Alsaleh Ghada , Simon Anna Katharina 
Published: September 2024

ABSTRACTA hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Here, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy regulates purine nucleoside metabolism in obese adipocytes, preventing excessive release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings reveal a novel role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.
WITHDRAWN: Strand dependent bypass of DNA lesions during fork reversal by ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF
Authors: Adolph Madison B. , Warren Garrett M. , Couch Frank B. , Greer Briana H. , Eichman Brandt F. , Cortez David 
Published: September 2024

Withdrawal StatementThe authors have withdrawn this manuscript because they identified problems with how some figure panels were processed. Those experiments will be repeated before deposition of a new manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors.