bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bet-hedging and variability in plant development: seed germination and beyond
Authors: Abley Katie , Goswami Rituparna , Locke James C. W. 
Published: March 2024

When future conditions are unpredictable, bet-hedging strategies can be advantageous. This can involve isogenic individuals producing different phenotypes, under the same environmental conditions. Ecological studies provide evidence that variability in seed germination time has been selected for as a bet-hedging strategy. We demonstrate how variability in germination time found in Arabidopsis could function as a bet-hedging strategy in the face of unpredictable lethal stresses. Despite a body of knowledge on how the degree of seed dormancy versus germination is controlled, relatively little is known about how differences between isogenic seeds in a batch are generated. We review proposed mechanisms for generating variability in germination time and the current limitations and new possibilities for testing the model predictions. We then look beyond germination to the role of variability in seedling and adult plant growth and review new technologies for quantification of noisy gene expression dynamics. We discuss evidence for phenotypic variability in plant traits beyond germination being under genetic control and propose that variability in stress response gene expression could function as a bet-hedging strategy. We discuss open questions about how noisy gene expression could lead to between-plant heterogeneity in gene expression and phenotypes.
This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Development of an all-in-one real-time PCR assay for simultaneous detection of spotted fever group rickettsiae, severe fever with thrombocytopenia syndrome virus and orthohantavirus hantanense prevalent in central China
Authors: Wang Cuixiang , Chen liangjun , Li xingrong , Gu jihong , Xiang yating , Fang Liang , Chen Lili , Li Yirong 
Published: March 2024

AbstractCentral China has been reported to be one of the most important endemic areas of zoonotic infection by spotted fever group rickettsiae(SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and orthohantavirus hantanense(HTNV). Due to similar clinical symptoms, it is challenging to make a definite diagnosis rapidly and accurately in the absence of microbiological tests. In the present study, an all-in-one real-time PCR assay was developed for the simultaneous detection of nucleic acids from SFGR, SFTSV and HTNV. Three linear standard curves for determining SFGR-ompA, SFTSV-Land HTNV-Lwere obtained within the range of 101-106copies/μL, with the PCR amplification efficiencies ranging from 93.46% to 96.88% and the regression coefficients R2of >0.99. The detection limit was 1.108 copies/μL for SFGR-ompA, 1.075 copies/μL for SFTSV-Land 1.006 copies/μL for HTNV-L, respectively. Both the within-run and within-laboratory coefficients of variation on the cycle threshold (Ct) values were within the range of 0.53%-2.15%. It was also found there was no statistical difference in the Ct values between with and without other non-target bloodborne virus nucleic acids (PSFGR-ompA=0.186, PSFTSV-L=0.612, PHTNV-L=0.298). The sensitivity, specificity, positive and negative predictive value were all 100% for determining SFGR-ompAand SFTSV-L, 97%, 100%, 100% and 99.6% for HTNV-L, respectively. Therefore, the all-in-one real-time PCR assay appears to be a reliable, sensitive, rapid, high-throughput and low cost-effective method to diagnose the zoonotic infection by SFGR, SFTSV and HTNV.Author SummarySpotted fever, severe fever with thrombocytopenia syndrome (SFTS), and hemorrhagic fever with renal syndrome (HFRS) sporadically have outbreaks in central China. Due to the similarities in clinical symptoms and the absence of reliable diagnostic methods, clinical diagnosis and treatment frequently result in misdiagnosis or missed diagnosis. Thus, the development of a fast and accurate diagnostic method is crucial for prevention and precise treatment. In this study, we designed an all-in-one real-time PCR assay to differentiate spotted fever group rickettsiae(SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and orthohantavirus hantanense(HTNV). The geneompAof SFGR, as well as the gene segmentLof SFTSV and HTNV, were used as targets to design primers and probes for amplification. Through the verification of nucleic acid and clinical sample detection, the sensitivity of this detection method exceeded 97%, and its specificity was 100%.This new assay could be applied in epidemiology and clinical diagnosis, to control new outbreaks, reduce diagnostic and identification time, and improve test efficiency.
Cross-Sectional and Longitudinal Evaluation of Heart-to-Brachium Pulse Wave Velocity for Cardiovascular Disease Risk
Authors: Sugawara Jun , Tanaka Hirofumi , Yamashina Akira , Tomiyama Hirofumi 
Published: March 2024

