bluuebunny/crossref_metadata_2025 huggingface dataset:
Early-Onset Complete Atrioventricular Block – Prevalence, Etiology and Utilization of Cardiac Implantable Electronic Devices
Authors: Margolis Gilad , Chee Jennifer , Kazatsker Mark , Roguin Ariel , Madias Christopher , Homoud Munther , Kobo Ofer , Hamuda Nashed , Dimri Inon , Heist E.Kevin , Ruskin Jeremy N. , Leshem Eran , Rozen Guy
Published: March 2023

Background

Information regarding the prevalence and etiologies of complete atrioventricular block (CAVB) in younger patients is scarce. We aimed to investigate the potential causes for non-iatrogenic CAVB, the prevalence of CAVB without an identified etiology, the utilization of guidelines-recommended advanced imaging modalities in adults presenting with an early-onset CAVB of unidentified etiology, as well as to identify the predictors for cardiac implantable electronic device (CIED) insertion.

Methods

Using the National Inpatient Sample (NIS) database, we identified patients aged 18-60 hospitalized with non-iatrogenic CAVB in the US between 2015 (last quarter)-2019. Baseline demographics, clinical characteristics, potential etiologies for CAVB, advanced imaging utilization as well as outcomes including the need for temporary cardiac pacing (TCP) and CIED implantation were analyzed. Multivariable logistic regression models were used to identify predictors of CIED implantation.

Results

An estimated total of 14,495 patients aged 18-60 with non-iatrogenic CAVB were identified. The mean age was 51 years, 60% were males and 3,050 (21%) had documentation of a prior conduction disorder. Eleven percent of the patients had a diagnosis of syncope and 6% suffered from a cardiac arrest. Two third of the patients (9,735, 67%) had no identified etiology for CAVB, of whom 8,205 (84%) were implanted with a permanent pacemaker (PPM), 180 patients (2%) with an implantable cardioverter-defibrillator (ICD), and 295 patients (3%) with a cardiac resynchronization therapy device. Only 40 patients (0.3%) underwent advanced imaging during their hospitalization. In multivariate analyses, older age [adjusted OR 1.046 (1.04-1.05), p<0.001] and the need for TCP [adjusted OR 1.543 (1.29-1.84), p<0.001], emerged as predictors for PPM implantation. Cardiac arrest [adjusted OR 2.786 (1.69-4.58), p<0.001] and younger age [adjusted OR 0.98 (0.96-0.99), p=0.02], were associated with ICD implantation. 185 patients (1.3%) died during their hospitalization.

Conclusion

The majority of patients, hospitalized in the US for non-iatrogenic early-onset CAVB, had no identified etiology for their conduction disease. Despite the current US and European guidelines recommendation, advanced imaging prior to CIED implantation was under-utilized in this patient population.
The Effects of Medication Strategies on Cardiovascular Outcomes in Patients with Marfan Syndrome: A Consistency Model Analysis
Authors: Huang Sih-Huan , Lin Chin-Yi , Wu Mei-Hwan , Kang Yi-No , Hui-Chiu Hsin
Published: March 2023

BACKGROUND

Drug options for the treatment of Marfan syndrome (MFS) still warrant further investigation. Beta-blockers (BB) have long been considered the standard treatment, though several medications other than BB and angiotensin receptor blockers (ARB) have entered clinical practice and trials. However, no synthesis gathers evidence on medications other than BB or ARB. Therefore, this study aimed to investigate the effects and safety of medication strategies in managing MFS by synthesizing relevant randomized controlled trials (RCT).

METHODS

Three databases were searched for potential evidence using relevant keywords in both free-text and medical subject headings. Outcomes of interests were aortic root growth, aortic root Z score, aortic surgery, moderate-to-severe adverse events, cardiovascular and all-cause mortality. Quantitative data were pooled using frequentist-approach network meta-analysis in random-effects model.

RESULTS

Sixteen reports derived from 13 RCTs contributed to a seven-node consistency model including no treatment, BB, ARB, ARB+BB, calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEI), and combination of BB and renin inhibitor (RI). As compared with no treatment, RI+BB showed significant protection of aortic root growth (standardized mean difference [SMD]= -1.90, 95% confidence interval [CI]: -2.91, -0.89), followed by ARB+BB (SMD= -1.75, 95%CI: -2.40, -1.10). Nevertheless, no significant findings were seen in other clinical outcomes.

CONCLUSION

RI or ARB added on BB appear to be the optimal medication strategies to slow the progression of aortic root growth in MFS patients. However, we found no statistically significant difference in the risk of aortic surgeries, adverse effects, cardiovascular and all-cause mortality among medications. More RCTs with longer follow-up periods or bigger populations are needed to draw stronger evidence for clinical practices.
Factors associated with acceptance of COVID-19 vaccination among women in Guinea: Analysis of the first vaccination phase in March 2021
Authors: Touré Almamy Amara , Barry Ibrahima , Magassouba Aboubacar Sidiki , Bah Kadiatou , Cisse Diao , Sylla Younoussa , Camara Alsény Yarie , Loua Gaspard , Diallo Abdourahamane
Published: March 2023

Vaccination remains the primary strategy for ending the COVID-19 pandemic. However, vaccination rates are still low in low-income countries. The primary goal of this study was to describe the status of COVID-19 vaccine acceptance and hesitancy among women in Guinea and to identify associated predictors.Weconducted a cross-sectional study in five Guinean cities (Conakry, Mamou, Kindia, Kankan and N’zérékoré) across the four natural regions between Mar 22 and Aug 25 2021. Participants aged 18 were randomly recruited from the healthcare workers (HCWs) and the general population (GP). We used multivariate logistic regression to identify facilitators and barriers to acceptance of COVID-19 vaccination and a classification and regression tree (CART) to extract the profile of predictors.We included2,208 women among the HCWs and 1,121 in the GP. Most HCWs (63%) were already vaccinated, compared to only 28% of GP. The main factors associated with acceptance of a COVID-19 vaccine in the HCWs were an absence of pregnancy ORA = 4.46 [CI95%: 3.08, 6.52] and positive subjective norms ORA = 2.34 [CI95%: 1.92, 2.84].

Regarding the GP, the main factors were the ability to receive the vaccine ORA = 5.20 [CI95%: 3.45, 8.01] and being adult ORA = 2.25 [CI95%: 1.34, 3.79] associated with acceptance of vaccination. Vaccination rates were higher in the HCWs. Favourable subjective norms and ability to receive the vaccine were facilitators of acceptance of COVID-19 vaccination, while youth and pregnancy were barriers to the approval of the COVID-19 vaccine.
Tools and methods for high-throughput single-cell imaging with the mother machine
Authors: Thiermann Ryan , Sandler Michael , Ahir Gursharan , Sauls John T. , Schroeder Jeremy W. , Brown Steven D. , Treut Guillaume Le , Si Fangwei , Li Dongyang , Wang Jue D. , Jun Suckjoon
Published: March 2023

Despite much progress, image processing remains a significant bottleneck for high-throughput analysis of microscopy data. One popular platform for single-cell time-lapse imaging is the mother machine, which enables long-term tracking of microbial cells under precisely controlled growth conditions. While several mother machine image analysis pipelines have been developed in the past several years, adoption by a non-expert audience remains a challenge. To fill this gap, we implemented our own software, MM3, as a plugin for the multidimensional image viewer napari. napari-MM3 is a complete and modular image analysis pipeline for mother machine data, which takes advantage of the high-level interactivity of napari. Here, we give an overview of napari-MM3 and test it against several well-designed and widely-used image analysis pipelines, including BACMMAN and DeLTA. Researchers often analyze mother machine data with custom scripts using varied image analysis methods, but a quantitative comparison of the output of different pipelines has been lacking. To this end, we show that key single-cell physiological parameter correlations and distributions are robust to the choice of analysis method. However, we also find that small changes in thresholding parameters can systematically alter parameters extracted from single-cell imaging experiments. Moreover, we explicitly show that in deep learning based segmentation, “what you put is what you get” (WYPIWYG) – i.e., pixel-level variation in training data for cell segmentation can propagate to the model output and bias spatial and temporal measurements. Finally, while the primary purpose of this work is to introduce the image analysis software that we have developed over the last decade in our lab, we also provide information for those who want to implement mother-machine-based high-throughput imaging and analysis methods in their research.
Expanding the family of genetically encoded voltage indicators: Insights from heliorhodopsins
Authors: Ganapathy Srividya , Meng Xin , Mossel Delizzia , Jagt Mels , Brinks Daan
Published: March 2023

Genetically encoded voltage indicators (GEVIs), particularly those based on microbial rhodopsins, are gaining traction in neuroscience as fluorescent sensors for imaging voltage dynamics with high-spatiotemporal precision. Here we establish a novel GEVI candidate based on the recently discovered subfamily of the microbial rhodopsin clade, termed heliorhodopsins. We discovered that upon excitation at 530-560nm, wild type heliorhodopsin exhibits near infra-red fluorescence which is sensitive to membrane voltage. We characterized the fluorescence brightness, photostability, voltage sensitivity and kinetics of wild type heliorhodopsin in HEK293T cells and further examined the impact of mutating key residues near the retinal chromophore. The S237A mutation significantly improved the fluorescence response of heliorhodopsin by 76% providing a highly promising starting point for further protein evolution.
Energetics and kinetics of membrane permeation of photoresists for bioprinting
Authors: Diedrich Lucas , Brosz Matthias , Abele Tobias , Steinke Salome , Gräter Frauke , Göpfrich Kerstin , Aponte-Santamaría Camilo
Published: March 2023

