bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agent-based model predicts that layered structure and 3D movement work synergistically to reduce bacterial load in 3D in vitro models of tuberculosis granuloma
Authors: Petrucciani Alexa , Hoerter Alexis , Kotze Leigh , Du Plessis Nelita , Pienaar Elsje 
Published: October 2023

AbstractTuberculosis (TB) remains a global public health threat with increasing prevalence. Understanding the dynamics of host-pathogen interactions within TB granulomas will assist in identifying what leads to successful elimination of infection.In vitroTB models provide a controllable environment to study these granuloma dynamics. Previously we developed a biomimetic 3D spheroid granuloma model that controls bacteria better than a traditional monolayer culture counterpart. We used agent-based simulations to predict the mechanistic reason for this difference. Our calibrated simulations were able to predict heterogeneous bacterial dynamics that are consistent with experimental data. In one group of simulations, spheroids are found to have a higher macrophage activation than their traditional counterparts, leading to better bacterial control. This higher macrophage activation in the spheroids was not due to higher T cell activation, rather fewer activated T cells were able to activate more macrophages due to the proximity of these cells within the spheroid. In a second group of simulations, spheroids again have more macrophage activation but also more T cell activation, specifically CD8+ T cells. This higher level of CD8+ T cell activation is predicted to be due to the proximity of these cells to the cells that activate them. Multiple mechanisms of control were predicted. Virtual knockouts show one group has a CD4+ T cell dominant response, while the other has a mixed/CD8+ T cell dominant response. Lastly, we demonstrated that the initial structure and movement rules work synergistically to reduce bacterial load. These findings provide valuable insights into how the structural complexity ofin vitromodels impacts immune responses. Moreover, our study has implications for engineering more physiologically relevantin vitromodels and advancing our understanding of TB pathogenesis and potential therapeutic interventions.
Differences Between Brachial And Aortic Blood Pressure In Adolescence and their implications for diagnosis of hypertension
Authors: Hughes Alun D , Smith George Davey , Howe Laura D , Lawlor Deborah , Jones Siana , Park Chloe M , Chaturvedi Nish 
Published: October 2023

AbstractObjectivesBlood pressure is the leading global cause of mortality, and its prevalence is increasing in children and adolescents. Aortic blood pressure (BP) is lower than brachial BP in adults. We aimed to assess the extent of this difference and its impact on the diagnosis of hypertension among adolescents.MethodsWe used data from 3850 participants from a UK cohort of births in the early 1990s in the Southwest of England, who attended their ∼17 year follow-up and had valid measures of brachial and aortic BP at that clinic (mean(SD) age 17.8(0.4)y, 66% female). Data are presented as mean differences [95% prediction intervals] for both sexes.ResultsAortic systolic BP was lower than brachial systolic BP (male, -22.3[-31.2, - 13.3]mmHg; female, -17.8[-25.5, -10.0]mmHg). Differences between aortic and brachial diastolic BP were minimal. Based on brachial BP measurements, 101 males (6%) and 22 females (1%) were classified as hypertensive. In contrast, only nine males (<1%) and 14 females (<1%) met the criteria for hypertension based on aortic BP, and the predictive value of brachial BP for aortic hypertension was poor (positive predictive value = 13.8%). Participants with aortic hypertension had a higher left ventricular mass index than those with brachial hypertension.ConclusionsBrachial BP substantially overestimates aortic BP in adolescents due to marked aortic-to-brachial pulse pressure amplification. The use of brachial BP measurement may result in an overdiagnosis of hypertension during screening in adolescence.
Predictive value of Serum CCL21 and CCL19 levels in heart failure patients : A prospective study
Authors: Zeng Wenfei , Li Ling , Wang Liman , Lin Biting , Lin Kailing , Yu Peng , Yu Huizhen 
Published: October 2023