ABSTRACTBACKGROUNDHeart-brachium pulse wave velocity (hbPWV) is a measure of proximal aortic stiffness and does not require the technical placement of transducers. To characterize age-associated changes and the clinical utilities of heart-brachium pulse wave velocity (hbPWV), we conducted both cross-sectional and longitudinal analyses and used brachial-ankle pulse wave velocity (baPWV) as a comparative measure.METHODSVarious measures of CVD risk factors and arterial stiffness were obtained in 7,868 adults in the cross-sectional study. In the longitudinal study, 3,710 adults were followed for 9.1 ± 2.0 years. Repeated-measures correlation (rmcorr) and regression analyses were used to characterize associations of PWVs with age and Framingham’s general CVD risk score (FRS).RESULTSIn the cross-sectional study, hbPWV showed a stronger linear (r=0.796) association with age than baPWV (r=0.554). In the longitudinal study, hbPWV also showed a significantly higher rmcorr coefficient with age than baPWV (rrm=0.511 vs. 0.307, P<0.0001). Age-related increases in hbPWV were fairly steady starting from young adults while baPWV displayed accelerated increases with age. A receiver operating characteristic curve analysis indicated that hbPWV depicted a more robust ability to stratify general cardiovascular disease (CVD) risk compared with baPWV (AUC=0.913 vs. 0.833, P<0.0001). The results of the 10-year follow-up study were consistent with the findings of the cross-sectional investigation.CONCLUSIONShbPWV exhibits steady and more pronounced increases from an early age and may be more effective in stratifying general CVD risk.NOVELTY AND RELEVANCEWhat Is New?Using the cross-sectional and longitudinal study designs in a large cohort of middle-aged Japanese workers, we confirmed that hbPWV, a promising method for assessing proximal aortic stiffness, undergoes a linear augmentation with age, commencing from an early life stage onward, rendering it a potential marker for discerning CVD risk.What Is Relevant?The stiffening of the arterial wall with advancing age is particularly pronounced in the proximal aorta and contributes importantly to elevated risks of CVD, cardiovascular events, and all-cause mortalities.Clinical/Pathophysiological Implications?Early-life assessment of proximal aortic stiffening through hbPWV has the potential to mitigate the pervasive impact of CVD on a global scale.
Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening
Authors: Bruge Celine , Bourg Nathalie , Pellier Emilie , Tournois Johana , Polentes Jerome , Benabides Manon , Grossi Noella , Bigot Anne , Brureau Anthony , Richard Isabelle , Nissan Xavier 
Published: March 2024

AbstractLGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. We report here the development of anin vitrohigh-throughput assay using immortalized myoblasts and monitored reallocation of an aggregated mutant form of dysferlin (DYSFL1341P). Using this assay, we screened a library of 2239 drugs and identified two autophagy inducers, namely saracatinib and bazedoxifene, as potential drugs to repurpose for LGMD R2 patients carrying theDYSFL1341Pmutation. Functional characterization of these drugs revealed that saracatinib and bazedoxifene had a protective effect on the plasma membrane in osmotic shock assay. While saracatinib restores functionality in membrane resealing through a specific rescue of L1341P dysferlin from degradation, bazedoxifene demonstrates an additional protective effect on dysferlin KO mice muscle fibers. Finally, further investigations into the molecular mechanism of action of bazedoxifene revealed an induction of autophagy flux, which may underlie the molecule’s effect on the survival of LGMD R2 myofibers.
The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine
Authors: Kamath Srinivas , Hunter Alexander , Collins Kate , Wignall Anthony , Joyce Paul 
Published: March 2024

