bluuebunny/crossref_metadata_2025_split huggingface dataset:
Number of ancestors and length of identity-by-descent tracks over time
Authors: Eriksen Mikkel Spallou , Renaud Gabriel 
Published: August 2024

AbstractThe divergence between genetic ancestors (those who have contributed to an individual’s DNA) and genealogical ancestors (individuals recognized as ancestors in a societal context) evolves significantly over time. This study focuses on small, insular populations, where the number of genetic ancestors can swiftly encompass the entirety of genealogical ancestors. Additionally, in these populations, runs of homozygosity (ROHs) frequently occur due to random chance. This study used a forward-in-time simulation based on the Wright-Fisher model to analyze genealogical and genetic relatedness, haplotype block lengths, and runs of homozygosity (ROH) across generations. In small, insular populations, the number of genetic ancestors rapidly encompassed the total number of potential ancestors, and ROHs occurred frequently due to genetic drift. Our results showed that while genealogical ancestors followed an initial exponential growth phase before stabilizing, genetic ancestors grew more slowly. This was especially the case when the initial population size was large. These findings highlight the high frequency of ROHs in smaller populations, providing insights into the genetic structure of historically isolated groups.
Altered Copper Transport in Oxidative Stress-Dependent Brain Endothelial Barrier Dysfunction Associated with Alzheimer’s Disease
Authors: Hossain Md. Selim , Das Archita , Rafiq Ashiq M. , Deák Ferenc , Bagi Zsolt , Outlaw Rashelle , Sudhahar Varadarajan , Yamamoto Mai , Kaplan Jack H. , Ushio-Fukai Masuko , Fukai Tohru 
Published: August 2024

AbstractOxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer’s Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A and/or ATP7B were downregulated in the hippocampus of AD mouse models, and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function in hBMEC (measured by transendothelial electrical resistance), and tyrosine phosphorylation of VE-cadherin were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and VE-Cadherin phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.HighlightsUpregulation of the Cu importer CTR1 and downregulation of the Cu exporter ATP7A in the hippocampus of AD mouse modelsAβ42 increases CTR1 expression while reduces ATP7A and ATP7B levels in human brain microvascular ECs.Aβ42 triggers increased reactive oxygen species (ROS) production in human brain microvascular ECs through a CTR1- and Cu-dependent manner.Aβ42 induces endothelial barrier dysfunction in human brain microvascular ECs through a CTR1-Cu-ROS-pendent manner.
Selective autophagy fine-tunes Stat92E activity by degrading Su(var)2-10/PIAS during glial injury signaling inDrosophila
Authors: Vincze Virág , Esküdt Zsombor , Fehér-Juhász Erzsébet , Chhatre Aishwarya Sanjay , Jipa András , Csordós Martin , Galambos Anna Rita , Feil-Börcsök Dalma , Juhász Gábor , Szabó Áron 
Published: August 2024

AbstractGlial immunity plays a pivotal role in the maintenance of nervous system homeostasis and in responses to stress conditions, including neural injuries. The transcription factor Stat92E is activated independently of the canonical JAK/STAT pathway inDrosophilaglial cells following central nervous system injury to shape glial reactivity towards degenerating axons. However, the upstream regulatory mechanisms governing Stat92E activation remain elusive. Here we reveal that selective autophagy mediates degradation of the PIAS SUMO ligase family member Stat92E repressor, Su(var)2-10 in glia. Autophagic elimination of Su(var)2-10 mediated by its co-localization and interaction with the core autophagy factor Atg8a is required for efficient Stat92E-dependent transcription after injury. In line with this, we demonstrate that autophagy is essential for the upregulation of an innate immune pathway in glial cells following axon injury, characterized by the induction ofvirus-induced RNA 1(vir-1). We propose that autophagic Su(var)2-10 breakdown controls Stat92E activation to allow glial reactivity. These findings identify a critical role for autophagy in glial immunity as part of neural injury responses.
Hemifusomes and Interacting Proteolipid Nanodroplets: Formation of a Novel Cellular Organelle Complex
Authors: Tavakoli Amirrasoul , Hu Shiqiong , Ebrahim Seham , Kachar Bechara 
Published: August 2024

