bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial transcriptomics exploration of the primary neuroblastoma microenvironment unveils novel paracrine interactions
Authors: Siaw Joachim T. , Merseburger Peter , Borenäs Marcus , Jansson Caroline , Karlson Jenny , Claeys Arne , Jennische Eva , Lind Dan E. , Gisselsson Nord David , Palmer Ruth H. , Van den Eynden Jimmy
Published: January 2025

High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this gap, we profiled untreated and chemotherapy-treated high-risk neuroblastomas from 2 patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p-gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokineCCL18and its receptorPITPNM3was predicted between these cells and we experimentally demonstrated thatCCL18increases neuroblastoma cell migration. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical-like cells expressed the ALK ligandALKAL2and were predicted to communicate with neighboringALKexpressing cancer cells. We demonstrated a unique developmental pattern of adrenal medulla-specific expression ofALKand adrenocortical-specific expression ofALKAL2, suggesting a role of these signaling interactions in neuroblastoma carcinogenesis.
Role of the NHE1 exchanger in the antitumor effects of copper(II) complexes and phenanthroline derivatives
Authors: Muñoz Garzón K.S. , Martínez V. , de Giusti V. , Pérez Visñuk D. , Villaverde M. , Alvarez N. , Facchin G. , Di Virgilio A.L.
Published: January 2025

Three copper(II) complexes containing 1,10-phenanthroline ([CuCl2(phen)]·4H2O,1), neocuproine ([CuCl2(neo)]·4H2O,2) and tetramethyl-phenanthroline ([CuCl2(tmp)]·4H2O,3) as the primary ligand and another three copper(II) complexes with the L-Ala-Phe dipeptide as an auxiliary ligand: [Cu(L-Ala-Phe)(phen)]·4H2O (4), [Cu(L-Ala-Phe)(neo)]·4H2O (5) and [Cu(L-Ala-Phe)(tmp)]·4H2O (6), inhibited cell viability in breast cancer MCF-7 cell line, both in the monolayer and spheroid cell culture models. The pair with tetramethyl-phenanthroline displayed a better selectivity index than cisPt and non-cytotoxicity-related ROS induction and apoptosis in the monolayer breast cancer model. Cell proliferation was affected by all compounds in a concentration-dependent manner, with a more substantial effect on the tetramethyl-phenanthroline complexes. Cell viability on multicellular spheroids showed a concentration-dependent reduction from 1 μM, with IC50that were half the one for cisplatin. All copper complexes, except for1showed DNA damage, demonstrated by the comet assay at a concentration below the IC50. The role of NHE1 has been linked to many types of cancers. Our study revealed that all compounds inhibited NHE1 activity in MCF-7 cells. However, only complexes containing the dipeptide auxiliary ligand could extend their effect on cell migration (Wound Healing Assay) and MMP-9 activity studied by zimography. Wester Blot analysis showed that expressions of MMP-2, MMP-9, and NHE1 were affected when MCF7 cells were treated with the six compounds as well. Overall, our results reveal an antitumor effect of all copper(II) complexes studied in breast cancer cells and a fundamental role of NHE1 in cell migration.
Decreased BOLD signal variability in middle-aged and older adults on the Autism Spectrum
Authors: Pedrahita Stephanie , Linke Annika , Cordova Michaela , Wilkinson Molly , Hau Janice , Toro Gioia , Alemu Kalekirstos , Kohli Jiwandeep , Müller Ralph-Axel , Carper Ruth
Published: January 2025

Purpose

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder. Preliminary evidence suggests an increased risk for accelerated or early-onset cognitive and neurological decline in ASD. While it is well established that brain development in children, adolescents and young adults with ASD diverges from neurotypical (NT) peers, it is unknown how brain function is impacted in older adults with ASD. Understanding age-related changes of brain function in ASD is crucial to establish best practices for cognitive and health screenings in adults with ASD and develop interventions that might reduce the risk of accelerated decline. Decreases in blood-oxygenation-level-dependent (BOLD) signal variability (BSV) in typical aging have been shown across multiple studies, likely reflecting declining Gamma-Aminobutyric Acid (GABA) activity, and is associated with poorer cognitive performance. We hypothesized that adults with ASD would show reduced BSV compared to the NT group, with steeper negative age associations in the ASD than NT group.