AbstractBackground and PurposeAntipsychotics like olanzapine are associated with significant metabolic dysfunction, attributable to gut microbiota dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiota has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting, with most reports observing weight loss rather than gain. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiota to explore the hypothesis of “gut neutrality” for lurasidone exposure.Experimental ApproachUsing a Sprague-Dawley rat model, the impact of olanzapine and lurasidone administration on the gut microbiota was explored. Faecal and blood samples were collected weekly over a 21-day period to analyse changes to the gut microbiota and related metabolic markers.Key ResultsLurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating gut microbiota through increases in mean OTUs (+50 OTUs) and alpha diversity (+0.5 increase in Shannon’s index). This novel finding suggests an underlying mechanism for lurasidone’s metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs (−75 OTUs) and substantial compositional variation, suggesting a decrease in microbial richness. Microbiota alterations correlated with metabolic dysfunction, evidenced through a statistically significant 30% increase in weight gain, increase in pro-inflammatory cytokine expression, and increase in blood triglycerides and glycaemic levels.Conclusion and ImplicationsThe study challenges the notion that all antipsychotics disrupt the gut microbiota similarly and highlights the potential benefits of gut positive or neutral antipsychotics like lurasidone in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia.Bullet point summary-What is already known:Olanzapine induces weight gain by disrupting the gut microbiome.The impact of lurasidone on the gut microbiome is unknown and weight gaining propensities unclear.-What this study adds:Lurasidone positively modulates gut microbiota through enhancement of microbial diversity and richness.Potential mechanisms underlying lurasidone’s weight and metabolic neutrality are elucidated.-Clinical significance:Gut neutral antipsychotics like lurasidone could be favourable alternatives for patients unable to tolerate olanzapine.Personalised treatment for schizophrenia considering individual sensitivities to metabolic effects is emphasised.
RNA Polymerase II hypertranscription at histone genes in cancer FFPE samples
Authors: Henikoff Steven , Zheng Ye , Paranal Ronald M. , Xu Yiling , Greene Jacob E. , Henikoff Jorja G. , Russell Zachary R. , Szulzewsky Frank , Thirimanne H. Nayanga , Kugel Sita , Holland Eric C. , Ahmad Kami 
Published: March 2024

AbstractGenome-wide hypertranscription is common in hu-man cancer and predicts poor prognosis. To under-stand how hypertranscription might drive cancer, we applied our FFPE-CUTAC method for mapping RNA Polymerase II (RNAPII) genome-wide in formalin-fixed paraffin-embedded (FFPE) sections. We demonstrate global RNAPII elevations in mouse gliomas and assort-ed human tumors in small clinical samples and discov-er regional elevations corresponding tode novoHER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at replication-coupled histone genes correlated with WHO grade in meningiomas, ac-curately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneu-ploidy in cancer, with general implications for precision oncology.
DeepKymoTracker: A tool for accurate construction of cell lineage trees for highly motile cells
Authors: Fedorchuk Khelina , Russell Sarah M. , Zibaei Kajal , Yassin Mohammed , Hicks Damien G. 
Published: March 2024

