bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges in Estimating Time-Varying Epidemic Severity Rates from Aggregate Data
Authors: Goldwasser Jeremy , Hu Addison J. , Bilinski Alyssa , McDonald Daniel J. , Tibshirani Ryan J. 
Published: January 2025

AbstractSeverity rates like the case-fatality rate and infection-fatality rate are key metrics in public health. To guide decision-making in response to changes like new variants or vaccines, it is imperative to understand how these rates shift in real time. In practice, time-varying severity rates are typically estimated using a ratio of aggregate counts. We demonstrate that these estimators are capable of exhibiting large statistical biases, with concerning implications for public health practice, as they may fail to detect heightened risks or falsely signal nonexistent surges. We supplement our mathematical analyses with experimental results on real and simulated COVID-19 data. Finally, we briefly discuss strategies to mitigate this bias, drawing connections with effective reproduction number (Rt) estimation.
Prognostic impact of E-wave and A-wave overlap after atrial fibrillation ablation
Authors: Saito Jumpei , Daiki Kato , Hirotoshi Sato , Matsuda Toshihiko , Koyanagi Yui , Yoshihiro Katsuya , Gibo Yuma , Shigehiro Ishigaki , Usumoto Soichiro , Kimura Taro , Shimazu Suguru , Igawa Wataru , Ebara Seitaro , Okabe Toshitaka , Isomura Naoei , Ochiai Masahiko 
Published: January 2025

AbstractBackgroundIn adult patients with systolic heart failure, the presence of adjacent, nonoverlapping E and A waves on Doppler echocardiography is associated with optimal cardiac output and favorable clinical outcomes. However, the clinical significance of echocardiographic overlap in patients with atrial fibrillation (AF) remains uncertain. This study aimed to explore the relationship between E-wave and A-wave overlap, assessed the day after catheter ablation, and the recurrence of atrial arrhythmias (AR) following AF ablation.MethodsPatients with AF who underwent first-time arrhythmia ablation were included in this study. Transthoracic echocardiography was performed on the day following catheter ablation to evaluate the presence of E- and A-wave overlap. The relationship between overlap length and recurrence of AR after AF ablation was analyzed.ResultsThe study included 175 patients (124 males; mean age: 68 years [range 52–79]; mean CHA2DS2-Vasc score: 2 [range 0–4]; and 93 with paroxysmal AF) who underwent AF ablation. There were no significant differences between the two groups in terms of heart failure history or echocardiographic parameters prior to catheter ablation. However, the absolute overlap length was significantly prolonged in the AR group (59 ms [range 9–160] vs. 120 ms [range 28.6–226]; P < .001). Furthermore, the rate of AR was significantly lower in the group without prolonged overlap length (HR, 0.15 [95% CI, 0.07–0.30]; P < .001). These findings were consistent across all AF types.ConclusionsThe length of E-wave and A-wave overlap appears to be a significant predictor of AR following AF ablation.
Personalized electric field simulations of deformable large TMS coils based on automatic position and shape optimization
Authors: Worbs Torge , Rumi Bianka , Madsen Kristoffer H. , Thielscher Axel 
Published: January 2025

AbstractBackgroundTranscranial Magnetic Stimulation (TMS) therapies use both focal and unfocal coil designs. Unfocal designs often employ bendable windings and moveable parts, making realistic simulations of their electric fields in inter-individually varying head sizes and shapes challenging. This hampers comparisons of the various coil designs and prevents systematic evaluations of their dose-response relationships.ObjectiveIntroduce and validate a novel method for optimizing the position and shape of flexible coils taking individual head anatomies into account. Evaluate the impact of realistic modeling of flexible coils on the electric field simulated in the brain.MethodsAccurate models of four coils (Brainsway H1, H4, H7; MagVenture MST-Twin) were derived from computed tomography data and mechanical measurements. A generic representation of coil deformations by concatenated linear transformations was introduced and validated. This served as basis for a principled approach to optimize the coil positions and shapes, and to optionally maximize the electric field strength in a region of interest (ROI).ResultsFor all four coil models, the new method achieved configurations that followed the scalp anatomy while robustly preventing coil-scalp intersections on N=1100 head models. In contrast, setting only the coil center positions without shape deformation regularly led to physically impossible configurations. This also affected the electric field calculated in the cortex, with a median peak difference of ∼16%. In addition, the new method outperformed grid search-based optimization for maximizing the electric field of a standard figure 8 coil in a ROI with a comparable computational complexity.ConclusionOur approach alleviates practical hurdles that so far hampered accurate simulations of bendable coils. This enables systematic comparison of dose-response relationships across the various coil designs employed in therapy.Highlightsautomatic positioning and shape optimization of large deformable TMS coilsensures adherence to the head anatomy and prevents coil-head intersectionsenable automatic electric field maximization in target brain regionsoutperforms grid search for standard flat coilsprovides accurate computational models of four coils used in clinical practice
Novel Glomeromycotina-Moss Associations Identified in California Dryland Biocrusts
Authors: Kelly Kian H. , Coleine Claudia , Coshland Chris , Stajich Jason E. 
Published: January 2025

AbstractDrylands, which comprise ~45% of Earth’s land area, host biological soil crusts (biocrusts)—symbiotic communities of cyanobacteria, fungi, algae, lichen, and bryophytes that stabilize soil and support key ecosystem functions. Moss dominated biocrusts in particular are interesting due to their potential to illuminate ancient bryophyte-fungal interactions, but their associated microbial communities remain poorly characterized. To test the hypothesis that mosses in biocrusts harbor specific fungal associates, we conducted amplicon metabarcoding and microscopic surveys employing fungal staining across an aridity gradient. We identified novel associations between mosses and arbuscular mycorrhizal fungi (AMF), with phylogenetic analyses revealing distinct fungal communities in moss biocrusts compared to adjacent bare soil. Intracellular branching by fungi resembling Glomeromycotina was observed within healthyTrichostomopsis australaceaecells, suggesting interactions beyond saprotrophy. Moreover, shifts in AMF community composition along an aridity gradient highlight the potential vulnerability of biocrust mycobiomes to climate change. These findings provide critical insights into ancient bryophyte-fungal symbioses, potentially analogous to those enabling early land plant colonization during the Ordovician (~470 Ma). They also underscore the need to understand and protect biocrust microbial communities as aridity intensifies under climate change.
LC-MS/MS characterization of SOBERANA®02, a receptor binding domain-tetanus toxoid conjugate vaccine against SARS-CoV-2
Authors: Martínez Olivia , Santana-Medero Darielys , Pousa Satomy , Soubal Jean Pierre , Rodríguez-Ulloa Arielis , Ramos-Bermúdez Pablo E. , Besada Vladimir , Garrido Raine , Carvalho Paulo , Batista Michel , Zetl Katharina , Wiśniewski Jacek , Boggiano Tamy , Valdés-Balbín Yury , García-Rivera Dagmar , Rivera Daniel G. , Verez-Bencomo Vicente , González Luis Javier 
Published: January 2025

AbstractSOBERANA®02 is a safe and effective conjugate vaccine against SARS-CoV-2, produced using the maleimide-thiol chemistry. In this vaccine, the Cys538in the recombinant receptor binding domain (RBD) of SARS-CoV-2 is linked, through a thiosuccinimide linker, to lysine residues of tetanus toxoid (TT) preparation. LC-MS/MS analysis revealed that TT is a complex mixture of proteins, similar to other TTs where the detoxified tetanus neurotoxin (d-TeNT) has been shown to be the most abundant protein (30-56%), regardless the quantification method used. The fifteen most abundant proteins account for approximately 78% of the total proteins. LC-MS/MS analysis of the activation process showed that 102 out of 107 lysine residues in the d-TeNT incorporated a maleimide group. In contrast, when tryptic peptides isolated by Ni2+-NTA affinity chromatography, were analyzed by LC-MS/MS, only 22 Lys residues in the d-TeNT were cross-linked to the RBDC-terminal tryptic peptide (538CVNF541-HHHHHH), probably due to steric hindrance. Twelve and eighteen conjugation sites were assigned based on the identification of linear peptides carrying a conjugated lysine residues (Δm = +1454.58 Da or Δm = +1472.59 Da) and cross-linked peptides with stabilized linker forms, respectively. Eight conjugation sites were coincidently assigned by both strategies. The assignment of the conjugation sites was manually validated by observed regularities (z≥3+, XIC, immonium ions, specific linker fragment ions) not considered by the identification software (PEAKS, Kojak and pLink2). The RBD was also conjugated, but to a lesser extent, to ten other low abundance carrier proteins. To our knowledge, this work is the first report of conjugation site assignment in a TT-based conjugate vaccine.
Green SynthesizedMagnolia albaSilver Nanoparticles Kill Pathogens, Inhibit Cancer, and Display Antioxidant and Photocatalytic Properties
Authors: De Mel Shaveen , Gruenler Juliana , Khoury Logan , Heynes Ashton , Frazekas Julianne , Damaske Kendra , Galbadage Thushara , Gunasekera Richard S. , Anderson Ross S. 
Published: January 2025

AbstractThe biosynthesis of silver nanoparticles has recently emerged as a promising approach in nanomedicine, particularly for targeted therapeutic applications. Green synthesized (plant-based) nanoparticles have been shown to offer enhanced reduction efficiency, greater bioavailability, and improved stability compared to synthetic nanoparticles. Here, we report the green synthesis of silver nanoparticles (AgNPs) usingMagnolia albaleaf extract. The formation of these Magnolia-derived silver nanoparticles (MAgNPs) was verified through UV-Vis spectroscopy and further characterized by scanning electron microscopy (SEM) which showed that the MAgNPs have a mean diameter of 40 nm and a spherical morphology. The antibacterial efficacy of MAgNPs, evaluated by the well diffusion method, showed significant activity againstE. coli,Klebsiella pneumoniae,Pseudomonas aeruginosa,Enterococcus faecalis,and strains of methicillin-resistant and -sensitiveStaphylococcus aureus.Disc diffusion and plaque assays demonstrated notable antifungal activity againstCandida albicansand antiviral activity against bacteriophage T7.In vitrostudies with HCT-116 human colon cancer cells, MAgNPs exhibited significant bi-phasic inhibition of cancer cell growth. These effects were greater than that of the magnolia leaf extracts alone, confirming the green synthesized nanoparticles’ bioactive efficacy. These findings suggest that MAgNPs possess significant antimicrobial and anticancer activities, indicating their potential as therapeutic agents for certain infections and cancers. Antioxidant assays indicated that MAgNPs exhibit greater antioxidant activity than magnolia leaf extract alone. Results suggest that MAgNPs may have promise as antioxidants for treating free radical-induced disorders. Additionally, MAgNPs showed efficient photocatalytic degradation of the azo bond in methyl orange within 30 minutes, suggesting they may provide a sustainable approach to certain types of environmental pollution. To our knowledge, this is the first report of the biosynthesis of silver nanoparticles usingMagnolia albaand examination of their antioxidant and photocatalytic properties, their killing and inhibitory effects on various bacteria, fungi, bacteriophages, and colon cancer.
An Automated and Portable Platform for Rapid Cell-Free DNA Isolation and Its Application in Microbial DNA Sequencing from Human Blood Samples
Authors: Marriott Linda , Martinez-Lopez Ana , Liga Antonio , Horiba Kazuhiro , Warr Amanda , Phulusa Jacob N. , Shantha Kumar Radhe , Carey Laura , Ito Yoshinori , Parcell Benjamin J. , Leslie Nicholas R. , Feasey Nicholas A. , Jacob Shevin T. , Rylance Jamie , Kersaudy-Kerhoas Maïwenn 
Published: January 2025