Three-dimensional (3D) bioprinting is a promising technology which typically uses bioinks to pattern cells and their scaffolds. The selection of cytocompatible inks is critical for the printing success. In laserbased 3D bioprinting, photoresist molecules are used as bioinks. We propose that cytotoxicity can be a consequence of the interaction of photoresists with lipid membranes and their permeation into the cell. Here, molecular dynamics simulations and in vitro assays address this issue, retrieving partition coefficients, free energies, and permeabilities for eight commonly-used photoresists in model lipid bilayers. Crossing the hydrophobic center of the membrane constitutes the rate limiting step during permeation. In addition, three photoresists feature a preferential localization site at the acyl chain headgroup interface. Photoresist permeabilities range over eight orders of magnitude, with some molecules being membrane-permeable on bioprinting timescales. Moreover, permeation correlates well with the oil-water partition coefficients and is severely hampered by the lipid ordering imposed by the lipid saturation. Overall, the mechanism of interaction of photoresists with model lipid bilayers is provided here, helping to classify them according to their residence in the membrane and permeation through it. This is useful information to guide the selection of cytocompatible photoresists for 3D bioprinting.
Nitrogen assimilation plays a role in balancing the chloroplastic glutathione redox state under high-light conditions
Authors: Gilad Gal , Sapir Omer , Hipsch Matanel , Waiger Daniel , Ben-Ari Julius , Lampl Nardy , Rosenwasser Shilo
Published: March 2023

Nitrate reduction and subsequent ammonium assimilation require reducing equivalents directly produced by the photosynthetic electron transport chain. Therefore, it has been suggested that nitrate assimilation provides a valuable sink for excess electrons under high-light (HL) conditions, which protects the photosynthetic apparatus from excessive harmful reactive oxygen species. This work experimentally tested this hypothesis by monitoring photosynthetic efficiency and the chloroplastic glutathione redox state (chl-EGSH) of plant lines with mutated glutamine synthetase 2 (GS2) and ferredoxin-dependent glutamate synthase 1 (GOGAT1), two key enzymes of the nitrogen assimilation pathway. Unlike wild-type (WT) plants, mutant lines incorporated significantly less isotopically-labeled nitrate into amino acids, demonstrating impaired nitrogen assimilation. When nitrate assimilation was compromised, photosystem II (PSII) proved more vulnerable to photodamage, as shown by the low PSII quantum yields recorded in the mutant lines. High temporal resolution monitoring of the redox state of chloroplast-targeted reduction-oxidation sensitive green fluorescent protein 2 (chl-roGFP2), expressed in the background of the mutant lines, enabled assessment of the effect of the nitrate assimilation pathway on the chl-EGSH. Remarkably, while oxidation followed by reduction of chl-roGFP2 was detected in WT plants in response to HL, oxidation values were stable in the mutant lines, suggesting that the relaxation of chl-EGSHafter HL-induced oxidation is achieved by diverting excess electrons to the nitrogen assimilation pathway. Together, these findings indicate that the nitrogen assimilation pathway serves as a sustainable energy dissipation route, ensuring efficient photosynthetic activity and fine-tuning redox metabolism under light-saturated conditions.
TemStaPro: protein thermostability prediction using sequence representations from protein language models
Authors: Pudžiuvelytė Ieva , Olechnovič Kliment , Godliauskaite Egle , Sermokas Kristupas , Urbaitis Tomas , Gasiunas Giedrius , Kazlauskas Darius
Published: March 2023

Motivation

Reliable prediction of protein thermostability from its sequence is valuable for both academic and industrial research. This prediction problem can be tackled using machine learning and by taking advantage of the recent blossoming of deep learning methods for sequence analysis. These methods can facilitate training on more data and, possibly, enable development of more versatile thermostability predictors for multiple ranges of temperatures.

Results

We applied the principle of transfer learning to predict protein thermostability using embeddings generated by protein language models (pLMs) from an input protein sequence. We used large pLMs that were pre-trained on hundreds of millions of known sequences. The embeddings from such models allowed us to efficiently train and validate a high-performing prediction method using over one million sequences that we collected from organisms with annotated growth temperatures. Our method, TemStaPro (Temperatures of Stability for Proteins), was used to predict thermostability of CRISPR-Cas Class II effector proteins (C2EPs). Predictions indicated sharp differences among groups of C2EPs in terms of thermostability and were largely in tune with previously published and our newly obtained experimental data.

Availability and Implementation

TemStaPro software and the related data are freely available fromhttps://github.com/ievapudz/TemStaProandhttps://doi.org/10.5281/zenodo.7743637.
Dynamics of the rice yellow mottle disease in western Burkina Faso: epidemic monitoring, spatio-temporal variation of viral diversity and pathogenicity in a disease hotspot
Authors: Billard Estelle , Barro Mariam , Sérémé Drissa , Bangratz Martine , Wonni Issa , Koala Moustapha , Kassankogno Abalo Itolou , Hébrard Eugénie , Thébaud Gaël , Brugidou Christophe , Poulicard Nils , Tollenaere Charlotte
Published: March 2023

The rice yellow mottle virus (RYMV) is a model in plant virus molecular epidemiology and phylogeography, with the reconstruction of historical introduction routes at the scale of the African continent. However, information on patterns of viral prevalence and viral diversity over multiple years at local scale remain scarce, in spite of potential implications for crop protection.

Here we describe a five-years monitoring of RYMV prevalence in six sites from western Burkina Faso. This study confirmed one irrigated site as a disease hotspot, and found two rainfed lowland sites with occasional high prevalence levels. Within studied field, a pattern of disease aggregation was evidenced at a five-meter distance, as expected for a mechanically transmitted virus.