AbstractBackgroundChemokine C-C motif ligand (CCL)21 and CCL19 are well-recognized to associate with adverse events of cardiovascular disease, especially long-term prognosis. However, few studies have reported its correlation with heart failure.PurposeTo investigate and compare the predictive value of CCL21 and CCL19 serum levels in patients with heart failure.MethodsIn this prospective, observational, single-center study, 221 patients with heart failure and 55 healthy controls were included. ROC curves were generated to analyze and compare the serum levels of CCL21 and CCL19 in predicting all-cause mortality and composite events. Cox regression and Kaplan-Meier survival analyses were performed to identify independent risk factors for prognosis. Pearson correlation was used to measure the correlation between creatinine and CCL21 / CCL19 levels.ResultsThe study observed 108 events (30 deaths and 78 occurred composite endpoints) over a median follow-up of 494.5(231.5,950.0) days. CCL21 showed strong predictive value for both all-cause mortality (AUC were 0.694,P=0.001) and composite endpoints (AUC 0.661,P=0.006 and <0.001). while the combination of CCL21 and NT-proBNP further improved the predictive power, with AUC being 0.796 and 0.662 on all-cause mortality and composite endpoints, respectively (bothP<0.001). K-M survival analysis revealed that patients with increased CCL21 and CCL19 exhibited higher all-cause mortality (bothP<0.05). Meanwhile, higher incidence of composite endpoint events was also observed in patients with elevated CCL21 (P<0.05). Importantly, multivariate COX regression analysis demonstrated that smoking, higher level of CCL21 and ischemic heart disease were independent risk factors for all-cause mortality (P<0.001). Furthermore, diabetes and elevation of CCL21 were associated with an increased risk of composite endpoints (P<0.001). On the other hand, changes in CCL19 levels showed a graded association with worse renal function, resulting in a slight increasing trend in G3 and G4/5, (HR = 2.64, 95% CI= 2.26-2.66, vs. HR 2.67, 95% CI 2.57-2.91, overall interactionP<0.05), with higher concentrations in G3 and G4/5(HR = 3.67, 95% CI= 3.27-3.85, vs. HR 4.11, 95% CI 3.67-4.38; overall interactionP<0.05).ConclusionsSerum concentrations of CCL21 and CCL19 were significantly elevated in heart failure patients. High level of CCL21 is an independent risk factor for the adverse events in heart failure and may complement the prediction of those events which are less affected by renal function.
In vitrodevelopment and optimization of cell-laden injectable bioprinted gelatin methacryloyl (GelMA) microgels mineralized on the nanoscale
Authors: Sousa Mauricio Gonçalves da Costa , Balbinot Gabriela de Souza , Subbiah Ramesh , Visalakshan Rahul Madathiparambil , Tahayeri Anthony , Lima Verde Maria Elisa , Athirasala Avathamsa , Romanowicz Genevieve , Guldberg Robert E. , Bertassoni Luiz E. 
Published: October 2023

AbstractBone defects may occur in different sizes and shapes due to trauma, infections, and cancer resection. Autografts are still considered the primary treatment choice for bone regeneration. However, they are hard to source and often create donor-site morbidity. Injectable microgels have attracted much attention in tissue engineering and regenerative medicine due to their ability to replace inert implants with a minimally invasive delivery. Here, we developed novel cell-laden bioprinted gelatin methacrylate (GelMA) injectable microgels, with controllable shapes and sizes that can be controllably mineralized on the nanoscale, while stimulating the response of cells embedded within the matrix. The injectable microgels were mineralized using a calcium and phosphate-rich medium that resulted in nanoscale crystalline hydroxyapatite deposition and increased stiffness within the crosslinked matrix of bioprinted GelMA microparticles. Next, we studied the effect of mineralization in osteocytes, a key bone homeostasis regulator. Viability stains showed that osteocytes were maintained at 98% viability after mineralization with elevated expression of sclerostin in mineralized compared to non-mineralized microgels, indicating that mineralization effectively enhances osteocyte maturation. Based on our findings, bioprinted mineralized GelMA microgels appear to be an efficient material to approximate the bone microarchitecture and composition with desirable control of sample injectability and polymerization. These bone-like bioprinted mineralized biomaterials are exciting platforms for potential minimally invasive translational methods in bone regenerative therapies.
Overriding Mendelian inheritance inArabidopsiswith a CRISPR toxin-antidote gene drive that impairs pollen germination
Authors: Liu Yang , Jiao Bingke , Champer Jackson , Qian Wenfeng 
Published: October 2023