ABSTRACTBackgroundThe prompt identification of pathogens in human circulation in a clinically deployable format remains an unmet clinical need. The established test for infection diagnostics remains blood culture, which typically takes 2-4 days and is positive in less than 15% of cases, with many prevalent pathogens difficult or impossible to culture. While microbial cfDNA in blood could facilitate the diagnosis of sepsis and febrile and infectious conditions, sample preparation for cell-free DNA (cfDNA) analysis in decentralised settings presents challenges due to its complexity and the low concentration and fragmented nature of cfDNA in blood plasma.MethodsWe developed a portable and automated platform (CNASafe) for cfDNA isolation from human plasma samples. Device performance was evaluated by comparing cfDNA yield against a reference (QIAGEN QIAamp Circulating Nucleic Acid Kit). cfDNA eluates from ten non-cultured blood samples from hospital patients were sequenced on a nanopore sequencer, and results compared to blood cultures.ResultsExtraction of cfDNA using the CNASafe device was completed in 40 minutes, compared to the 2-hour reference protocol. The device achieved an average relative cfDNA recovery of 100.5% over 333 unique extractions encompassing all parameter variations, demonstrating a performance equivalent to the reference kit. From the patient samples, a sufficient quantity of microbial cfDNA was extracted to either identify pathogens missed by blood cultures or confirm negative cultures.ConclusionsThe CNASafe platform and real-time nanopore sequencing offer a promising solution for the rapid deployment of metagenomic diagnostics, enabling pathogen identification within a few hours in decentralised clinical environments.
Transcriptomic analysis reveals vector attraction to potato virus Y is mediated through temporal regulation ofTERPENE SYNTHASE 1(TPS1)
Authors: Nihranz Chad T. , Garg Prakriti , Shin Junha , Dumas Madeleine , McCalla Sunnie Grace , Roy Sushmita , Casteel Clare L. 
Published: January 2025

AbstractVirus-plant dynamics change over time, influencing interactions between plants and insect vectors. However, the signaling pathways and regulators that control these temporal responses remain largely unknown. In this study, we used insect performance and preference bioassays, RNA-Seq, and genetic tools to identify underlying mechanisms mediating temporal variation in plant-virus-vector interactions. We show that settlement and fecundity of the aphid vector,Myzus persicae, is increased on potato virus Y (PVY)-infectedNicotiana benthamianaplants two weeks after inoculation but not after six weeks. RNA-Seg analysis revealed transcripts related to plant defense and amino acid biosynthesis are upregulated in response to PVY infection and down regulated in response to aphid herbivory, and these patterns changed over time. Based on this analysis we identified a sesquiterpene synthase gene, terpene synthase 1 (NbTPS1), that is upregulated early in PVY infection, but not at later infection time points. Using virus-induced gene silencing and transient overexpression inN. benthamianawe demonstrate that PVY induction ofNbTPS1is required for increased aphid attraction to PVY-infected plants in the early stages of infection. Taken together, PVY temporally regulates transcriptional pathways related to plant defense responses and volatile organic compounds that influence aphid vector performance and preference.
A 3D-printed cradle for mouse preclinical MRI with an integrated water heating system
Authors: Gaudin Romain , Bernard Jeremy , Glatigny Melissa , Boido Davide 
Published: January 2025

AbstractFunctional Magnetic Resonance Imaging (fMRI) of small animals is mainly performed under sedation or anesthesia to avoid movement, which is detrimental to image quality. Heating systems to warm the animals usually rely on airflow or heating blankets or pads with circulating water to comply with MR compatibility requirements. However, these solutions are often suboptimal for small animals like mice scanned at ultra-high magnetic fields with long-bore MR scanners. We designed and built an MR cradle with an integrated water chamber, maximizing the contact surface with the mouse’s body.This large contact surface helps maintain body temperature without overheating the animal, thus reducing the risk of burns and hyperthermia. Our cradle keeps the mouse’s body temperature stable within the physiological range during an MRI session and fits the bore of a Bruker 17.2T scanner. We share the 3D drawings and all the information needed to replicate the cradle. Our design can be adapted to work on preclinical scanners with similar bore sizes and customized to add stimulation devices.
Gene Conversion Directed Successive Engineering of Modular Polyketide Synthases
Authors: Jin Wenzheng , Tu Jiaming , Zhang Bei , Wu Xuri , Chen Yijun 
Published: January 2025

AbstractModular polyketide synthases (PKSs) can produce various secondary metabolites in a collinearity fashion. Although rational engineering of modular PKS can ultimately create a diverse array of novel compounds,de novogeneration of defined structures usually results in the loss or remarkable decline of productivity due primarily to the incompatibility of different elements. Here, we present a modular PKS engineering strategy driven by an evolutionary event of gene conversion to accomplish successive engineering of the modular PKS in cinnamomycin biosynthetic gene cluster (cmmBGC). By simulating the gene conversion process,cmmBGC is consecutively reprogrammed to generate a novel macrolide with predicted structural features. Moreover, in contrast to previous notion, the intra-module KS domain is demonstrated to associate with the selectivity of extender units. Collectively, the coordination between evolutionary consequence and functional manipulation of assembly line may shed a new light on modular PKS engineering.Graphical AbstractGene conversion process, typically occurred in KS (purple squares) and AT (blue squares), plays an integral role of structural diversity of polyketides. In this study, an unusual gene conversion was observed incmmBGC. Subsequently, a homologous BGC was obtained through genome mining by a gene conversion-associated KS domain. Under the direction of gene conversion, the modular PKS incmmBGC was successively reprogrammed, resulting inde novobiosynthesis of a new-to-nature polyketide.
Structural basis of phosphate export by human XPR1
Authors: Wang Yifei , Wang Yuechan , Yang Hui , Li Ao , Ma Dan , Shen Huaizong 
Published: January 2025

AbstractPhosphate is essential for all life forms because of its indispensable roles in energy metabolism, nucleic acid and phospholipid synthesis, cellular signaling, and the formation of bones and teeth. Its homeostasis is maintained through balanced import and export processes. In humans, XPR1 has been proposed as the sole phosphate exporter, although some controversy remains. Here, we report the closed and open structures of human XPR1, purified in the absence and presence of exogenous InsP6, respectively. The exporter forms a symmetric homodimer, with transmembrane helix (TM) 1 serving as the dimeric interface. The transmembrane domain of each protomer contains a transport module (TM5-10) and a supporting module (TM1-4). Compared to the closed XPR1, the open structure demonstrates a significant displacement of the extracellular portion of TM9 towards the periphery of the phosphate transport pathway, creating an open portal to the extracellular milieu. Additionally, a potential phosphate ion coordination site is strategically located in the middle of the transport pathway. On the intracellular side, the pathway entrance is obstructed by a cluster of residues, the C-plug, positioned on the carboxyl side of TM10. Consistently, the removal of the C-terminus significantly increases the transport activity of XPR1 in reconstituted liposomes. Our findings provide a comprehensive understanding of the export mechanism of human XPR1 and hold promise for the development of potential therapeutics for primary familial brain calcification and ovarian cancer.
Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms
Authors: Mallik Bhagaban , Frank C. Andrew 
Published: January 2025

SUMMARYNeurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunc-tional mitochondria trigger problems in various neuronal tasks. Using theDrosophilaneuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here we report tissue-specific ad-aptations at the NMJ when MCI is depleted. InDrosophilamotor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But in-stead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destruc-tive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmis-sion. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in theDrosophilasystem are potentially relevant to forms of mitochondrial pathogenesis.
Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control
Authors: Pérez María J. , Colombo Rocío B. , Real Sebastián M. , Branham María T. , Laurito Sergio R. , Moraes Carlos T. , Mayorga Lía 
Published: January 2025

ABSTRACTMitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy.Using cybrid models harboring two disease-causing mtDNA mutations—m.13513G>A and m.8344A>G—at varying heteroplasmy levels, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern to be critical for the survival of high-heteroplasmy cells but not for the low-heteroplasmy ones. Consequently, by disrupting this epigenetic programming with FDA approved DNA methylation inhibitors we managed to selectively impact high-heteroplasmy cybrids and reduce heteroplasmy. These findings were validated in both cultured cells and anin vivoxenograft model.Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.