Next, we monitored RYMV genetic diversity in the irrigated disease hotspot site, revealing a high viral diversity, with the current coexistence of various distinct genetic groups at the site-scale (irrigated perimeter of ca. 520 ha), and also within various specific fields (25 meters side). One genetic lineage, named S1bzn, is the most recently introduced group and increased in frequency over the studied period. Its genome results from a recombination between two other lineages.

Finally, experimental work evidenced no differences between three rice varieties cultivated in Burkina Faso in terms of resistance level, and no statistical effect of RYMV genetic group on symptom expression and viral load. We found however, that infection outcome depended on the specific RYMV isolate, with various isolates from the lineage S1bzn found to be particularly aggressive, including one accumulating at highest level.

Overall, this study documents a case of high viral prevalence and high viral diversity, with the co-occurrence of divergent genetic lineages at small geographic scale. A recently introduced lineage, that includes viral isolates with high symptoms and accumulation in controlled conditions, could be recently rising though natural selection. Following up the monitoring of RYMV genetic and pathogenic diversity in the area is required to confirm this trend and further understand the factors driving the maintenance of viral diversity at local scale.
Exploring the Effects of Ecological Parameters on the Spatial Structure of Genealogies
Authors: Ianni-Ravn Mariadaria K. , Petr Martin , Racimo Fernando
Published: March 2023

1

Geographic space is a fundamental dimension of evolutionary change, determining how individuals disperse and interact with each other. Consequently, space has an important influence on the structure of genealogies and the distribution of genetic variants over time. Recently, the development of highly flexible simulation tools and computational methods for genealogical inference has greatly increased the potential for incorporating space into models of population genetic variation. It is now possible to explore how spatial ecological parameters can influence the distribution of genetic variation among individuals in unprecedented detail. In this study, we explore the effects of three specific parameters (the dispersal distance, competition distance and mate choice distance) on the spatial structure of genealogies. We carry out a series ofin silicoexperiments using forwards-in-time simulations to determine how these parameters influence the distance between closely- and distantly-related individuals. We also assess the accuracy of the maximum likelihood estimation of the dispersal distance in a Gaussian model of dispersal from tree-sequence data, and highlight how it is affected by realistic factors such as finite habitat size and limited data. We find overall that the scale of mate choice in particular has marked patterns on short and long terms patterns of dispersal, as well as on the positions of individuals within a habitat. Our results showcase the potential for linking phylogeography, population genetics and ecology, in order to answer fundamental questions about the nature of spatial interactions across a landscape.
Therapeutic targeting of ACLY in T-ALLin vivo
Authors: da Silva-Diz Victoria , Singh Amartya , Aleksandrova Maya , Kim Oekyung , Thai Christopher , Lancho Olga , Nunes Patricia Renck , Affronti Hayley , Su Xiaoyang , Wellen Kathryn E. , Herranz Daniel
Published: March 2023

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as overexpressed and as a novel therapeutic target in T-ALL. To test the effects of ACLY in leukemia progression, we developed an isogenic model of NOTCH1-inducedAclyconditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibitionin vivo.Metabolomic profiling upon ACLY loss revealed a metabolic crisis with reduced acetyl-CoA levels, as well as a decreased oxygen consumption rate. Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of MYC lossin vivo. Mechanistically, the decrease in acetyl-CoA led to reduced H3K27ac levels inMyc, resulting in transcriptional downregulation ofMycand drastically reduced MYC protein levels. Interestingly, our analyses also revealed a reciprocal relationship wherebyACLYitself is a direct transcriptional target of MYC, thus establishing a feedforward loop that is important for leukemia progression. Overall, our results identified a relevant ACLY-MYC axis and unveiled ACLY as a novel promising target for T-ALL treatment.
Image-based temporal profiling of autophagy-related phenotypes
Authors: Beesabathuni Nitin Sai , Thilakaratne Eshan , Shah Priya S.
Published: March 2023

Autophagy is a dynamic process that is critical in maintaining cellular homeostasis. Dysregulation of autophagy is linked to many diseases and is emerging as a promising therapeutic target. High-throughput methods to characterize autophagy are essential for accelerating drug discovery and characterizing mechanisms of action. In this study, we developed a highly scalable image-based profiling approach to characterize ∼900 morphological features at a single cell level with high temporal resolution. We differentiated drug treatments based on morphological profiles using a random forest classifier with ∼90% accuracy and identified the key features that govern the classification. Additionally, temporal morphological profiles accurately predicted biologically relevant changes in autophagy after perturbation, such as total cargo degradation. Therefore, this study acts as proof-of-principle for using image-based profiling to differentiate autophagy perturbations in a high-throughput manner and identify biologically relevant autophagy phenotypes, which can accelerate drug discovery.
Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules
Authors: Harriot Anicca , Altair-Morris Tessa , Venegas Camilo , Kallenbach Jacob , Pinto Kaylie , Joca Humberto C. , Moutin Marie-Jose , Shi Guoli , Ursitti Jeanine , Grosberg Anna , Ward Christopher W.
Published: March 2023

