bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of 3.6 million individuals yields minimal evidence of pairwise genetic interactions for height
Authors: Jabalameli M.Reza , Holmes Michael V , Hinds David ,   23andMe Research Team, Auton Adam , Fontanillas Pierre 
Published: August 2024

AbstractAdult height is a highly heritable polygenic trait with heritability attributable to thousands of independent variants. Large-scale studies have been able to detect genetic variants with contributions to height in the range of approximately 1.2 millimetre per allele copy on average. Non-additive genetic interactions may, in part, account for the difference between broad-sense and narrow-sense heritability estimates. However, prior studies have failed to identify variants with non-additive effects, possibly due to the lack of statistical power. Leveraging 3.6M individuals of European genetic ancestry in the 23andMe research cohort, we performed a genome-wide analysis study (GWAS) to select 1,063 independent common SNPs associated with height (p-value < 5e-8), and then screened for evidence of non-additive effects by analysing 564,453 models including a pairwise SNP-SNP interaction term. We identified 69 pairwise models with suggestive evidence of SNP-SNP interaction (p-value < 1e-4) and, for each SNP pair, we evaluated a fully saturated model including additive, dominant, and epistatic (additive-by-additive, additive-by-dominance and dominance-by-dominance) terms. We tested for the presence of epistatic interactions by comparing models with and without epistatic terms using a likelihood ratio test. Assuming a strict Bonferroni-corrected threshold of 8.9e-8 (0.05/564,453), we found no evidence of epistatic interactions (Likelihood ratio test (LRT) p-value < 9e-07 for all models). Our analysis rules out the existence of epistatic interactions between alleles of >1% frequency with effect sizes larger than 2.42mm. Our large-scale analysis provides further evidence of the minimal contribution of non-additivity in the genetic architecture of adult human height.
Efficacy and Safety of Albendazole 400 mg for 30 Days in Adults Patients with LowLoa loaMicrofilaremia: A Non-Inferiority Randomized Controlled Trial Compared to Ivermectin
Authors: Akomezoghe Luccheri Ndong , M’Bondoukwé Noé Patrick , Mawili Mboumba Denise Patricia , Ndong Ngomo Jacques Mari , Bridy Chesli Moutombi Ditombi , Sibi Matotou Hadry Roger , Migueba Valentin , Bouyou Akotet Marielle Karine 
Published: August 2024

AbstractBackgroundLoa loainfection is endemic in central African countries like Gabon and in West Africa. Treatment typically involves the use of ivermectin and albendazole, with albendazole often used to reduce microfilaremia in individuals with high microfilaremia before administering ivermectin. This study aims to evaluate the efficacy and safety of albendazole in patients with low microfilaremia.Methodology and principal findingsThe study was conducted from November 7 to April 1 across 31 villages in the Woleu-Ntem province of northern Gabon. Following a questionnaire, venous blood was collected in EDTA tubes forLoa loadiagnosis. Eligible individuals were randomized into two treatment groups and followed for 30 days. One group received daily albendazole tablets (400 mg), while the other received a single dose of ivermectin (200μg/kg). The study reported a 33.0% prevalence ofLoa loainfection in northern Gabon. In the per-protocol analysis, the mean microfilaremia decreased significantly by 82.3% and 90.4% in the ALB and IVM groups, respectively (p˂ 0.001). The risk difference between the treatments was 8.1% [95% CI: 16.8; −0.6%]. For the intention-to-treat analysis, the mean microfilaremia decreased significantly by 82.4% and 90.8% in the ALB and IVM groups, respectively (p˂ 0.001), with a risk difference of 8.4% [95% CI: 16.2; 0.6%]. Eosinophil rates decreased by day 30 in both groups, though not significantly different (p>0.05).Conclusions/SignificanceThe prevalence ofLoa loainfection (33.05%) is notably high in northern Gabon. Albendazole demonstrated microfilaricidal activity in individuals with lowLoa loamicrofilaremia. However, its efficacy appears inferior to that of ivermectin and seems to diminish at very low microfilarial loads.Author summaryLoa loainfection is endemic in central African countries, including Gabon, and across West Africa. Despite the absence of specific treatments developed forLoa loa, current therapeutic approaches predominantly rely on diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB). Although ALB is more readily available, it is typically reserved for patients with high microfilaremia due to potential severe adverse effects following treatment with IVM. This study aimed to evaluate the efficacy and safety of ALB as an alternative treatment for patients with low microfilaremia compared to IVM. The findings suggest that ALB could serve as a viable alternative for the treatment of microfilaremic loiasis. Moreover, ALB treatment demonstrated adequate clinical efficacy and safety comparable to that of IVM.
Cardiovascular health in early pregnancy and circulating biomarkers of placental health and function
Authors: Kozai Andrea C. , Gibbs Bethany Barone , Parry Samuel , Khan Sadiya S. , Grobman William , Levine Lisa D. , McNeil Rebecca , Haas David M. , Pippen Jessica L. , Silver Robert M. , Catov Janet M. 
Published: August 2024

AbstractBackgroundMaternal cardiovascular health (CVH) and placental health are related to pregnancy outcomes, yet how early pregnancy CVH affects placentation is not well characterized. The objective of this study was to determine associations between CVH and concentrations of placental proteins.MethodsParticipants from the nuMoM2b prospective cohort were included (n=2188). Maternal CVH was defined three ways: (1) composite scores using 6 components measured in the 1sttrimester (four behavioral components of physical activity, diet, sleep duration, and smoking, and the health factors of blood pressure and body mass index); (2) latent classes of the four behavioral components; and (3) individual health behaviors. Linear regression associated composite CVH, latent classes, and individual health behaviors with 1stand 2ndtrimester circulating markers of placental growth and development (pregnancy-associated plasma protein A, PAPP-A), pro-angiogenic (vascular endothelial growth factor, VEGF; placental growth factor, PlGF), and anti-angiogenic factors (soluble FMS-like tyrosine kinase 1, sFlt-1; soluble endoglin, sEng).Results and ConclusionsMore favorable composite CVH was associated with higher PAPP-A (representing better 1sttrimester placental growth and development) and lower VEGF and higher sEng (representing an anti-angiogenic 1sttrimester profile). Higher levels of physical activity were associated with lower 2ndtrimester PAPP-A and higher 1sttrimester VEGF and lower sFlt-1 (pro-angiogenic). In the four groups identified with latent class analysis (Healthy Behaviors, Active with Poor Diet, Inactive with Poor Diet, and Less Healthy Behaviors), first trimester sFlt- 1 was lower in the Healthy Behaviors group compared to Inactive with Poor Diet group. Modifiable aspects of CVH in early pregnancy are related to placental health and function and may be useful targets for intervention.Clinical PerspectiveWhat is New?Combinations of modifiable health behaviors in early pregnancy are related to circulating markers of placental development and function.These associations varied according to trimester of placental biomarker assessment, suggesting that patterns across gestation may be informative.More physical activity in the 1sttrimester was associated with lower PAPP-A concentrations in the 2ndtrimester without a concurrent increase in the rate of adverse outcomes.What are the Clinical Implications?This study suggests that more favorable cardiovascular health in early pregnancy may be related to differences in placental health and function as reflected by higher concentrations of PAPP-A.One mechanism of the benefits of physical activity in early pregnancy may be through improved angiogenic/anti-angiogenic balance as measured by VEGF and sFlt-1 in the 1sttrimester.
Data-driven risk/benefit estimator for multiple sclerosis therapies
Authors: Bielekova Bibiana , Wu Tianxia , Kosa Peter , Calcagni Michael 
Published: August 2024

AbstractBackgroundMultiple sclerosis (MS) disease-modifying treatments (DMTs) are tested in patients pre-selected for favorable risk/benefits ratios but prescribed broadly in clinical practice. We aimed to establish data-driven computations of individualized risk/benefit ratios to optimize MS care.MethodsWe derived determinants of DMTs efficacy on disability progression from re-analysis and integration of 61 randomized, blinded Phase 2b/3 clinical trials that studied 46,611 patients for 91,787 patient-years. From each arm we extracted 80 and computed 30 features to identify and adjust for biases, and to use in multiple regression models. DMTs mortality risks were estimated from age mortality tables modified by published hazard ratios.FindingsBaseline characteristics of the recruited patients determine disability progression rates and DMTs efficacies with high effect sizes. DMTs efficacies increase with MS lesional activity (LA) measured by relapses or contrast-enhancing lesions and decrease with increasing age, disease duration and disability. Unexpectedly, as placebo arms’ relapse rate rapidly declines with trial duration, efficacy of MS DMTs likewise decreases quickly with treatment duration. Conversely, DMTs morbidity/mortality risks increase with age, advanced disability, and comorbidities. We integrated these results into an interactive personalized web based DMTs risk/benefit estimator.InterpretationResults predict that prescribing DMTs to patients traditionally excluded from MS clinical trials causes more harm than benefit. Treatment with high efficacy drugs at MS onset followed by de-escalation to DMTs that do not increase infectious risks would optimize risk/benefit. DMTs targeting mechanisms of progression independent of LA are greatly needed as current DMTs inhibit disability caused by LA only.
Phylogenetic analysis of Centralspindlin and Ect2 provides mechanistic insights into the emergence of Metazoa and multicellularity
Authors: Glotzer Michael 
Published: August 2024