AbstractSynthetic gene drives, inspired by natural selfish genetic elements, present transformative potential for disseminating traits that benefit humans throughout wild populations, irrespective of potential fitness costs. Here, we constructed a gene drive system called CRISPR-Assisted Inheritance utilizingNPG1(CAIN), which employs a toxin-antidote mechanism in the male germline to override Mendelian inheritance in plants. Specifically, a gRNA-Cas9 cassette targets the essentialNo Pollen Germination 1(NPG1) gene, serving as the toxin to block pollen germination. A recoded, CRISPR-resistant copy ofNPG1serves as the antidote, providing rescue only in pollen cells that carry the drive. To limit potential consequences of inadvertent release, we used self-pollinatingArabidopsis thalianaas a model. The drive demonstrated a robust 88–99% transmission rate over two successive generations, producing minimal resistance alleles that are unlikely to inhibit drive spread. Our study provides a strong basis for rapid genetic modification or suppression of outcrossing plant populations.
Unprecedented spike flexibility revealed by BSL3 Cryo-ET of active SARS-CoV-2 virions
Authors: Fukuhara Hideo , Dokainish Hisham M. , Kita Shunsuke , Tabata Koshiro , Takasu Akira , Huiskonen Juha T. , Anraku Yuki , Senda Toshiya , Stuart David I. , Sasaki Michihito , Orba Yasuko , Suzuki Yasuhiko , Sawa Hirofumi , Maenaka Katsumi 
Published: October 2023

AbstractUnderstanding the molecular properties of SARS-CoV-2 is crucial to tackle future outbreaks. Current knowledge of the trimeric spike protein relies on truncated recombinant proteins and inactivated full-length forms, which may suffer from overstabilization. Here, we apply cryo-electron tomography (cryo-ET) at a Biosafety level 3 facility to study the virus structure in its native, active state. The virus particles show variable shapes with diffusible spikes, with the majority in typical prefusion conformations. Notably, we also identified unprecedented, atypical open-trimer prefusion states, revealing hidden flexibility. The sub-tomogram averaged structure suggests a loosely packed trimer. The observed dynamics uncover conserved cryptic regions that can be targeted for broadly effective vaccines. Structural analysis of active viruses will have implications on understanding overlooked fusion mechanism and vaccine, antibody/drug design. (124 words)One-Sentence SummaryThe BSL3 cryo-electron microscopy uncovered significant flexibility of the spike protein on active viruses, which will facilitate the design of broadly effective vaccines and drugs.
Seminal plasma inhibits Chlamydia trachomatis infectionin vitro, and may have consequences on mucosal immunity
Authors: Reot Louis , Adapen Cindy , Cannou Claude , Nunez Natalia , Lakoum Sabrine , Pimienta Camille , Lacroix Laetitia , Binois Olivier , Frydman Nelly , Nugeyre Marie-Thérèse , Le Grand Roger , Menu Elisabeth 
Published: October 2023

AbstractSeminal plasma (SP) is the main vector ofC. trachomatis(CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimentalin vitromodel to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.
Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells
Authors: Deen Ashik Jawahar , Adinolfi Simone , Härkönen Jouni , Patinen Tommi , Liu Xiaonan , Laitinen Tuomo , Takabe Piia , Kainulainen Kirsi , Pasonen-Seppänen Sanna , Gawriyski Lisa M , Arasu Uma Thanigai , Selvarajan Ilakya , Mäkinen Petri , Laitinen Hanna , Kansanen Emilia , Kaikkonen Minna U , Poso Antti , Varjosalo Markku , Levonen Anna-Liisa 
Published: October 2023

AbstractThe Kelch-like ECH-associated protein 1 (KEAP1) – Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα)–Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and the mutants was employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.
Inferring ecological selection from multidimensional community trait distributions along environmental gradients
Authors: Kaarlejärvi Elina , Itter Malcolm , Tonteri Tiina , Hamberg Leena , Salemaa Maija , Merilä Päivi , Vanhatalo Jarno , Laine Anna-Liisa 
Published: October 2023