In Duchenne muscular dystrophy (DMD), alterations in the myofibrillar structure of skeletal muscle fibers that impair contractile function and increase injury susceptibility arise as a consequence of dystrophic pathology. In murine DMD (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established the densification of microtubules (MTs) post-translationally modified by detyrosination (deTyr-MTs) as a negative disease modifier. Given the essential role of MTs in myofibrillar growth, maintenance, and repair, we examined the increased abundance of deTyr-MTs as a potential mechanism for these myofibrillar alterations. Here we find increased levels of deTyr-MTs as an early event in dystrophic pathology (4 weeks) with no evidence of myofibrillar alterations. At 16 weeks, we show the level of deTyr-MTs is significantly increased and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we identify vasohibin 2 (VASH2) and small vasohibin binding protein (SVBP) significantly elevated in themdxmuscle at 4 wks. We then use the genetic increase in VASH2/SVBP expression in 4 wk wild-type mice and find densified deTyr-MTs that co-segregate with myofibrillar malformations similar to those in the 16 wkmdx. Given that no changes were identified in fibers expressing EGFP as a control, we conclude that disease dependent densification of deTyr-MTs underscores the altered myofibrillar structure in dystrophic skeletal muscle fibers.
Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors
Authors: Sahgal Pranshu , Patil Deepa T. , Sztupinszki Zsofia M. , Tisza Viktoria , Spisak Sandor , Huffman Brandon , Prosz Aurel , Singh Harshabad , Lazaro Jean-Bernard , Szallasi Zoltan , Cleary James M. , Sethi Nilay S.
Published: March 2023

Gastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD). Moreover, high expression of DNA damage markerH2AXcorrelated with CIN, WGD, and inferior patient survival. By developing and implementing a composite diagnostic score that incorporatesTP53mutation status, ploidy abnormalities, andH2AXexpression, among other genomic information, we can identify GEA cell lines with enhanced sensitivity to DDR pathway inhibitors targeting Chk1/2 and Wee1. Anti-tumor properties were further augmented in combination with irinotecan (SN38) but not gemcitabine chemotherapy. These results implicate specific DDR biomarkers and ploidy abnormalities as diagnostic proxy that may predict premalignant progression and response to DDR pathway inhibitors.
Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age
Authors: Ruby J. Graham , Smith Megan , Buffenstein Rochelle
Published: March 2023

The naked mole-rat (Heterocephalus glaber) is a mouse-sized rodent species, notable for its eusociality and long lifespan. Previously, we reported that demographic aging, i.e., the exponential increase of mortality hazard that accompanies advancing age in mammals and other organisms, does not occur in naked mole-rats (Ruby et al, 2018). The demographic data supporting that conclusion had taken over three decades to accumulate, starting with the original rearing ofH.glaberin captivity. In the five years following that study, we ∼doubled our quantity of demographic data. Here, we re-evaluated our prior conclusions in light of these new data and found them to be supported and indeed strengthened. We additionally provided insight into the social dynamics of captiveH.glaberwith data and analyses of body weight and colony size versus mortality. Finally, we provide a phylogenetically-proximal comparator in the form of lifespan data from our Damaraland mole-rat (Fukomys damarensis) colony and demographic meta-analysis of those data along with published data from Ansell’s mole-rat (Fukomys anselli). We foundFukomysmortality hazard to increase gradually with age, an observation with implications on the evolution of exceptional lifespan among mole-rats and the ecological factors that may have accompanied that evolution.
Terrestrial Support of Aquatic Food Webs via an Overlooked Pathway—Inorganic Carbon and its Significance to Global Carbon Cycle
Authors: Wang Junna , Durand John R. , Lawler Sharon P. , Chen Pinyuan , Dong Xiaoli
Published: March 2023

Freshwater ecosystems receive substantial terrestrial organic matter (t-OM) from surrounding landscapes. How the t-OM is transferred affects aquatic food webs and global carbon budgets. Previous studies have emphasized terrestrial support of aquatic ecosystems via direct organic carbon subsidy, overlooking the dissolved inorganic carbon (DIC) pathway, that is, DIC from t-OM decomposition is used by aquatic primary producers, supporting higher trophic levels. Using 2-year13C and15N measurements of phytoplankton, zooplankton, terrestrial plants, sediments, dissolved and particulate organic matter from seasonal wetlands, we found that while zooplankton (mid-trophic consumers) used t-OM directly in January, in March and May zooplankton were mainly supported by phytoplankton that used DIC recycled from t-OM mineralization and methanogenesis. The dominance of this DIC pathway is tightly coupled with the characteristics of these systems. Mineralization and methanogenesis of rich fresh t-OM resulted in supersaturated CO2with high CO2and CH4emissions. Atmospheric CO2diffusion and methanogenesis significantly enrichedδ13Cof DIC, leading to wide variations inδ13Cof DIC between -12.4 and 6.7 ‰, which provided ideal conditions to quantify carbon cycling in these widespread but understudied ecosystems. Our findings draw attention to potentially high carbon emissions from temporary freshwater ecosystems that are being increasingly common under warming climate.
Phage-Antibiotic Combination: An Effective Method for Eradication ofStaphylococcus aureus
Authors: Loganathan Archana , Manohar Prasanth , Nachimuthu Ramesh
Published: March 2023