AbstractWithin cells, vesicle fusion, scission, and the formation of intraluminal vesicles are critical processes that facilitate traffic, degradation, and recycling of cellular components, and maintenance of cellular homeostasis. Despite significant advancements in elucidating the molecular mechanisms that drive these dynamic processes, the direct in situ visualization of membrane remodeling intermediates remains challenging. Here, through the application of cryo-electron tomography in mammalian cells, we have identified a previously undescribed vesicular organelle complex with unique membrane topology: heterotypic hemifused vesicles that share extended hemifusion diaphragms (HDs) with a 42 nm proteolipid nanodroplet (PND) at their rim. We have termed these organelle complexes “hemifusomes”. The HDs of hemifusomes exhibit a range of sizes and curvatures, including the formation of lens-shaped compartments encapsulated within the membrane bilayer. The morphological diversity of the lens-shaped vesicle aligns with a step-wise process of their intraluminal budding, ultimately leading to their scission and the generation of intraluminal vesicles. We propose that hemifusomes function as versatile platforms for protein and lipid sorting and as central hubs for the biogenesis of intraluminal vesicles and the formation of multivesicular bodies.
Scanning probe microscopy elucidates gelation and rejuvenation of biomolecular condensates
Authors: Naghilou Aida , Armbruster Oskar , Mashaghi Alireza 
Published: August 2024

AbstractComprehensive understanding of dynamics and disease-associated solidification of biomolecular condensates is closely tied to analysis of their mechanical characteristics. Despite recent technical advances in rheological studies of condensates, these still vastly rely on methods restricted to small forces, rendering measurements of droplets with higher elasticities and after transition to solid challenging. Here, we develop assays for in-depth mechanical characterization of biomolecular condensates by scanning probe microscopy. We demonstrate this technique by measuring the rheological behavior of heterotypic poly-L-lysine heparin condensates, showcasing their multi-route liquid to gel transition, as well as their rejuvenation by chemical alterations to the medium. Due to the wide-spread application of scanning probe microscopy in biological fields, its capability for rapid, high throughput, high force range studies, and integration with nanoscale morphological measurements, our probe-based method is a significant breakthrough in investigating condensate behavior, leading to accelerated development of therapies.
Responses of root architectural and anatomical traits to low nitrogen stress in rice
Authors: Tian Tian , Lynch Jonathan P. , Brown Kathleen M. 
Published: August 2024

AbstractImproving nitrogen use efficiency in rice would provide economic and environmental benefits, but little is known about root morphological and anatomical responses to low nitrogen. In this study, two sets of rice genotypes, one set from the RDP1 panel, and one set of recombinant inbred lines, were used to characterize responses to gradual nitrogen depletion by plant uptake and movement of nitrogen to deeper soil strata as a result of leaching, so that more nitrogen was available at depth in aerobic soil mesocosms in a greenhouse. There was significant genetic variation in shoot biomass reductions in response to low nitrogen. The root to shoot biomass ratio was increased by low nitrogen in both sets of genotypes. Relative investment in nodal root number was accentuated with low nitrogen, and shoot biomass was correlated with numbers and lengths of nodal and large lateral roots. There was genetic variation for nodal root number and length in both sets of genotypes. Anatomical responses to low nitrogen were assessed in nodal roots of the RILs, where root cross-sectional area, stele area, and metaxylem vessel number were reduced by low nitrogen, and root diameter was reduced in the RDP1 genotypes. There were significant interactions of nitrogen with genotype for stele area and percent aerenchyma in the RILs. Genetic variation for low nitrogen responses may be useful for selection of rice lines with greater nitrogen acquisition under nitrogen-leaching conditions.
Live Cell Painting: image-based profiling in live cells using Acridine Orange
Authors: Garcia-Fossa Fernanda , Moraes-Lacerda Thaís , Rodrigues-da-Silva Mariana , Diaz-Rohrer Barbara , Singh Shantanu , Carpenter Anne E. , Cimini Beth A. , de Jesus Marcelo Bispo 
Published: August 2024

AbstractImage-based profiling has been used to analyze cell health, drug mechanism of action, CRISPR-edited cells, and overall cytotoxicity. Cell Painting is a broadly used image-based assay that uses morphological features to capture how cells respond to treatments. However, this method requires cell fixation for staining, which prevents examining live cells. To address this limitation, here we present Live Cell Painting (LCP), a high-content method based on Acridine orange, a metachromatic dye that labels different organelles and cellular structures. We began by showing that LCP can be applied to follow acidic vesicle redistribution of cells exposed to acidic vesicles inhibitors. Next, we show that LCP can identify subtle changes in cells exposed to silver nanoparticles that are not detected by techniques such as MTT assay. In drug treatments, LCP was helpful in assessing the dose-response relationship and creating profiles that allow clustering of drugs that cause liver injury. Here, we present an affordable and easy-to-use image-based assay capable of assessing overall cell health and showing promise for use in various applications such as assessing drugs and nanoparticles. We envisage the use of Live Cell Painting as an initial screening of overall cell health while providing insights into new biological questions.
Temperature effects on interspecific eavesdropping in the wild
Authors: Rossi Sarina M. , Fowler-Finn Kasey D. , Gray David A. 
Published: August 2024