AbstractObligate multicellularity evolved at least 5 times in eukaryotes, including at the origin of Metazoa [1, 2]. However, the molecular events leading to the acquisition of multicellularity are not understood in any lineage. Here, I present an integrated analysis into the contemporaneous emergence of three regulators of cytokinesis and the Metazoan kingdom. Phylogenetic and computational structural analyses indicate that the simultaneous presence of three key regulators of cytokinesis, Kif23, Cyk4, and Ect2 is Metazoan-specific. Structurally, these proteins are highly conserved across all Metazoa. These cytokinetic regulators link the plane of cell division with the position of the spindle during anaphase and subsequently nucleate assembly of stable intercellular bridges [3–6], structures prevalent in Metazoan germlines [7]. Furthermore, certain Choanoflagellates and more basal amoeboid species, some of which exhibit incomplete cytokinesis, encode divergent orthologs of these regulators. These findings, in conjunction with prior knowledge, suggests that evolutionary refinement of these three cytokinetic regulators directly contributed to the evolution of Metazoan multicellularity and germline development.
Toss GERALT into chloroplast to make it green: a new regulator of chloroplast biogenesis and chlorophyll biosynthesis
Authors: Banaś Agnieszka Katarzyna , Grzyb Joanna , Zgłobicki Piotr , Pacak Andrzej , Myśliwa-Kurdziel Beata , Leja Katarzyna , Kozieradzka-Kiszkurno Małgorzata , Kłodawska Kinga , Konieczny Robert , Pilarska Maria , Niewiadomska Ewa , Bażant Aneta , Szewc Łukasz , Kowalska Ewa B. , Strzałka Wojciech 
Published: August 2024

AbstractProteins belonging into cryptochrome/photolyase family act as either blue light photoreceptors or as enzymes responsible for repair of pyrimidine dimers produced under UV. Surprisingly, the members of plant-specific photolyase/blue-light receptor 2 (PPL/PHR2) subclade of this family, are almost completely uncharacterized. Here, we focused on the physiological role of protein encoded by ArabidopsisAt2g47590gene. Our results demonstrate for the first time its crucial role in cotyledon greening and maintenance of plant fitness. Based on the phenotype of the mutant inAt2g47590gene i.e. albino cotyledons and pale green true leaves we named this geneGERALT(GERMINATIONALBINOTRANSIENT).Using different approach including analysis of plant phenotypes, chloroplast sizes and architecture, transcriptomes, photosynthetic pigments, maximum PSII quantum yield (FV/FM) we show that the proper plant functioning is the effect of co-operation of GERALT-dependent and -independent pathways with the role of the former diminishing with plant age. Lower levels of transcripts dependent on plastid encoded polymerase and higher levels of these dependent on nuclear encoded polymerase, smaller chloroplasts with large grana stacks and very weakly developed stromal thylakoids, lower levels of photosynthetic pigments with higher chlorophyll a/b ratio, are among characteristic features ofgeraltplants. We believe that these results encourage scientific community to study PPL/PHR2 proteins which seems to play a special role in plants.
Identification of stable reference genes inEdwardsiella ictalurifor accurate gene expression analysis
Authors: Lu Jingjun , Abdelhamed Hossam , Al-Janabi Nawar , Eissa Nour , Lawrence Mark , Karsi Attila 
Published: August 2024

