bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probing the basis of disease heterogeneity in multiple sclerosis using genetically diverse mice
Authors: Holt Emily A. , Tyler Anna , Lakusta-Wong Taylor , Lahue Karolyn G. , Hankes Katherine C. , Teuscher Cory , Lynch Rachel M. , Ferris Martin T. , Mahoney J. Matthew , Krementsov Dimitry N. 
Published: June 2024

AbstractMultiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The thirty-two CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary (AR)-EAE, accompanied by distinct immunopathology. Sex differences in EAE severity were observed in six strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4andGpc6) and AR-EAE (Yap1andDync2h1). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.SummaryThe genetic basis of disease heterogeneity in multiple sclerosis (MS) remains elusive. We leveraged the Collaborative Cross to expand the phenotypic repertoire of the experimental autoimmune encephalomyelitis (EAE) model of MS and identify loci controlling EAE severity, trajectory, and presentation.
Reassessing Retinal Pigment Epithelial Ketogenesis: Enzymatic Assays for Ketone Body Levels Provide Inaccurate Results
Authors: Gulette Gillian A. , Hass Daniel T. , Pandey Kriti , Zhang Qitao , Han John Y.S. , Engel Abbi , Chao Jennifer R. , Philp Nancy J. , Hurley James B. , Miller Jason M.L. 
Published: June 2024

AbstractThe retinal pigment epithelium (RPE) is omnivorous and can utilize a wide range of substrates for oxidative phosphorylation. Certain tissues with high mitochondrial metabolic load are capable of ketogenesis, a biochemical pathway that consolidates acetyl-CoA into ketone bodies. Earlier work demonstrated that the RPE expresses the rate-limiting enzyme for ketogenesis, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and that the RPE indeed produces ketone bodies, including beta-hydroxybutyrate (β-HB). Prior work, based on detecting β-HB via enzymatic assays, suggested that differentiated cultures of primary RPE preferentially export β-HB across the apical membrane. Here, we compare the accuracy of measuring β-HB by enzymatic assay kits to mass spectrometry analysis. We found that commercial kits lack the sensitivity to accurately measure the levels of β-HB in RPE cultures and are prone to artifact. Using mass spectrometry, we found that while RPE cultures secrete β-HB, they do so equally to both apical and basal sides. We also find RPE is capable of consuming β-HB as levels rise. Using isotopically labeled glucose, amino acid, and fatty acid tracers, we found that carbons from both fatty acids and ketogenic amino acids, but not from glucose, produce β-HB. Altogether, we substantiate β-HB secretion in RPE but find that the secretion is equal apically and basally, RPE β-HB can derive from ketogenic amino acids or fatty acids, and accurate β-HB assessment requires mass spectrometric analysis.
Resistance Exercise and Mechanical Overload Upregulate Vimentin for Skeletal Muscle Remodeling
Authors: Godwin Joshua S. , Michel J. Max , Libardi Cleiton A. , Kavazis Andreas N. , Fry Christopher S. , Frugé Andrew D. , McCashland Mariah , Vechetti Ivan J. , McCarthy John J. , Mobley C. Brooks , Roberts Michael D. 
Published: June 2024