AbstractTime-lapse microscopy has long been used to record cell lineage trees. Successful construction of a lineage tree requires tracking and preserving the identity of multiple cells across many images. If a single cell is misidentified the identity of all its progeny will be corrupted and inferences about heritability may be incorrect. Successfully avoiding such identity errors is challenging, however, when studying cells such as T lymphocytes. These are highly motile and readily change shape from one image to the next. To address this problem, we developed DeepKymoTracker, a pipeline for combined tracking and segmentation. Central to DeepKymoTracker is the use of a seed, a marker which transmits information about cell position and identity between sets of images during tracking, as well as between tracking and segmentation steps. The seed allows a 3D convolutional neural network (CNN) to detect and associate cells across several consecutive images in an integrated way, reducing the risk of a single poor image corrupting cell identity. DeepKymoTracker was trained extensively on synthetic and experimental T lymphocyte images. It was benchmarked against five publicly available, automatic cell-analysis tools and outperformed them in almost all respects. The software is written in pure Python and is freely available. We suggest this tool is particularly suited to the tracking of cells in suspension, whose fast motion makes lineage assembly particularly difficult.Author SummaryCell lineage trees provide a striking visual representation of cellular decision-making and fate determination in a proliferating clone. Traditionally, these trees have been recorded using time-lapse microscopy movies of a dividing clone. Extracting lineage trees of T lymphocytes from microscopy movies is particularly challenging, however, because the cells are highly motile, readily change shape, and are easily damaged by excessive illumination and frame rates. Here we present a deep-learning approach to extracting cell lineage trees from movies of proliferating T cells. Using 3D convolutional neural networks for tracking and separate networks for segmentation we were able to reduce misidentification errors and record cell lineage trees with high fidelity. In benchmark tests, our algorithm was found to outperform all other state-of-the-art algorithms in both tracking and segmentation.
Beyond Kaftrio : mechanistic insights to maximize N1303K-CFTR rescue
Authors: Pranke Iwona , Capurro Valeria , Chevalier Benoit , Pesce Emanuela , Tomati Valeria , Pastorino Cristina , Hatton Aurelie , Urien Saik , Lena Mariateresa , Dréano Elise , Bocciardi Renata , Zara Federico , Pantano Stefano , Terlizzi Vito , Lucanto Cristina , Costa Stefano , Claut Laura , Daccò Valeria , Poli Piercarlo , Maschio Massimo , Fabrizzi Benedetta , Caporelli Nicole , Cipolli Marco , Volpi Sonia , Jung Vincent , Roger Kevin , Chedevergne Frederique , Cosson Laure , Macey Julie , LeBihan Jean , Weiss Laurence , Grenet Dominique , Viala Laurence LeClainche , Douvry Benoit , Ravoninjatovo Bruno , Audousset Camille , Tatopoulos Aurélie , Thiriez Bénédicte Richaud , Baravalle Melissa , Thouvenin Guillaume , Labbé Guillaume , Mittaine Marie , Reix Philippe , Durieu Isabelle , Mankikian Julie , Bui Stéphanie , Kelly-Aubert Mairead , Nguyen–Khoa Thao , Khoukh Karim , Martin Clémence , Guerrera Chiarra , Silva Jennifer Da , di Carli Paola , Castellani Carlo , Cresta Federico , Galietta Luis , Guillemaut Anne , Bouazza Naim , Girodon Emmanuelle , Remus Natacha , Burgel Pierre Régis , Sermet-Gaudelus Isabelle , Hinzpeter Alexandre , Pedemonte Nicoletta 
Published: March 2024

AbstractIntroductionN1303K is the fourth most frequent Cystic Fibrosis (CF) causing mutation. People with CF (pwCF) clinical status can be improved by Elexacaftor(ELX)/Tezacaftor(TEZ)/Ivacaftor (ETI) combotherapy. We investigated the mechanism underlying N1303K-CFTR rescue.MethodsN1303K-CFTR expression and maturation was evaluated by Western Blot in cell lines and Human Nasal Epithelial Primary Cells (HNECs). Cell surface expression was studied by nanoluciferase complementation assay and TurboID proximity labeling. Functional rescue was testedin vitroby YFP-Based Assay and Short Circuit Current.ResultsCorrection by ELX/TEZ increases N1303K-CFTR amounts, but not its maturation in CFTR-expressing HEK and 16HBEge cell lines and in HNECs. In control conditions, N1303K-CFTR is more distributed at the cell surface and significantly more surface partners are identified in the N1303K-CFTR interactome as compared to F508del-CFTR in HEK cells. ELX/TEZ induces a global stabilization of N1303K-CFTR without favoring its plasma membrane relocation in contrast to F508del-CFTR which is redistributed to the membrane. ETI increases N1303K-CFTR activity in HNECs and can be increased by API co-potentiation with a predicted increase in Forced Expiratory Volume in 1 second (ppFEV1) by respectively 13(2)% and 18%(3). This is consistent with a gain in ppFEV1 reported in pwCF carrying the N1303K mutation and additional improvement by API in a patient.ConclusionThese results support the expansion of ETI approval to N1303K mutation but highlight different mechanisms of action than for F508del.
Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells
Authors: Tada Keisuke , Nishizawa Hironari , Shima Hiroki , Muto Akihiko , Wada Motoshi , Igarashi Kazuhiko 
Published: March 2024