Increasing antibiotic resistance poses a serious threat, especially in patients admitted to ICUs. The use of phages in combination with antibiotics as compassionate therapy has become a choice of treatment for pan-drug-resistant bacteria. Here, we studied the cumulative effect of phages with four antibiotics, fosfomycin, ciprofloxacin, vancomycin and oxacillin using three different treatment orders againstS. aureus. The antibiotic disc synergy method showed that the plaque size of the phage increased in the subinhibitory antibiotic zone. The sub-inhibitory antibiotic amended in the agar media showed that the plaque size increased between 0.25 μg/mL and 1 μg/mL of antibiotics. It increases from 0.5 ± 0.1 mm (phage-alone control) to 4 ± 0.2 mm, 1.6 ± 0.1 mm, and 1.6 ± 0.4 mm with fosfomycin, ciprofloxacin, and oxacillin, respectively. Checkerboard analysis showed that phages and antibiotics were synergistic with the FIC index of less than 0.5. So, phage-antibiotic combination treatment appeared to be effective. However, the highest efficiency was observed when the antibiotics were administered after phage treatment. A maximum of 39.4-, 39.4-, and 37.0-fold reduction relative to untreated bacterial culture was observed with fosfomycin, oxacillin, and ciprofloxacin. Vancomycin antibiotic had a least 14.7-fold reduction. Finally, our findings emphasize the potential benefits of phage-antibiotic combination therapy compared with phage-alone therapy to treatS. aureusinfections.
Exploring the Impact of the Covid-19 Pandemic on Health-Related Behaviours: A Person-Centred Analysis of Two British Longitudinal Cohort Studies
Authors: Kiri Janet , Brandt Valerie
Published: March 2023

The current study explored the impact of the Covid-19 pandemic on health-related behaviours in the United Kingdom. We conducted a repeated measures latent class analysis with five indicators of health-related behaviours; frequency of alcohol consumption, binge drinking, smoking, BMI and sleep, to identify distinct subgroups of individuals with similar patterns of change across three timepoints during the first 9 months of the pandemic. We hypothesised that various psychosocial risk factors, such as a history of adverse childhood experiences would predict membership in latent classes with a higher probability of engaging in risky health behaviours, and that protective factors, like social support, would be associated with membership in classes with less risky health behaviours. We identified 5 latent classes, and multinomial logistic regression analyses revealed multiple predictors of class membership. Our findings did not support the relationship between poor mental health and the adoption of risky health behaviours.
Insomnia and early incident atrial fibrillation: A 16-year cohort study of younger men and women Veterans
Authors: Gaffey Allison E. , Rosman Lindsey , Lampert Rachel , Yaggi Henry K. , Haskell Sally G. , Brandt Cynthia A. , Enriquez Alan D. , Mazzella Anthony J. , Burg Matthew M.
Published: March 2023

Background

There is growing consideration of sleep disturbances and disorders in early cardiovascular risk, including atrial fibrillation (AF). Obstructive sleep apnea (OSA) confers risk for AF but is highly comorbid with insomnia, another common sleep disorder. The objectives of this investigation were first to determine the association of insomnia and early incident AF risk and second, to determine if AF onset is earlier among those with insomnia.

Methods

This retrospective analysis used electronic health records from a cohort study of U.S. Veterans who were discharged from military service as of October 1, 2001 (i.e., post-9/11) and received Veterans Health Administration (VA) healthcare, 2001-2017. Time-varying, multivariate Cox proportional hazard models were used to examine the independent contribution of insomnia diagnosis to AF incidence while serially adjusting for demographics, lifestyle factors, clinical comorbidities including OSA, psychiatric disorders, and healthcare utilization.

Results

Overall, 1,063,723 post-9/11 Veterans (Mage=28.2 years, 12% women) were followed for 10 years on average. There were 4168 cases of AF (0.42/1000 person-years). Insomnia was associated with a 32% greater, adjusted risk of AF (95% CI, 1.21-1.43), and Veterans with insomnia showed AF onset up to two years earlier. Insomnia-AF associations were similar after accounting for healthcare utilization, excluding Veterans with OSA, and among those with a sleep study (adjusted hazard ratios [aHR]: 1.29-1.34).

Conclusions

In younger adults, insomnia was independently associated with incident AF even when accounting for OSA. Additional studies should determine if this association differs by sex and if behavioral or pharmacological treatment for insomnia attenuates AF risk.

Clinical Perspective

1.

What is new?

In more than one million younger men and women Veterans with 16 years of follow-up, a history of insomnia conferred a 32% increase in risk for atrial fibrillation (AF).

The insomnia-AF association persisted despite accounting for obstructive sleep apnea, a well-known risk factor for AF, and other demographic, lifestyle, and clinical factors.

Veterans with insomnia may also present with AF up to 2 years earlier compared to those without insomnia.

2.

What are the clinical implications?

Insomnia is a potentially modifiable risk factor for AF and sleep should be a focus for AF prevention.

Screening and referral for insomnia and other sleep symptoms is critical, particularly among patients with an elevated risk for cardiovascular disease, as observed in the Veteran population.