AbstractEdwardsiella ictaluriis a Gram-negative bacterium causing enteric septicemia of catfish (ESC), leading to significant economic losses in the catfish farming industry. RT-PCR analysis is a powerful technique for quantifying gene expression, but normalization of expression data is critical to control experimental errors. Using stable reference genes, also known as housekeeping genes, is a common strategy for normalization, yet reference gene selection often lacks proper validation. In this work, our goal was to determine the most stable reference genes inE. ictaluriduring catfish serum exposure and various growth phases. To this goal, we evaluated the expression of 27 classical reference genes (16SrRNA,abcZ,adk,arc,aroE,aspA,atpA,cyaA,dnaG,fumC,g6pd,gdhA,glnA,gltA,glyA,grpE,gyrB,mdh,mutS,pgi,pgm,pntA,recA,recP,rpoS,tkt,and tpi) using five analytical programs (GeNorm, BestKeeper, NormFinder, Comparative ΔCT, and Comprehensive Ranking). Results showed thataspA,atpA,dnaG,glyA,gyrB,mutS,recP,rpoS,tkt, andtpiwere the most stable reference genes during serum exposure, whereasfumC,g6pd,gdhA,glnA, andmdhwere the least stable. During various growth phases,aspA,g6pd,glyA,gyrB,mdh,mutS,pgm,recA,recP,and tktwere the most stable, while 16S rRNA,atpA,grpE,and tpiwere the least stable. At least four analysis methods confirmed the stability ofaspA,glyA,gyrB,mutS,recP, andtktduring serum exposure and different growth stages. However, no consensus was found among the programs for unstable reference genes under both conditions.
3D Microphysiological Tumor Model for Dual-Targeting CAR T Cell Immunotherapy
Authors: Peng Xuan , Janićijević Željko , Loureiro Liliana Rodrigues , Hoffmann Lydia , Lee Poh Soo , Cela Isli , Kruppke Benjamin , Kegler Alexandra , Feldmann Anja , Bachmann Michael , Baraban Larysa 
Published: August 2024

AbstractThe efficiency of immunotherapy stays limited for solid tumors. It is mainly caused by the tumoral structural heterogeneity and its complex microenvironment, which impede the infiltration of immune cells into malignant tissues. Mimicking this environment in frames of microphysiological models remains a challenge, significantly increasing costs of the clinical translation for the new therapies. Here, we study a 3D multi-spheroid model incorporating prostate stem cell antigen (PSCA) modified PC3 human prostate cancer cells and fibroblast activation protein (FAP) expressing fibrosarcoma HT1080 cells embedded within the soft hydrogel microbeads. We use this model to trial the immunotherapy based on the universal chimeric antigen receptor (UniCAR) T cells, and to better understand the impact of FAP on the immunotherapeutic treatment of solid tumors. First, we demonstrate the successful chemoattraction and infiltration of UniCAR T cells into the area of solid tumors, as well as the ability of UniCAR T cells to navigate through artificial extracellular matrix barriers. We further observe the synergistic efficacy of a dual-targeting UniCAR T cell approach against FAP and PSCA antigens, which represent the tumor microenvironment and the tumor, respectively. The results of our studies offer valuable methodologies and insights for engineering different 3D tumor models and studying immunotargeting of small-sized solid tumors (e.g., metastases and residual tumors). The developed microphysiological system has great potential to advance cancer research efforts aiming to elucidate the pivotal role of microenvironment in solid tumor development, enabling therapy trials and more precise prognosis for patients.
The abundance change of age-regulated secreted proteins affects lifespan ofC. elegans
Authors: Bhunia Prasun Kumar , Raj Vishwajeet , Kasturi Prasad 
Published: August 2024

AbstractProteome integrity is vital for survival and failure to maintain it results in uncontrolled protein abundances, misfolding and aggregation which cause proteotoxicity. In multicellular organisms, proteotoxic stress is communicated among tissues to maintain proteome integrity for organismal stress resistance and survival. However, nature of these signalling molecules and their regulation in extracellular space is largely unknown. Secreted proteins are induced in response to various stresses and aging, indicating their roles in the inter tissue communication. To study fates of age-regulated proteins with potential localization to extracellular, we analysed publicly available age-related proteome data ofC. elegans. We found that abundance of proteins with signal peptides (SP) increases with age and result in their aggregation. Intriguingly, these changes are differentially regulated in the lifespan mutants. A subset of these SP proteins is also found in the cargo of extracellular vesicles. Many of these proteins are novel and functionally uncharacterized. Reducing levels of a few extracellular proteins result in increasing lifespan. This suggest that uncontrolled levels of extracellular proteins might disturb proteostasis and limit the lifespan. Overall, our findings suggest that the age induced secreted proteins might be the potential candidates to be considered as biomarkers or for mitigating age-related pathological conditions.
Tryptophanase disruption underlies the evolution of insect-bacterium mutualism
Authors: Wang Yayun , Moriyama Minoru , Koga Ryuichi , Oguchi Kohei , Hosokawa Takahiro , Takai Hiroki , Shigenobu Shuji , Nikoh Naruo , Fukatsu Takema 
Published: August 2024