ABSTRACTOur laboratory has performed various experiments examining the proteomic alterations that occur with mechanical overload (MOV)-induced skeletal muscle hypertrophy. In the current study we first sought to determine how 10 weeks of resistance training in 15 college-aged females affected protein concentrations in different tissue fractions. Training, which promoted significantly lower body muscle- and fiber-level hypertrophy, notably increased sarcolemmal/membrane protein content (+10.1%, p<0.05). Sarcolemmal/membrane protein isolates were queried using mass spectrometry-based proteomics, ∼10% (38/387) of proteins associated with the sarcolemma were up-regulated (>1.5-fold, p<0.05), and one of these targets (the intermediate filament vimentin; VIM) warranted further mechanistic investigation. VIM expression was first examined in the plantaris muscles of 4-month-old C57BL/6J mice following 10- and 20-days of MOV via synergist ablation. Relative to Sham (control) mice, VIM mRNA and protein content was significantly higher in MOV mice and immunohistochemistry indicated that VIM was predominantly present in the extracellular matrix (ECM). The 10- and 20-day MOV experiments were replicated in Pax7-DTA (tamoxifen-induced, satellite cell depleted) mice, which reduced the presence of VIM in the ECM. Finally, a third set of 10- and 20-day MOV experiments were performed in C57BL/6 mice intramuscularly injected with either AAV9-scrambled (control) or AAV9-VIM shRNA. While VIM shRNA mice presented with lower VIM in the ECM (∼50%), plantaris masses in response to MOV were similar between the injection groups. However, VIM shRNA mice presented with appreciably more MyHCemb-positive fibers with centrally located nuclei, indicating a regenerative phenotype. Using an integrative approach, we propose that skeletal muscle VIM is a mechanosensitive target predominantly localized to the ECM, and satellite cells are involved in its expression. Moreover, a disruption in VIM expression during MOV leads to dysfunctional skeletal muscle hypertrophy.
CTPS1 inhibition synergizes with replication stress signaling inhibition inMYC-amplified Group 3 medulloblastoma
Authors: Hathaway Matthew R , Gadek Katherine E , Jagana Hawa L , Terrones Isabella C , Hemenway John M , Miyaki Aya , Rajendran Ashmitha , Meechan Michael , Elena-Sanchez Leonel , Vitanza Nicholas A , Slusher Barbara S , Pattwell Siobhan S , Evans Myron K 
Published: June 2024

AbstractMYC-driven medulloblastomas (MBs) represent the most aggressive and deadly subgroup of MB, the most common malignant pediatric tumor. Direct targeting of MYC itself remains an unmet clinical need, therefore focusing on vulnerabilities driven by MYC may be a viable option for novel therapeutic interventions. Using whole-genome CRISPR screening, we identified thede novopyrimidine synthesis enzyme CTP synthase (CTPS1) as a strong dependency inMYC-driven MB. CTPS1 is the final and rate-limiting step in thede novopyrimidine synthesis pathway. Targeted inhibition of CTPS1 leads to decreased tumor cell proliferation and markedly reduces MYC expression in G3 MB models. Mechanistically, we demonstrate that single agent CTPS1 inhibition activates the replication stress signaling pathway mediated by ATM-CHK2 and ATR-CHK1. Blockade of CHK1 kinase activity increases sensitivity to CTPS1 inhibition and significantly impedes heterotopic MB tumor growth. CTPS1 enzymatic activity requires the amino acid glutamine, therefore we inhibited CTPS1 using the glutamine antagonists, JHU083 and JHU395. These compounds are prodrugs of 6-diazo-5-oxo-L-norleucine (DON) which were developed to exhibit exquisite blood-brain barrier penetrability. Combining JHU083 and CHK1 inhibition demonstrates potent synergy against patient-derived MB xenograftsin vivo. Our findings strongly suggest that combiningde novopyrimidine synthesis and ATR-CHK1 inhibitors is a promising treatment forMYC-driven MBs.Key PointsCTPS1is a unique vulnerability in MYC-driven medulloblastomaCTPS1 inhibition activates the ATR-CHK1 replication stress response pathway for cell survivalBlockade of CTPS1 enzymatic activity synergizes with CHK1 inhibitionin vitroandin vivoImportance of the StudyMYC hyperactivation in tumors drives multiple anabolic processes which contribute to tumor proliferation and aggressiveness in patients. We show that targetingde novopyrimidine synthesis (via CTPS1) limits tumor growth and targets MYC itself through a feedback mechanism. CTPS1 inhibition potently combines with CHK1 blockade and enhances disease control in both heterotopic and orthotopic models of medulloblastoma (MB). Our results support the clinical evaluation of combined CTPS1 and CHK1 inhibition in patients withMYC-driven MB.
URA6mutations provide an alternative mechanism for 5-FOA resistance inSaccharomyces cerevisiae
Authors: Armstrong Joseph O. , Jiang Pengyao , Tsai Skyler , Phan Megan My-Ngan , Harris Kelley , Dunham Maitreya J. 
Published: June 2024

AbstractURA3is frequently used in the yeast community as the mutation target for 5-fluoroorotic acid (5-FOA) resistance. We identified a novel class ofura6mutants that can grow in the presence of 5-FOA. Unlikeura3mutants,ura6mutants remain prototrophic and grow in the absence of uracil. In addition to 5-FOA resistance, we found that mutations toURA6also confer resistance to 5-fluorocytosine (5-FC) and 5-fluorouracil (5-FU). In total, we identified 50 unique missense mutations across 32 residues ofURA6. We found that 28 out of the 32 affected residues are located in regions conserved betweenSaccharomyces cerevisiaeand three clinically relevant pathogenic fungi. These findings suggest that mutations toURA6present a second target for mutation screens utilizing 5-FOA as a selection marker as well as a potential mode of resistance to the antifungal therapeutic 5-FC.
Magnified interaural level differences enhance binaural unmasking in bilateral cochlear implant users
Authors: Richardson Benjamin N. , Kainerstorfer Jana M. , Shinn-Cunningham Barbara G. , Brown Christopher A. 
Published: June 2024

ABSTRACTBilateral cochlear implant (BiCI) usage makes binaural benefits a possibility for implant users. Yet for BiCI users, limited access to interaural time difference (ITD) cues and reduced saliency of interaural level difference (ILD) cues restricts perceptual benefits of spatially separating a target from masker sounds. The present study explored whether magnifying ILD cues improves intelligibility of masked speech for BiCI listeners in a “symmetrical-masker” configuration, which ensures that neither ear benefits from a long-term positive target-to-masker ratio (TMR) due to naturally occurring ILD cues. ILD magnification estimates moment-to-moment ITDs in octave-wide frequency bands, and applies corresponding ILDs to the target-masker mixtures reaching the two ears at each specific time and frequency band. ILD magnification significantly improved intelligibility in two experiments: one with NH listeners using vocoded stimuli and one with BiCI users. BiCI listeners showed no benefit of spatial separation between target and maskers with natural ILDs, even for the largest target-masker separation. Because ILD magnification relies on and manipulates only the mixed signals at each ear, the strategy never alters the monaural TMR in either ear at any time. Thus, the observed improvements to masked speech intelligibility come from binaural effects, likely from increased perceptual separation of the competing sources.
ECloudGen: Leveraging Electron Clouds as a Latent Variable to Scale Up Structure-based Molecular Design
Authors: Zhang Odin , Jin Jieyu , Wu Zhenxing , Zhang Jintu , Yuan Po , Lin Haitao , Zhong Haiyang , Zhang Xujun , Hua Chenqing , Zhao Weibo , Zhang Zhengshuo , Ying Kejun , Huang Yufei , Zhao Huifeng , Yu Yuntao , Kang Yu , Pan Peichen , Wang Jike , Guo Dong , Zheng Shuangjia , Hsieh Chang-Yu , Hou Tingjun 
Published: June 2024