AbstractUnderstanding the drivers of community assembly is critical for predicting the future of biodiversity and ecosystem services. While trait-based frameworks are often used to this end, correlations among traits and the assumption of unimodal trait-abundance distributions confound detection of the underlying processes. To overcome these caveats, here we quantify multidimensional trait distributions of communities (community trait niches), which we use to identify ecological selection types shaping communities along environmental gradients. We find that directional, stabilizing, and divergent selection all modify community trait niches in over 3600 boreal forest understory plant communities, and selection on a particular trait may change from one type to another over time. Our results provide novel and rare empirical evidence from a natural system for divergent selection. The results also show that while higher trait diversity (measured as trait niche volume) is generally associated with higher species richness, high resource availability may enable tighter niche packing. Jointly our approach provides a framework for identifying key traits under selection and facilitates the detection of processes underlying community dynamics.
Male gonad-enriched microRNAs function to control sperm production inC. elegans
Authors: Lu Lu , Abbott Allison L. 
Published: October 2023

AbstractGerm cell development and gamete production in animals require small RNA pathways. While studies indicate that microRNAs (miRNAs) are necessary for normal sperm production and function, the specific roles for individual miRNAs are largely unknown. Here, we use small RNA sequencing of dissected gonads and functional analysis of new loss of function alleles to identify functions for miRNAs in the control of fecundity and sperm production inCaenorhabditis elegansmales and hermaphrodites. We describe a set of 29 male gonad-enriched miRNAs and identify a set of 3 individual miRNAs (mir-58.1, mir-83,andmir-235)and a miRNA cluster (mir-4807-4810.1)that are required for optimal sperm production at 20°C and 5 additional miRNAs (mir-49, mir-57, mir-261,andmir-357/358) that are required for sperm production at 25°C. We observed defects in meiotic progression inmir-58.1, mir-83, mir-235,andmir-4807-4810.1mutants that may contribute to the reduced number of sperm. Further, analysis of multiple mutants of these miRNAs suggested complex genetic interactions between these miRNAs for sperm production. This study provides insights on the regulatory roles of miRNAs that promote optimal sperm production and fecundity in males and hermaphrodites.Article SummaryMicroRNAs are small non-coding RNAs that are required for the normal production of sperm but the roles of individual microRNAs in the process of spermatogenesis are not well understood. Here, we use the nematodeCaenorhabditis elegansto identify microRNAs that are enriched in the male gonad to identify specific microRNAs that regulate male fertility. We generated new loss of function mutants for functional analysis to identify a set of microRNAs that are necessary for optimal fertility and fecundity in males.
HetMM: A Michaelis-Menten model for non-homogeneous enzyme mixtures
Authors: Douglas Jordan , Carter Charles W. , Wills Peter R. 
Published: October 2023

AbstractThe Michaelis-Menten model requires its reaction velocities to be measured from a preparation of homogeneous enzymes, with identical or near-identical catalytic activities. However, there are many cases where enzyme preparations do not satisfy this condition, or where one may wish to test the validity of this assumption. We introduce a kinetic model that relaxes this requirement, by assuming there are an unknown number of enzyme species drawn from an unknown probability distribution. This model features one additional parameter over the Michaelis-Menten model, describing the standard deviation of this distribution. We show that the assumption of homogeneity is usually sufficient even in non-homogeneous solutions, and only fails under extreme conditions where Km spans orders of magnitude. We validate this method through simulation studies, demonstrating the method does not overfit to random noise, despite its increase in dimensionality. The two models can be accurately discriminated between even with moderate levels of experimental error. We applied this model to three homogeneous and three heterogeneous biological systems, showing that the standard and heterogeneous models outperform in either case, respectively. Lastly, we show that heterogeneity is not readily distinguished from negatively-cooperative binding under the Hill model. These two fundamentally distinct properties - inequality in catalytic ability and interference between binding sites - give similar Michaelis-Menten curves that are not readily resolved without further experimentation. Our method allows testing for homogeneity and performing parameter inference in a Bayesian framework, and is available online in the user-friendly HetMM package athttps://github.com/jordandouglas/HetMM.
Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis
Authors: Wang Qi , Huang Taida , Zheng Zihan , Su Yixun , Wu Zhonghao , Yu Guangdan , Liu Yang , Wang Xiaorui , Li Hui , Chen Xiaoying , Jiang Zhuoxu , Zhang Jinyu , Zhuang Yuan , Tian Yi , Yang Qingwu , Verkhratsky Alexei , Wan Ying , Yi Chenju , Niu Jianqin 
Published: October 2023

SummaryThe immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+T-helper 1 (Th1) cells into the spinal cord and brain through CC-chemokine ligand 4 (CCL4), whilst OPCs cooperate with Th1 cells inducing transformation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology.