bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders
Authors: Viardot-Foucault Veronique , Zhou Jieliang , Bi Dexi , Takinami Yoshihiko , Chan Jerry. K. Y. , Lee Yie Hou 
Published: June 2023

Abstract
Background
Poor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes through tightly controlled metabolism and cell signaling. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment, but the impact DHEA imposes on the FF metabolome and cytokine profiles is unknown. Therefore, the objective of this study is to profile and identify metabolomic changes in the FF with DHEA supplementation in POR patients.

Methods
FF samples collected from 52 POR patients who underwent IVF with DHEA supplementation (DHEA +) and without (DHEA-; controls) were analyzed using untargeted liquid chromatography-tandem mass spectrometry (LC–MS/MS) metabolomics and a large-scale multiplex suspension immunoassay covering 65 cytokines, chemokines and growth factors. Multivariate statistical modelling by partial least squares-discriminant regression (PLSR) analysis was performed for revealing metabolome-scale differences. Further, differential metabolite analysis between the two groups was performed by PLSR β-coefficient regression analysis and Student’s t-test.

Results
Untargeted metabolomics identified 118 FF metabolites of diverse chemistries and concentrations which spanned three orders of magnitude. They include metabolic products highly associated with ovarian function – amino acids for regulating pH and osmolarity, lipids such fatty acids and cholesterols for oocyte maturation, and glucocorticoids for ovarian steroidogenesis. Four metabolites, namely, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA + relative to DHEA- (p < 0.05–0.005). The area under the curves of progesterone glycerophosphocholine, linoleic acid and valine are 0.711, 0.730, 0.785 and 0.818 (p < 0.05–0.01). In DHEA + patients, progesterone positively correlated with IGF-1 (Pearson r: 0.6757, p < 0.01); glycerophosphocholine negatively correlated with AMH (Pearson r: -0.5815; p < 0.05); linoleic acid correlated with estradiol and IGF-1 (Pearson r: 0.7016 and 0.8203, respectively; p < 0.01 for both).
In DHEA- patients, valine negatively correlated with serum-free testosterone (Pearson r: -0.8774; p < 0.0001). Using the large-scale immunoassay of 45 cytokines, we observed significantly lower MCP1, IFNγ, LIF and VEGF-D levels in DHEA + relative to DHEA.

Conclusions
In POR patients, DHEA supplementation altered the FF metabolome and cytokine profile. The identified four FF metabolites that significantly changed with DHEA may provide information for titrating and monitoring individual DHEA supplementation.
One-pot synthesis of fuel precursor from acetoin fermentation broth using ionic liquid-based salting-out extraction system
Authors: Zhang Hanxiao , Li Yan , Zhuang Jing , Dai Jianying , Xiu Zhi-Long , Quan Chunshan 
Published: June 2023

Abstract
Background
The development of biofuels, especially liquid hydrocarbon fuels, has been widely concerned due to the depletion of fossil resources. In order to obtain fuel precursors, the reaction of C–C bond formation is usually carried out with biomass derived ketones/aldehydes as reactants. Acetoin and 2,3-butanediol are two platform chemicals, which are co-existed in fermentation broth and traditionally separated by distillation, and then acetoin could be use as C4 building block to prepare hydrocarbon fuels. In order to mitigate the process complexity, direct aldol condensation reaction of acetoin in fermentation broth was studied in this work.

Results
A one-pot process of product separation and acetoin derivative synthesis was proposed based on salting-out extraction (SOE). Aldol condensation reaction of acetoin and 5-methyl furfural in different SOE systems was compared, and the results showed that the synthesis of C10 fuel precursors and separation of C10 products and 2,3-butanediol from fermentation broth were achieved in one-pot with ethanolammonium butyrate (EOAB) and K2HPO4 as SOE reagents and catalysts. The SOE and reaction conditions such as the concentrations of EOAB and K2HPO4, reaction temperature and time were optimized. When the system was composed of 6 wt% EOAB-44 wt% K2HPO4 and the mixture was stirred for 6 h at 200 rpm, 40 ℃, the yield of C10 products was 80.7%, and 95.5% 2,3-butanediol was distributed to the top EOAB-rich phase. The exploration of reaction mechanism showed that an imine intermediate was rapidly formed and the subsequent C10 product formation was the key step for aldol condensation reaction.

Conclusions
With EOAB and K2HPO4 as SOE reagents and catalysts, one-pot synthesis of fuel precursor from acetoin fermentation broth was achieved without prior purification. A yield of 80.7% for C10 products was obtained which was accumulated at the interface of two aqueous-phase, and 95.5% 2,3-BD was distributed to the top EOAB-rich phase. This work provides a new integration process of product separation and derivative synthesis from fermentation broth based on ionic liquid SOE.