AbstractMating signals are targets of conspecific signal recognition and sexual selection, but are also subject to abiotic temperature effects and to biotic interspecific eavesdroppers. In crickets, the male calling song becomes faster at warmer temperatures, and female crickets’ recognition of male song tracks temperature in a coordinated manner, termed ‘temperature coupling.’ But female crickets are not the only ecologically relevant listeners: some cricket species are parasitized byOrmia ochracea, a parasitoid fly which finds its cricket hosts by eavesdropping on male cricket song. How temperature affects parasitoid fly phonotaxis to song is largely unexplored, with only one previous study conducted under field conditions. Here we explore six possible patterns of thermal effects on fly responses to cricket song, including temperature coupling, using field playbacks of syntheticGryllus lineaticepssongs designed to be species-typical at various temperatures. We find that temperature does affect fly response, but that the temperature deviation of songs from ambient does not impact numbers of flies caught. We extend this finding by comparing the temperatures of the air and ground to show that temperature coupling is unlikely to be effective given microhabitat variation and differential rates of cooling in the evening hours when flies are most active. Our results can be interpreted more broadly to suggest (i) temperature effects on intraspecific communication systems may be more tightly coupled than are effects on interspecific eavesdropping, and (ii) variation in thermal microhabitats in the field make it difficult to translate laboratory physiological responses to natural selection in the wild.Lay SummaryMating signals and signal recognition change with temperature, and sometimes mating signals are intercepted by predators or parasites. By using playbacks of cricket song in the wild, we show that temperature changes do affect the response of a parasitoid fly to cricket song. However, parasitoid responses are not tightly coupled to temperature induced changes in cricket song, in part due to unpredictable variation in microhabitat temperatures typical of crickets and flies.
Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines
Authors: Purcell Connor , Srinivasan Praveen R. , Pinho-Schwermann Maximilian , MacDonald William J. , Ding Elizabeth , El-Deiry Wafik S. 
Published: August 2024

AbstractProstate cancer (PCa) is the leading cause death from cancer in men worldwide. Approximately 30% of castrate-resistant PCa’s become refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of androgen-sensitive tumors. First-in-class imipridone ONC201/TIC10 has shown clinical activity against midline gliomas, neuroendocrine tumors and PCa. We explored the question of whether NED promotes sensitivity to imipridones ONC201 and ONC206 by inducible overexpression of SOX2 and BRN2, well-known neuroendocrine drivers, in human PCa cell lines DU145 or LNCaP. Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells but this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells. The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.
3D-Aligner: An advanced computational tool designed to correct image distortion in expansion microscopy for precise 3D reconstitution and quantitative analysis
Authors: Loi Jonathan , Ghone Dhaval , Qu Xiaofei , Suzuki Aussie 
Published: August 2024

AbstractExpansion Microscopy (ExM) is an innovative and cost-effective super-resolution microscopy technique that has become popular in cell biology research. It achieves super-resolution by physically expanding specimens. Since its introduction, ExM has undergone continuous methodological developments to enhance its resolution and labeling capabilities. However, ExM imaging often encounters sample drift during image acquisition due to the physical movement of the expanded hydrogel, posing a significant challenge for accurate image reconstruction. Despite many proposed experimental solutions to mitigate sample drift, a universal solution has yet to be established. In response to this challenge, we developed 3D-Aligner, an advanced and user-friendly image analysis tool designed to computationally correct drift in ExM images for precise three-dimensional image reconstruction and downstream quantification. We demonstrate that 3D-Aligner effectively determines and corrects drift in ExM images with different expansion rates and various fluorescently labeled biological targets, showcasing its capabilities and robustness in drift correction. Additionally, we validate the precision of 3D-Aligner by comparing drift values across different labeled targets and highlight the importance of drift correction in quantification of biological structures.
Prediction and principle discovery of drug combination based on multimodal friendship features
Authors: Chen He-Gang , Zhou Xionghui 
Published: August 2024

AbstractCombination therapy, which can improve therapeutic efficacy and reduce side effects, plays an important role in the treatment of multiple complex diseases. Yet, the design principles of molecular combinations remain unclear. In addition, the huge search space of candidate drug combinations and the numerous heterogeneous data has brought us a big challenge. Here, we proposed a Friendship based Method (FSM), which integrates diverse drug-to-drug information to predict drug combinations for specific diseases. By quantifying the friendship-based relationship between drugs, we found that there is a moderate similarity between the drugs of effective drug combinations in a high-dimensional, heterogeneous feature space. Following this discovery, FSM applied a two-step strategy to predict clinically efficacious drug combinations for specific diseases. First, our method employs the friendship features to evaluate whether each drug is combinable. Then, the synergistic potential of combinable drugs was further evaluated. FSM was validated on two types of disease. The results show that FSM achieves substantial performance improvement over other state-of-the-art methods and tends to have low toxicity. These results indicate that our model could potentially offer a generic, powerful strategy to identify efficacious combination therapies in the vast search space.
Caveolin assemblies displace one bilayer leaflet to organize and bend membranes
Authors: Doktorova Milka , Daum Sebastian , Ebenhan Jan , Neudorf Sarah , Han Bing , Sharma Satyan , Kasson Peter , Levental Kandice R. , Bacia Kirsten , Kenworthy Anne K. , Levental Ilya 
Published: August 2024

ABSTRACTCaveolin is a monotopic integral membrane protein, widely expressed in metazoa and responsible for constructing enigmatic membrane invaginations known as caveolae. Recently, the high-resolution structure of a purified human caveolin assembly, the CAV1-8S complex, revealed a unique organization of 11 protomers arranged in a tightly packed, radially symmetric spiral disc. One face and the outer rim of this disc are highly hydrophobic, suggesting that the complex incorporates into membranes by displacing hundreds of lipids from one leaflet. The feasibility of this unique molecular architecture and its biophysical and functional consequences are currently unknown. Using Langmuir film balance measurements, we find that CAV1-8S is highly surface active and intercalates into lipid monolayers. Molecular simulations of biomimetic bilayers support this ‘leaflet replacement’ model and reveal that while CAV1-8S effectively displaces phospholipids from one bilayer leaflet, it accumulates 40−70 cholesterol molecules into a disordered monolayer between the complex and its distal lipid leaflet. We find that CAV1-8S preferentially associates with positively curved membrane surfaces due to its influence on the conformations of distal leaflet lipids, and that these effects laterally sort lipids of the distal leaflet. Large-scale simulations of multiple caveolin assemblies confirmed their association with large, positively curved membrane morphologies, consistent with the shape of caveolae. Further, association with curved membranes regulates the exposure of caveolin residues implicated in protein-protein interactions. Altogether, the unique structure of CAV1-8S imparts unusual modes of membrane interaction with implications for membrane organization, morphology, and physiology.STATEMENT OF SIGNIFICANCECaveolae are membrane invaginations heavily implicated in cellular physiology and disease; however, how their unique shape and function are produced remains enigmatic. Here, following on recent characterization of the unusual structure of the CAV1-8S oligomer, we examine the molecular details of its interactions with its solvating lipid membrane. We describe a novel mode of membrane interaction—which we term ‘leaflet replacement’—for the CAV1-8S complex that has not previously been observed for any other protein. The biophysical consequences of this unique molecular organization provide mechanistic insights into the functions and organization of caveolae in cells.
Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil
Authors: Piekos Jacqueline A. , Amorim Gustavo , Ridolfi Felipe , Cordeiro-Santos Marcelo , Kritski Afrânio L. , Figueiredo Marina C. , Andrade Bruno B. , Santos Adalberto R. , Haas David W. , Sterling Timothy R. , Rolla Valeria C. , Edwards Digna R. Velez ,   the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium
Published: August 2024

ABSTRACTTuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV.#RePORT-Brazil Consortium members include:Aline Benjamin and Flavia M. Sant’AnnaInstituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, BrazilJamile Garcia de Oliveira and João MarineClínica de Saúde Rinaldo Delmare, Rio de Janeiro, BrazilAdriana Rezende and Anna Cristina CarvalhoSecretaria de Saúde de Duque de Caxias, Rio de Janeiro, BrazilMichael Rocha and Betânia NogueiraInstituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, BrazilAlexandra Brito and Renata SpenerFundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, BrazilMegan TurnerVanderbilt University Medical Center, Nashville, USA