AbstractAnimal-microbe symbioses are omnipresent, where both partners often gain benefits as mutualists. How such mutualism has evolved between originally unrelated organisms is of interest. Here we report that, using an experimental symbiotic system between the stinkbugPlautia staliand the model bacteriumEscherichia coli, disruption of a single bacterial genetnaAencoding tryptophanase makesE. colimutualistic toP. stali. Survey of natural bacterial mutualists across wild populations ofP. staliand other stinkbug species uncovered that theirPantoea-allied symbionts consistently lacktnaAgene. SomePantoeaspecies likeP. ananatisretaintnaAgene and cannot establish symbiosis withP. stali, buttnaA-disruptedP. ananatispartially restored the symbiotic capability. When a naturalPantoeamutualist ofP. staliwas transformed with a functionaltnaoperon, its symbiotic capability reduced significantly. Our finding suggests that tryptophanase disruption may have facilitated the evolution of gut bacterial mutualists in insects.
A chaotic study of love dynamics with competition using fractal-fractional operator
Authors: Kumar Anil , Shaw Pawan Kumar , Kumar Sunil 
Published: August 2024

PurposeThe objective of this work is to analyze the necessary conditions for chaotic behavior with fractional order and fractal dimension values of the fractal-fractional operator.Design/methodology/approachThe numerical technique based on the fractal-fractional derivative is implemented over the fractional model and analyzes the condition at the distinct values of fractional order and fractal dimension.FindingsThe obtained numerical solution from the numerical technique is analyzed at distinct fractional order and fractal dimension values, and it has been figured out that the behavior of the solution either chaotic or non-chaotic agrees with the condition.Originality/valueThe necessary condition is associated with the fractional order only. So, our work not only studies the condition with fractional order but also examines the model by simultaneously adjusting fractal dimension values. It is found that the model still has chaotic or non-chaotic behavior at certain fractal dimension values and fractional order values corresponding to the condition.
A group decision-making model for architectural programming in megaprojects
Authors: Tu Huijun , Jin Shitao 
Published: August 2024

PurposeDue to the complexity and diversity of megaprojects, the architectural programming process often involves multiple stakeholders, making decision-making difficult and susceptible to subjective factors. This study aims to propose an architectural programming methodology system (APMS) for megaprojects based on group decision-making model to enhance the accuracy and transparency of decision-making, and to facilitate participation and integration among stakeholders. This method allows multiple interest groups to participate in decision-making, gathers various perspectives and opinions, thereby improving the quality and efficiency of architectural programming and promoting the smooth implementation of projects.Design/methodology/approachThis study first clarifies the decision-making subjects, decision objects, and decision methods of APMS based on group decision-making theory and value-based architectural programming methods. Furthermore, the entropy weight method and fuzzy TOPSIS method are employed as calculation methods to comprehensively evaluate decision alternatives and derive optimal decision conclusions. The workflow of APMS consists of four stages: preparation, information, decision, and evaluation, ensuring the scientific and systematic of the decision-making process.FindingsThis study conducted field research and empirical analysis on a practical megaproject of a comprehensive transport hub to verify the effectiveness of APMS. The results show that, in terms of both short-distance and long-distance transportation modes, the decision-making results of APMS are largely consistent with the preliminary programming outcomes of the project. However, regarding transfer modes, the APMS decision-making results revealed certain discrepancies between the project's current status and the preliminary programming.Originality/valueAPMS addresses the shortcomings in decision accuracy and stakeholder participation and integration in the current field of architectural programming. It not only enhances stakeholder participation and interaction but also considers various opinions and interests comprehensively. Additionally, APMS has significant potential in optimizing project performance, accelerating project processes, and reducing resource waste.