AbstractStructure-based molecule generation represents a significant advancement in AI-aided drug design (AIDD). However, progress in this domain is constrained by the scarcity of structural data on protein-ligand complexes, a challenge we term the Paradox of Sparse Chemical Space Generation. To address this limitation, we propose a novel latent variable approach that bridges the data gap between ligand-only and protein-ligand complexes, enabling the target-aware generative models to explore a broader chemical space and enhancing the quality of molecular generation. Drawing inspiration from quantum molecular simulations, we introduce ECloudGen, a generative model that leverages electron clouds as meaningful latent variables—an innovative integration of physical principles into deep learning frameworks. ECloudGen incorporates modern techniques, including latent diffusion models, Llama architectures, and a newly proposed contrastive learning task, which organizes the chemical space into a structured and highly interpretable latent representation. Benchmark studies demonstrate that ECloudGen outperforms state-of-the-art methods by generating more potent binders with superior physiochemical properties and by covering a significantly broader chemical space. The incorporation of electron clouds as latent variables not only improves generative performance but also introduces model-level interpretability, as illustrated in a case study designing V2R inhibitors. Furthermore, ECloudGen’s structurally ordered modeling of chemical space enables the development of a model-agnostic optimizer, extending its utility to molecular optimization tasks. This capability has been validated through a single-objective oracle benchmark and a complex multi-objective optimization scenario involving the redesign of endogenous BRD4 ligands. In conclusion, ECloudGen effectively addresses the Paradox of Sparse Chemical Space Generation through its integration of theoretical insights, advanced generative techniques, and real-world validation. The newly proposed technique of leveraging physical entities (such as electron clouds) as latent variables within a deep learning framework may prove useful for computational biology fields beyond AIDD.
Inducible biosynthesis of bacterial cellulose in recombinantEnterobactersp. FY-07
Authors: Ren Jiaxun , Miao Liangtian , Feng Wei , Ma Ting , Jiang Huifeng 
Published: June 2024

AbstractBacterial cellulose (BC) is an extracellular polysaccharide with myriad unique properties, such as high purity, water-holding capacity and biocompatibility, making it attractive in materials science. However, genetic engineering techniques for BC-producing microorganisms are rare. Herein, the electroporation-based gene transformation and the λ Red-mediated gene knockout method with a nearly 100% recombination efficiency were established in the fast-growing and BC hyperproducerEnterobactersp. FY-07. This genetic manipulation toolkit was validated by inactivating the protein subunit BcsA in the cellulose synthase complex. Subsequently, the inducible BC-producing strains from glycerol were constructed through inducible expression of the key genefbpin the gluconeogenesis pathway, which recovered more than 80% of the BC production. Finally, the BC properties analysis results indicated that the induced-synthesized BC pellicles were looser, more porous and reduced crystallinity, which could further broaden the application prospects of BC. To our best knowledge, this is the first attempt to construct the completely inducible BC-producing strains. Our work paves the way for increasing BC productivity by metabolic engineering and broadens the available fabrication methods for BC-based advanced functional materials.
Modelling COVID-19 mutant dynamics: understanding the interplay between viral evolution and disease transmission dynamics
Authors: Saldaña Fernando , Stollenwerk Nico , Aguiar Maíra 
Published: June 2024

AbstractUnderstanding virus mutations is critical for shaping public health interventions. These mutations lead to complex multi-strain dynamics often underrepresented in models. Aiming to understand the factors influencing variants’ fitness and evolution, we explore several scenarios of virus spreading to gain qualitative insight into the factors dictating which variants ultimately predominate at the population level. To this end, we propose a two-strain stochastic model that accounts for asymptomatic transmission, mutations, and the possibility of disease import. We find that variants with milder symptoms are likely to spread faster than those with severe symptoms. This is because severe variants can prompt affected individuals to seek medical help earlier, potentially leading to quicker identification and isolation of cases. However, milder or asymptomatic cases may spread more widely, making it harder to control the spread. Therefore, increased transmissibility of milder variants can still result in higher hospitalizations and fatalities due to widespread infection. The proposed model highlights the interplay between viral evolution and transmission dynamics. Offering a nuanced view of factors influencing variant spread, the model provides a foundation for further investigation into mitigating strategies and public health interventions.
Ce3Bi4Ni3
– A large hybridization-gap variant of
Ce3Bi4Pt3
Authors: Kirschbaum D. M. , Yan X. , Waas M. , Svagera R. , Prokofiev A. , Stöger B. , Giester G. , Rogl P. , Oprea D.-G. , Felser C. , Valentí R. , Vergniory M. G. , Custers J. , Paschen S. , Zocco D. A. 
Published: June 2024

The family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65–70 meV, about eight times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3−Ce3Bi4Pd3−Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the d orbitals at the Fermi energy. This work opens the possibility to investigate the conditions under which topological states develop in this series of strongly correlated 3-4-3 materials.