ABSTRACTBackground and AimsMetabolic activities are also known to affect responses and disease processes of the liver which is a central organ for organismal metabolism. Liver diseases such as intestinal failure associated liver disease (IFALD) and hepatocellular carcinoma are known to be affected by nutrition contents, but the mechanisms behind them remain unclear. In this study, we aimed to reveal the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase (MAT), which plays the central role in methionine metabolism by synthesizingS-adenosylmethionine (SAM).MethodsMouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide (PI) and annexin V staining followed by flow cytometry. Inhibitors of ferroptosis (Fer-1), autophagy (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and DFMO) were used.ResultsCysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction-induced cell death was also suppressed by knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction.ConclusionsThese results suggest that SAM-polyamine metabolism is a critical modulator of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically in cancer cells without affecting normal cells in the liver.Graphical abstrct
Exploring Abeta42 Monomer Diffusion Dynamics on Fibril Surfaces through Molecular Simulations
Authors: Ma Yuan-Wei , Wang Guan-Fang , Chen Hong-Yi , Tsai Min-Yeh 
Published: March 2024

AbstractThis study provides critical insights into the role of surface-mediated secondary processes in Alzheimer’s disease, particularly regarding the aggregation of Abeta42 peptides. Employing coarse-grained molecular dynamics simulations, we focus on elucidating the molecular intricacies of these secondary processes beyond primary nucleation. Central to our investigation is the analysis of a freely diffusing Abeta42 monomer on pre-formed fibril structures. We conduct detailed calculations of the monomer’s diffusion coefficient on fibril surfaces (as a one-dimensional case), along with various monomer orientations. Our findings reveal a strong and consistent correlation between the monomer’s diffusion coefficient and its orientation on the surface. Further analysis differentiates the effects of parallel and perpendicular alignments with respect to the fibril axis. Additionally, we explore how different fibril surfaces influencèmonomer dynamics by comparing the C-terminal and N-terminal surfaces. We find that the monomer exhibits lower diffusion coefficients on the N-terminal surface. Differences in surface roughness (SR), quantified using root-mean-square distances, significantly affect monomer dynamics, thereby influencing the secondary aggregation process. Importanly, this study underscores that fibril twisting acts as a regulatory niche, selectively influencing these orientations and their diffusion properties necessary for facilitating fibril growth within biologically relevant time scales. This discovery opens new avenues for targeted therapeutic strategies aimed at manipulating fibril dynamics to mitigate the progression of Alzheimer’s disease.
Menopause has not evolved as a general trait in mammals: A response to ‘Do mammals have menopause?’
Authors: Chapman Simon N. , Ellis Samuel , Lahdenperä Mirkka , Croft Darren P. , Lummaa Virpi 
Published: March 2024

ABSTRACTReproductive senescence is widespread across mammals, but only a small number of species have physiological reproductive cessation and an extended post-reproductive lifespan. A recent commentary in Cell by Winkler & Goncalves (2023) suggests that menopause is actually a widespread trait of mammals, which would change our understanding of senescence and have implications for the study of menopause in humans. Here, we identify three main issues with the methodology of this commentary: the use of captive populations, the use of maximal lifespan, and misinterpretations of the data sources. We show that this methodology does not support the conclusions at the species-level, and conclude that, in line with the predictions of classic life-history theory, menopause is indeed a rare trait.