Methods

The study assessed BSV in a cohort of adults (40-70 years), 28 with ASD and 39 age-matched NT. General linear models tested for main effects of diagnostic group (ASD, NT), age and group-by-age interactions (controlling for RMSD).

Limitations

Our cross-sectional data and small sample size highlight the need for longitudinal analyses in larger cohorts, alongside exploring links to cognitive function. Additionally, psychotropic medications used by our cohort of adults on the autism spectrum may have affected BSV.

Results

Significant group-by-age interactions were observed for the right insular, left temporal occipital fusiform, right frontal orbital and right inferior lateral occipital cortex, with BSV showing strong negative associations with age in the ASD but not NT group.

Conclusion

These findings suggest that BSV decreases may occur earlier in adults on the autism spectrum compared to their neurotypical peers, possibly indicating accelerated aging. However, given limited prior research, additional longitudinal analyses will be necessary to determine if the results presented truly reflect accelerated aging or arise from lifelong persistent differences in brain function.
Analysis of plasma DNA fragmentation patterns from dried blood spots
Authors: Stephens Michelle D. , Dietmann Elise C. , McDonald Bradon R. , Nkadori Everlyne N. , Zafar Syed Nabeel , McGregor Stephanie M. , Murtaza Muhammed
Published: January 2025

Circulating tumor DNA analysis holds promise for early detection of cancer. However, costs and complexity of genomic methods, and logistical requirements for blood collection and processing limit large scale implementation. Here, we evaluated the feasibility of genome-wide analysis of fragmentation patterns in plasma DNA obtained from dried blood spots (DBS). Across 75 individuals including 25 patients with cancer, we prepared conventional DBS, and plasma-separating DBS (psDBS) from whole blood samples, prior to plasma separation. In paired comparisons of plasma DNA between psDBS and blood tubes, we observed correlated concentrations, similar distributions of fragment lengths, correlated genome-wide fragmentation features, and equivalent performance of machine learning algorithms for cancer detection. Our results provide proof-of-principle that plasma DNA fragmentation analysis can be performed from small amounts of DNA obtained from psDBS. With further development and validation, this approach can expand the reach and impact of blood-based early cancer detection, particularly for resource constrained environments such as low- and middle-income countries and rural healthcare systems.
Arabidopsis EID1 E3 ubiquitin ligase regulates acquired thermotolerance by modulating HSBP translocation
Authors: Tu Yi-Tsung , Yen Ting-Chen , Chuo Guan-Lin , Wu Zhi-Qing , Jinn Tsung-Luo , Lee Chin-Mei
Published: January 2025

Climate change is causing a rapid increase in global average temperatures and more frequent heatwaves, posing serious threats to agricultural production and global biodiversity. In response to heat stress (HS), plants can develop acquired thermotolerance (AT) by initiating a heat shock response (HSR) after mild HS priming, thereby enhancing their ability to withstand subsequent later lethal HS events. Central to this process are the HEAT SHOCK FACTORs (HSFs), which form trimeric complexes and activate the expression ofHEAT SHOCK PROTEINs (HSPs) and otherHSFsto maintain proper protein and cellular functionality. After heat stress subsides, the HSFs’ activities can be modulated to attenuate the negative effects of HSR during the heat. The SHOCK FACTOR BINDING PROTEIN (HSBP) is a conserved microprotein that plays a prominent role in modulating HSF activities. HSBP can translocate from the cytoplasm into the nucleus during heat stress to directly interact with HSFs and prevent the formation of HSF timers. However, the mechanism that regulates the HSBP cytoplasmic-nuclear shuttling remains unclear. Here, we identified an F-box E3 ubiquitin ligase, EMPFINDLICHER IM DUNKELROTEN LICHT 1 (EID1), whose mutant form shows reduced thermotolerance in AT. We showed that EID1 interacts with HSBP to modulate HSBP cytoplasm-nuclear localization during heat stress, possibly through modulating the K41 of HSBP. The decreased thermotolerance in theeid1mutant can be explained by alterations of someHSPsexpression caused by the mis-localization of HSBP. This finding provided a novel example of E3 ubiquitin-mediated regulation of heat stress in plants.
Clinical Profile of Vascular Behcet’s Disease Patients Over a 30-year Period: Insights from an Iranian Retrospective Cohort Study
Authors: Shadmanfar Soraya , Jazi Kimia , Faezi Seyedeh Tahereh , Akhlaghi Masoumeh , Kelarestaghi Hamidreza , Moghadam Zeynab Rastegar , Davatchi Fereydoun , Alavi Seyed Mojtaba , Masoumi Maryam
Published: January 2025

Vascular manifestations are rare and cause morbidity and mortality in patients with Behçet’s disease (BD). Owing to the lack of evidence, we aimed to retrospectively evaluate the clinical features and associated risk factors of vascular BD. This retrospective cohort study was conducted at the Rheumatology Research Center, Tehran, Iran, from 1982 to 2018. The demographics, laboratory results, severity at diagnosis, diagnosis interval, and clinical manifestations divided into major events as well as sub-events at each visit were recorded. Of 57 patients, 43 (75.44%) were male, with an M:F ratio of 3.07. The mean age at onset was 32.00 ± 8.05 years. The three major clinical events repeated during the study period were mucocutaneous (41.30%), ocular (17%), and vascular (16.8%). DVT (33.3 %), SVT (21.84 %), and thrombosis of the large vein extremities (17.24 %) were the most common vascular events. The presence of HLA-B51 was found to have a statistically significant impact on the distinct number of events (B=-0.39, 95% CI: -0.74, -0.03, p=0.039). Severity at diagnosis (Moderate Vs. mild and Severe Vs. mild) were found to be statistically significant predictors of the logarithm of distinct number of events (B=-0.68, 95% CI: -1.13, -0.24, p=0.004; B=-0.51, 95% CI: -0.93, -0.10, p=0.020). The odds of developing vasculitis decreased faster in patients with a family history of OA than in those without a family history of OA. The other variables were not found to have a statistically significant impact on the logarithm of distinct number of events. A family history of OA, HLA- B51 positivity, and disease severity at diagnosis were associated with the occurrence of vascular BD. Further longitudinal and large-sample size studies should be conducted to evaluate the risk factors for vascular events.
Nematode-Trapping FungusArthrobotrys oligosporais Hungry for COQ7 to Alleviate Environmentally Triggered Iron Overload
Authors: Wu Qunfu , Zhou Jiao , Wang Donglou , Xue Songhan , Li Ling , Wu Li , Yan Junxian , Niu Xuemei
Published: January 2025

Choosing the right and appropriate amount of substances in a changing environment is essential for the growth and survival of all species. We found that elevated oxygen levels significantly enhanced the iron-rich trapping devices of a nematode-trapping fungus (NTF),Arthrobotrys oligospora. Interestingly, genomic analysis revealed that all NTFs lackedcoq7, a key gene involved in ubiquinol (UQ) biosynthesis and iron chelation. Notably,A. oligosporautilizes UQ instead of UQ for low-aerobic respiration. Transcriptional, metabolic, mutational, and phenotypic analyses revealed thatA. oligosporaproduces a chemotaxonomic class of highly oxygenated arthrobotrins with characteristics similar to UQ skeleton, for high-aerobic respiration. Disruption of arthrobotrin biosynthesis in the Δartmutant not only enhanced UQ biosynthesis, but also triggered trapping device formation and nematicidal activity under elevated oxygen conditions. The addition of UQ to both wild-type and Δartmutants strongly inhibited trapping device development. Remarkably, the iron-rich trapping devices preferentially capture N2 nematodes harboring iron-chelating COQ7 with ferritin properties. Time-calibrated evolutionary analyses, combined with geological data, indicated that the NTF ancestor lost thecoq7gene after acquiring the arthrobotrin biosynthetic gene cluster during the "superoligotrophy" period, characterized by dramatic shifts in global oxygen levels and temperature changes. Our results demonstrate that oxygen is a critical factor in inducing iron overload, highlighting the origin and role ofcoq7loss in the evolution of predatory behavior of NTFs. Our finding that NTFs capture nematodes for iron chelation therapy, rather than for food, explains a long standing debate about the limited carnivorous ability of trapping devices.
Anatomy-to-Tract Mapping: Inferring White Matter Pathways Without Diffusion Streamline Propagation
Authors: Tan Yee-Fan , Liu Siyuan , Huynh Khoi Minh , Phan Raphaël C.-W. , Ting Chee-Ming , Yap Pew-Thian
Published: January 2025

Diffusion tractography, a cornerstone of white matter mapping, relies on point-to-point stream-line propagation—a process often compromised by errors stemming from inadequate signal-to-noise ratio and limited spatial-angular resolution in diffusion MRI (dMRI) data. Here, we present Anatomy-to-Tract Mapping (ATM), a novel deep learning framework that, for the first time, generates complete, bundle-specific streamlines directly from anatomical MRI, entirely bypassing the limitations of streamline propagation. ATM leverages the superior quality and minimal distortion of anatomical MRI, learning from multi-subject datasets to deliver robust, subject-specific streamline bundles while accurately preserving structural connectivity. This paradigm-shifting approach overcomes challenges associated with complex configurations, such as crossing, kissing, bending, and bottlenecks, providing anatomically precise reconstructions. Beyond individual-level mapping, ATM facilitates the creation of population-level streamline bundles aligned to average anatomical templates derived from diverse datasets. By offering global connectivity insights less affected by local uncertainties, ATM complements diffusion tractography, advancing white matter pathway reconstruction with a more reliable, anatomy-driven perspective.
Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms
Authors: Papale Andrea , Segueni Julie , Maroufi Hanae El , Noordermeer Daan , Holcman David
Published: January 2025

Topologically Associating Domains (TADs) are sub-Megabase regions in vertebrate genomes with enriched intra-domain interactions that restrict enhancer-promoter contacts across their boundaries. However, the mechanisms that separate TADs remain incompletely understood. Most boundaries between TADs contain CTCF binding sites (CBSs), which individually contribute to the blocking of Cohesin-mediated loop extrusion. Using genome-wide classification, we show here that TAD boundary width forms a continuum from narrow to highly extended and correlates with CBS distribution, chromatin features, and gene regulatory elements. To investigate how these boundary widths emerge, we modified the Random Cross-Linker (RCL) polymer model to incorporate specific boundary configurations, enabling us to evaluate the differential impact of boundary composition on TAD insulation. Our analysis identifies three generic boundary categories, each influencing TAD insulation differently, with varying local and distal effects on neighboring domains. Notably, we find that increasing boundary width reduces long-range inter-TAD contacts, as confirmed by Hi-C data. While blocking loop extrusion at boundaries indirectly promotes spurious intermingling of neighboring TADs, extended boundaries counteract this effect, emphasizing their role in maintaining genome structure. In conclusion, TAD boundary width not only enhances the efficiency of loop extrusion blocking but may also modulate enhancer-promoter contacts over long distances across TADs boundaries, providing a mechanism for transcriptional regulation.

Significance statement

Topologically Associating Domains (TADs) compartmentalize vertebrate genomes to limit cross-domain enhancer-promoter loops. Our study reveals that boundaries between TADs are diverse genomic entities that range from narrow to highly extended. Using an interdisciplinary approach that combines genome-wide data analysis with biophysical polymer modeling, we find that wider TAD boundaries reduce spurious long-range interactions between neighboring domains. Moreover, we reveal how different boundary components can create this difference in insulating capacity. Our identification and characterization of TAD boundary width and composition suggests they have the potential to regulate the formation of enhancer-promoter loops across TAD boundaries at close and long distance.
Subtyping of Type 2 Diabetes from a large Middle Eastern Biobank: Implications for Precision Medicine
Authors: Al-Thani Nayra M. , Zaghlool Shaza B , Abou-Samra Abdul Badi , Suhre Karsten , Albagha Omar M E
Published: January 2025

Background

Type 2 diabetes (T2D) can be classified into Severe Insulin-Deficient Diabetes (SIDD), Severe Insulin-Resistant Diabetes (SIRD), Mild Obesity-related Diabetes (MOD), and Mild Age-related Diabetes (MARD). This classification predicts disease complications and determines the best treatment for individuals. However, the classification’s applicability to non-European populations and sensitivity to confounding factors remain unclear.

Methods

We applied k-means clustering to a large Middle Eastern biobank cohort (Qatar Biobank; QBB, comprising 13,808 individuals; 2,687 with T2D). We evaluated the efficacy of the European cluster coordinates and analyzed the impact of using actual age on clustering outcomes. We examined sex differences, analyzed insulin treatment frequency, investigated the clustering of maturity-onset diabetes of the young (MODY), and evaluated the incidence of chronic kidney disease (CKD) among T2D subtypes.

Results

We identified the four T2D subtypes within a large Arab cohort. Data-derived centers outperformed European coordinates in classifying T2D. The use of actual age, as opposed to age of diagnosis, impacted MOD and MARD classification. Obesity prevalence was significantly higher in females, however, that did not translate to worse disease severity, as indicated by comparable levels of HbA1C and HOMA2-IR. Insulin was predominantly prescribed for individuals in SIDD and SIRD, which also displayed the highest risk of CKD, followed by MOD. Interestingly, most MODY individuals were clustered within MARD, further highlighting the need for precise classification and tailored interventions.

Conclusion

The observed sex differences underscore the importance of tailoring treatment plans for females compared to males. For SIDD and SIRD individuals, who are at a higher risk of CKD, insulin therapy requires closer monitoring and physician oversight. Additionally, in populations without access to genetic testing, likely MODY individuals can be identified within the MARD cluster. These findings strongly support the need for a transition to more personalized, data-driven treatment approaches to minimize diabetes-related complications and improve patient outcomes.
Epigenetic Age among U.S. Adults with Chronic Respiratory Diseases: Results from NHANES 1999-2002
Authors: Perez-Garcia Javier , Khodasevich Dennis , De Matteis Sara , Rice Mary B. , Needham Belinda L , Rehkopf David H , Cardenas Andres
Published: January 2025

Background

Chronic airway diseases are leading causes of mortality and morbidity worldwide. More evidence supports that lung aging can be reflected by changes in DNA methylation, which are relevant for lung diseases, given their ability to capture exposures over a lifetime.

Objective

We aimed to investigate the association and sex-specific associations of epigenetic age acceleration in whole blood with chronic respiratory diseases.

Methods

We analyzed public data from 2,402 adults from the National Health and Nutrition Examination Surveys (NHANES) 1999-2002 cycles. We examined the association between epigenetic age and respiratory traits using linear regression models corrected for age, age2, gender, race-ethnicity, survey cycles, and survey weights. Multiple comparisons were corrected using a false discovery rate <5%. We conducted stratified analyses by sex and sensitivity analyses adjusted by blood cell counts and clinical and socioeconomic status (SES) confounders.

Results

Individuals with wheezing showed accelerated epigenetic aging of up to 3.1 years (95% Confidence Interval [CI], 2.1, 4.1,p=8.4×10-6). Participants with COPD exhibited an epigenetic age acceleration potentially mediated by smoking, while those with emphysema showed epigenetic aging of up to 4.4 years (95% CI: 3.1, 5.8,p=3.4×10-6) independent of SES factors. Participants with early-onset COPD and those who ever have asthma showed suggestive accelerated biological aging (p<0.05). The accelerated pace of biological aging in COPD participants and the telomere length reduction in wheezing subjects were stronger in males than females.

Conclusion

Individuals with chronic respiratory diseases, such as wheezing, COPD, and asthma, have accelerated epigenetic aging in whole blood. Among COPD patients, those with emphysema might exhibit higher epigenetic age acceleration. These results suggest that different epigenetic clocks may capture aging mechanisms with sex-specific effects on chronic respiratory diseases.
Preventing premature deaths through polygenic risk scores
Authors: Chuong Melisa , Thompson Deborah , Weale Michael , Riveros-McKay Fernando , Samani Nilesh , Wells Daniel , Plagnol Vincent , McVean Gil , Ashley Euan A , Donnelly Peter , Harrison Seamus , O’Sullivan Jack W
Published: January 2025

Background

Polygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remain stable throughout life, we explore the potential of PRS to optimize existing screening programs.

Methods

Using UK Biobank (n = 444,949), we quantified the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs globally (breast cancer, prostate cancer, colorectal cancer, abdominal aortic aneurysm, type 2 diabetes, hypertension, and coronary artery disease). We identified individuals at high genetic risk (PRS OR>2) and very high genetic risk (PRS OR>3) and estimated the optimal screening ages for these genetically high risk individuals, based on the equivalent risk to population-level risk at recommended screening ages. We then leveraged published mortality estimates, with and without screening-based interventions, to assess the potential benefits of tailoring screening age based on genetic risk. We also estimated the case enrichment ratio, which is a ratio of the percentage of cases in the high PRS risk group and in the total population.

Findings

Very high risk individuals reach the risk level associated with usual starting screening age on average 10.8 years earlier, high risk individuals 8.9 years earlier and reduced risk individuals (OR<0.5) 16.8 years later. During this time, case enrichment in the high risk group is between 1.7 and 3.0 depending on disease. Across all seven diseases, appropriate interventions following PRS-guided screening would reduce premature deaths in high risk individuals by 19.0%.

Conclusion

Knowledge of genetic risk, measured using PRS, has the potential to deliver substantial public health benefits when aggregated across conditions, and could reduce premature mortality by tailoring existing screening programs.
Sugarcane carries relatively larger family of CAMTA transcription factors, active against drought stress
Authors: Costa da Silva Vitor Luciano , Matinez Ana Maria , Vincente Melissa Azevedo , Alam Maqsood , Noman Muhammad , Chalfun-Junior Antonio
Published: January 2025

As the highly demanding complex genome of the hybrid sugarcane cultivar became publicly available last year (2023), it opened avenues to further study this important crop at molecular level. We are interested in digging the multiple stress responsive transcription factors family, the Calmodulin-Binding Transcription Activator (CAMTA) of sugarcane. This manuscript presents a comprehensive study ofScCAMTAfamily based on the latest sugarcane genome sequence information. Within the 10 gb genome, through HMM model prepared from sorghum CAMTA common domains, we found 48 genes, 46 out of which carry all the CAMTA-associated domains including CG-1, TIG, IQ and Ank. The phylogenetic analysis clustered then into seven classes. Keeping sorghum as reference, we named them asScCAMTA1–ScCAMTA7, while each one representing a class having 5-7 copies such asScCAMTA1A–ScCAMTA1E, present in each sub-genome (chromosome) within the hybrid sugarcane. In parallel to determining their physico-chemical attributes, gene structure, promoter sequences, protein domains, miRNA targets, protein interaction network, GO, genome collinearity, their expression pattern against drought was determined using the RNAseq data which flaunted thatScCAMTA7is highly active under drought. This study furthers the insights into complex sugarcane genome and will assist in developing its drought-tolerant varieties.
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

Severity 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

Background

In 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.

Methods

Patients 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.

Results

The 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.

Conclusions

The 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

Background

Transcranial 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.

Objective

Introduce 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.

Methods

Accurate 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).

Results

For 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.

Conclusion

Our 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.

Highlights

automatic positioning and shape optimization of large deformable TMS coils

ensures adherence to the head anatomy and prevents coil-head intersections

enable automatic electric field maximization in target brain regions

outperforms grid search for standard flat coils

provides 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

Drylands, 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

SOBERANA®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

The 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

Background

The 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.

Methods

We 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.

Results

Extraction 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.

Conclusions

The 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

Virus-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

Functional 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

Modular 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 Abstract

Gene 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.
Symbiotic Bacterial Partners for Chemical Defense are Vertically Transmitted in a Marine Sponge
Authors: Fujita Masaki , Ise Yuji , Fukuoka Masashi , Kimura Nobutada , Ninomiya Akihiro , Yoshitake Kazutoshi , Matsunaga Shigeki , Sakai Ryuichi , Takada Kentaro
Published: January 2025

Marine sponges host diverse symbiotic bacteria, some of which are essential for chemical defense. However, the mechanisms governing the inheritance of these defensive symbionts remain elusive. Here we report the first case of a transmission mechanism for symbionts producing cytotoxins in the sponge Mycale nullarosette, for which we established the full life-cycle cultivation method. The identification of Candidatus Synechomycale tutelaris as the cytotoxins producer enabled us to unveil their vertical transmission to offspring via bacteriocyte-like structures from the embryonic stage. This study demonstrates that sponges have evolved a sophisticated system to ensure the inheritance of significant bacterial partners crucial for host defense, which is likely one of the reasons that sponges have survived throughout the long history of multicellular organisms.
Structural basis of phosphate export by human XPR1
Authors: Wang Yifei , Wang Yuechan , Yang Hui , Li Ao , Ma Dan , Shen Huaizong
Published: January 2025

Phosphate 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.