Published by the American Physical Society
2024
Response surface methodology and experimental evaluation of the inhibitory properties of corn leaf extract for aluminum corrosion in acid media
Authors: Emereole Justin C , Njoku Chigoziri N , Ikeuba Alexander I , Ekeke Ifenyinwa C , Yakubu Emmanuel , Nkuzinna Ogbonna C , Nnodum Nnamdi A , Nwakaudu Madueke S 
Published: June 2024

Purpose
This study aims to develop eco-friendly corrosion inhibitors for aluminum in acidic media by evaluating the corrosion inhibition properties of corn leaf extract (CLE) using response surface methodology (RSM) and experiments.

Design/methodology/approach
The RSM was combined with experiments to evaluate the corrosion inhibition properties of CLE on aluminum in acid media.

Findings
The effectiveness of the inhibition increased with increasing inhibitor concentration and time but decreased with increasing temperature. The corrosion inhibition mechanism revealed the corrosion process is spontaneous exothermic physical adsorption. Thermodynamic parameters revealed an activation energy between 32.1 and 24.7 kJ/mol, energy of adsorption between −14.53 and −65.07 and Gibbs free energy of −10.12 kJ/mol which indicated the CLE exothermically spontaneously physisorbed. A model was generated to estimate the effect of the process parameters (inhibitor concentration, reaction time and temperature) using the RSM. Optimization of the process factors was also carried out using the RSM. The percentage inhibition efficiency obtained experimentally (85.61%) was closely comparable to 84.89% obtained by the theoretical technique (RSM). The SEM observations of the inhibited and uninhibited Al samples demonstrated that CLE is an effective corrosion inhibitor for aluminum in acid media.

Originality/value
Results herein provide novel information on the possible application of CLEs as effective eco-friendly corrosion inhibitors.
Transaction costs and innovation outcomes: lessons from early adopters of housebuilding innovations
Authors: Kavaarpuo Godwin , Tiwari Piyush , Martel Andrew 
Published: June 2024

Purpose
This study aims to examine the transaction costs (TCs) involved in searching for a business case to adopt specific walling innovations by housing developers and the influence of these TCs on their adoption outcomes. This is against the backdrop that innovation adoption, like any new venture, is failure-prone but necessary for countries to reap the full benefits of technological innovation in residential developments, especially when these innovations are also green. Moreover, this issue is understudied.

Design/methodology/approach
The study uses a qualitative design and focuses on the early adopting developers in Ghana. The original theoretical framework integrates theories on entrepreneurial opportunity discovery and TC economics. The authors interviewed 12 developers and 13 industry stakeholders purposively identified. The authors analysed and triangulated the resulting transcripts using thematic analysis techniques.

Findings
The authors identified two types of early adopters who attempted eight types of walling innovations. Most efforts (71%) were partially successful or failed. The range of TCs identified differed by the adopter type, technology and knowledge coordination strategy. Although the common TCs that were consequential were associated with monitoring and supervision, construction, additional learning, acquiring specialised skills, design change and dispute resolutions, their influence on adoption outcomes is very nuanced.

Originality/value
To the best of the authors’ knowledge, this paper is among the first to link TCs with innovation adoption outcomes by housing developers in discovering profitable opportunities to adopt specific walling innovations. The findings and theoretical framework lay a foundation for in-depth analyses of the entrepreneurship of innovation adoption in residential real estate. The exploratory work will generate further interest in this area.