Although sex-specific associations could not be examined, insomnia is more prevalent among women, and it is possible that insomnia-AF associations may differ by sex.
Iron associated lipid peroxidation in Alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice
Authors: Thorwald Max A. , Godoy-Lugo Jose A. , Garcia Gilberto , Silva Justine , Kim Minhoo , Christensen Amy , Mack Wendy J. , Head Elizabeth , O’Day Peggy A. , Benayoun Bérénice A. , Morgan Todd E. , Pike Christian J. , Higuchi-Sanabria Ryo , Forman Henry Jay , Finch Caleb E.
Published: March 2023

ABSTRACT

Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimer’s disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice. AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. ApoE4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron to AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants. These novel molecular pathways in iron mediated damage during AD.

Graphical Abstract

Hypothesis: AD brain lipid peroxidation is driven by increased brain iron and decreased antioxidant defenses. Schema shows proteins that mediate iron metabolism in relation to lipid peroxidation (HNE) and antioxidant defenses in prefrontal cortex. AD-associated increase (red), decrease (blue), or no change (grey), relative to cognitively normal elderly controls. Aβ; amyloid beta, ALDH2; alcohol dehydrogenase, APP; amyloid precursor protein, DMT1; divalent metal transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1, which requires the quinol cycle to attenuate lipid peroxidation; FTH1, ferritin heavy chain; FTL; ferritin light chain; GCLC, glutathione cysteine ligase catalytic subunit; GCLM, glutathione cysteine ligase modulator; GPx4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; GSTA4, glutathione S-transferase A4; HMOX; heme oxygenase; IRP, iron regulatory protein; LAT1, large neutral amino acid transporter 1; LOOH, Lipid hydroperoxides; Nrf2, Nuclear factor erythroid 2-related factor 2; Prdx6, peroxiredoxin 6; TF, transferrin, TfR; Transferrin receptor; xCT, cysteine-glutamate antiporter.
Structural basis of membrane targeting and coatomer assembly by human GBP1
Authors: Kuhm Tanja , de Agrela Pinto Cecilia , Gross Luca , Huber Stefan T. , Taisne Clémence , Giannopoulou Evdokia A. , Pardon Els , Steyaert Jan , Tans Sander J. , Jakobi Arjen J.
Published: March 2023

Guanylate-Binding Proteins (GBPs) are interferon-inducible guanosine triphosphate hydrolases (GTPases) that mediate immune effector functions against intracellular pathogens. A key step for the antimicrobial activity of GBPs is the formation of homo- and heterooligomeric complexes on the membrane of pathogen-associated compartments or cytosolinvasive bacteria. Similar to other large GTPases of the dynamin family, oligomerisation and membrane association of GBPs depend on their GTPase activity. How nucleotide binding and hydrolysis prime GBPs for membrane targeting and coatomer formation remains unclear. Here, we report the cryo-EM structure of the full-length human GBP1 dimer in its guanine nucleotide-bound state and resolve the molecular ultrastructure of GBP1 coatomer assemblies on liposomes and bacterial lipopolysaccharide membranes. We show how nucleotide binding promotes large-scale conformational changes of the middle and GTPase effector domains that expose the isoprenylated carboxyl-terminus for association with lipid membranes. Our structure reveals how the α-helical stalks of the middle domain form a parallel arrangement firmly held in a unique cross-over arrangement by intermolecular contacts between adjacent monomers. This conformation is critical for GBP1 dimers to assemble into densely packed coatomers on target membranes. The extended α-helix of the effector domain is flexible and permits intercalation into the dense lipopolysaccharide layer on the outer membrane of gram-negative bacterial pathogens. We show that nucleotide-dependent oligomerisation and GTP hydrolysis yield GBP1 membrane scaffolds with contractile abilities that promote the formation of tubular membrane protrusions and membrane fragmentation. Collectively, our data provide a structural and mechanistic framework for interrogating the molecular basis for GBP1 effector functions in intracellular immunity.
Two haplotype-resolved genomes of highly heterozygous AAB allotriploid bananas provide insights into subgenome asymmetric evolution and banana wilt control
Authors: Xie Wen-Zhao , Zheng Yu-Yu , He Weidi , Bi Fangcheng , Li Yaoyao , Dou Tongxin , Zhou Run , Guo Yi-Xiong , Deng Guiming , Zhang Wen-Hui , Yuan Min-Hui , Sanz-Jimenez Pablo , Zhu Xi-Tong , Xu Xin-Dong , Zhou Zu-Wen , Zhou Zhi-Wei , Feng Jia-Wu , Liu Siwen , Li Chunyu , Yang Qiaosong , Hu Chunhua , Gao Huijun , Dong Tao , Dang Jiangbo , Guo Qigao , Cai Wenguo , Zhang Jianwei , Yi Ganjun , Song Jia-Ming , Sheng Ou , Chen Ling-Ling
Published: March 2023

Bananas (Musaspp.) are one of the most important tropical fruits and staple food, which are of great significance to human societies. Plantain and Silk are two important banana subgroups, which are both triploid hybrids (AAB) between the wild diploidMusa acuminataandM. balbisiana. In this study, we reported the first haplotype-resolved genome assembly of Plantain and Silk bananas with genome size of approximately 1.4 Gb. We discovered widespread asymmetric evolution in the subgenomes of Plantain and Silk, which could be linked to frequent homologous exchanges (HEs) events. This is the first study to uncover the genetic makeup of triploid banana and verify that subgenome B harbors a rich source of resistance genes. Of the 88,078 and 94,988 annotated genes in Plantain and Silk, only 58.5% and 59.4% were present in all three subgenomes, with >50% genes containing differently expressed alleles in different haplotypes. We also found that Plantain is more resistant to banana Fusarium wilt, exhibiting a much faster defense response after pathogenic fungi infection. Many differentially expressed genes in abscisic acid, ethylene, jasmonic acid and salicylic acid pathways were identified in Plantain. Our analysis revealed that MpMYB36 promotes the biosynthesis of secondary cell wall and deposition of lignin by directly binding to the promoter of MpPAL and MpHCT, which allows Plantain to inhibit the penetration of early infection. Moreover, the insertion of the key carotenoid synthesis gene (CRTISO) may be the potential genetic basis for the richness of carotenoids in Plantain. Our study provides an unprecedented genomic basis for basic research and the development of elite germplasm in cultivated bananas.
RecA-NT homology motif in ImuB is essential for mycobacterial ImuA’-ImuB protein interaction and mutasome function
Authors: Santos Joana A. , Timinskas Kęstutis , Lamers Meindert H. , Venclovas Česlovas , Warner Digby F. , Gessner Sophia J.
Published: March 2023

The mycobacterial mutasome – minimally comprising ImuA’, ImuB, and DnaE2 proteins – has been implicated in DNA damage-induced mutagenesis inMycobacterium tuberculosis. ImuB, predicted to enable mutasome function via its interaction with the β clamp, is a catalytically inactive member of the Y-family of DNA polymerases. Like other members of the Y family, ImuB features a recently identified amino acid motif with homology to the RecA-N-terminus (RecA-NT). In RecA, the motif mediates oligomerization of RecA monomers into RecA filaments. Given the role of ImuB in the mycobacterial mutasome, we hypothesized that the ImuB RecA-NT motif might mediate its interaction with ImuA’, a RecA homolog of unknown function. To investigate this possibility, we constructed a panel ofimuBalleles in which RecA-NT was removed, or mutated. Results from microbiological and biochemical assays indicate that RecA-NT is critical for the interaction of ImuB with ImuA’. A region downstream of RecA-NT (ImuB-C) also appears to stabilize the ImuB-ImuA’ interaction, but its removal does not prevent complex formation. In contrast, replacing two key hydrophobic residues of RecA-NT, L378 and V383, is sufficient to disrupt ImuA’-ImuB interaction. To our knowledge, this constitutes the first experimental evidence showing the role of the RecA-NT motif in mediating the interaction between a Y-family member and a RecA homolog.
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
Authors: Mate de Gerando Anastasie , Welikovitch Lindsay A , Khasnavis Anita , Commins Caitlin , Glynn Calina , Chun Joshua E , Perbet Romain , Hyman Bradley T
Published: March 2023

Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW) due to its properties on size exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sarkosyl insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of biophysical and bioactivity assays. Sarkosyl insoluble fibrillar tau is comprised of abundant paired helical filaments (PHF) as quantified by electron microscopy (EM), and is more resistant to proteinase K, compared to HMW tau which is mostly in an oligomeric form. Sarkosyl insoluble and HMW tau are nearly equivalent in potency in a HEK cell bioactivity assay for seeding aggregates and their injection reveals similar local uptake into hippocampal neurons in PS19 Tau transgenic mice. However, the HMW preparation appears to be far more potent in inducing a glial response including Clec7a-positive rod-microglia in the absence of neurodegeneration or synapse loss and promotes more rapid propagation of misfolded tau to distal, anatomically connected regions, such as entorhinal and perirhinal cortices. These data suggest that soluble HMW tau has similar properties to fibrillar sarkosyl insoluble tau with regard to tau seeding potential but may be equal or even more bioactive with respect to propagation across neural systems and activation of glial responses, both relevant tau-related Alzheimer phenotypes.
A quantitative description for optical mass measurement of single biomolecules
Authors: Becker Jan , Peters Jack S. , Crooks Ivor , Helmi Seham , Synakewicz Marie , Schuler Benjamin , Kukura Philipp
Published: March 2023

Label-free detection of single biomolecules in solution has been achieved using a variety of experimental approaches over the past decade. Yet, our understanding of the magnitude of the optical contrast and its relationship to the underlying atomic structure, as well as the achievable measurement sensitivity and precision remain poorly defined. Here, we use a Fourier optics approach combined with an atomic structure-based molecular polarizability model to simulate mass photometry experiments from first principles. We find excellent agreement between several key experimentally-determined parameters such as optical contrast-to-mass conversion, achievable mass accuracy and molecular shape/orientation dependence. This allows us to determine detection sensitivity and measurement precision that is mostly independent of the optical detection approach chosen, resulting in a general framework for light-based single molecule detection and quantification.