Graphical Abstract
Regression modelling of conditional morphogene expression links and quantifies the impact of growth rate, fitness and macromorphology with protein secretion in Aspergillus niger
Authors: Cairns Timothy C. , de Kanter Tom , Zheng Xiaomei Z. , Zheng Ping , Sun Jibin , Meyer Vera 
Published: June 2023

AbstractBackgroundFilamentous fungi are used as industrial cell factories to produce a diverse portfolio of proteins, organic acids, and secondary metabolites in submerged fermentation. Generating optimized strains for maximum product titres relies on a complex interplay of molecular, cellular, morphological, and macromorphological factors that are not yet fully understood.ResultsIn this study, we generate six conditional expression mutants in the protein producing ascomyceteAspergillus nigerand use them as tools to reverse engineer factors which impact total secreted protein during submerged growth. By harnessing gene coexpression network data, we bioinformatically predicted six morphology and productivity associated ‘morphogenes’, and placed them under control of a conditional Tet-on gene switch using CRISPR-Cas genome editing. Strains were phenotypically screened on solid and liquid media following titration of morphogene expression, generating quantitative measurements of growth rate, filamentous morphology, response to various abiotic perturbations, Euclidean parameters of submerged macromorphologies, and total secreted protein. These data were built into a multiple linear regression model, which identified radial growth rate and fitness under heat stress as positively correlated with protein titres. In contrast, diameter of submerged pellets and cell wall integrity were negatively associated with productivity. Remarkably, our model predicts over 60% of variation inA. nigersecreted protein titres is dependent on these four variables, suggesting that they play crucial roles in productivity and are high priority processes to be targeted in future engineering programs. Additionally, this study suggestsA. niger dlpAandcrzAgenes are promising new leads for enhancing protein titres during fermentation.ConclusionsTaken together this study has identified several potential genetic leads for maximizing protein titres, delivered a suite of chassis strains with user controllable macromorphologies during pilot fermentation studies, and has quantified four crucial factors which impact secreted protein titres inA. niger.
Utilizing biologic disease-modifying anti-rheumatic treatment sequences to subphenotype rheumatoid arthritis
Authors: Das Priyam , Weisenfeld Dana , Dahal Kumar , De Debsurya , Feathers Vivi , Coblyn Jonathan S. , Weinblatt Michael E. , Shadick Nancy A. , Cai Tianxi , Liao Katherine P. 
Published: June 2023

Abstract
Background
Many patients with rheumatoid arthritis (RA) require a trial of multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) to control their disease. With the availability of several bDMARD options, the history of bDMARDs may provide an alternative approach to understanding subphenotypes of RA. The objective of this study was to determine whether there exist distinct clusters of RA patients based on bDMARD prescription history to subphenotype RA.

Methods
We studied patients from a validated electronic health record-based RA cohort with data from January 1, 2008, through July 31, 2019; all subjects prescribed ≥ 1 bDMARD or targeted synthetic (ts) DMARD were included. To determine whether subjects had similar b/tsDMARD sequences, the sequences were considered as a Markov chain over the state-space of 5 classes of b/tsDMARDs. The maximum likelihood estimator (MLE)-based approach was used to estimate the Markov chain parameters to determine the clusters. The EHR data of study subjects were further linked with a registry containing prospectively collected data for RA disease activity, i.e., clinical disease activity index (CDAI). As a proof of concept, we tested whether the clusters derived from b/tsDMARD sequences correlated with clinical measures, specifically differing trajectories of CDAI.

Results
We studied 2172 RA subjects, mean age 52 years, RA duration 3.4 years, and 62% seropositive. We observed 550 unique b/tsDMARD sequences and identified 4 main clusters: (1) TNFi persisters (65.7%), (2) TNFi and abatacept therapy (8.0%), (3) on rituximab or multiple b/tsDMARDs (12.7%), (4) prescribed multiple therapies with tocilizumab predominant (13.6%). Compared to the other groups, TNFi persisters had the most favorable trajectory of CDAI over time.

Conclusion
We observed that RA subjects can be clustered based on the sequence of b/tsDMARD prescriptions over time and that the clusters were correlated with differing trajectories of disease activity over time. This study highlights an alternative approach to consider subphenotyping of patients with RA for studies aimed at understanding treatment response.
Real-time Remote Expert-guided Echocardiography by Medical Students
Authors: Solvin Håvard , Lippert Matthias , Holmstrøm Henrik , Elle Ole Jakob , Brun Henrik 
Published: June 2023

Abstract
Background
Echocardiography is a highly specialised examination performed by experienced healthcare professionals. These experienced healthcare professionals may not be available to patients during all hours in rural healthcare facilities. Remote-guided echocardiography could improve the availability of specialised care for patients living in rural areas. This study examined the feasibility of real-time remote guidance for medical students to perform an echocardiographic assessment of the left side of the heart. Thirteen healthy volunteers were recruited for remote-guided echocardiography, which was performed by 13 medical students. Student examinations/images were compared to reference echocardiography. Measurements of left ventricular fractional shortening and mitral valve blood flow velocity were also compared. Furthermore, guidance through a smartphone videoconference was compared to designated remote guidance software.

Results
Two-thirds of the images acquired by students were rated as medium or good quality and usable to evaluate two thirds of the cardiac structures. No significant bias was found for left ventricular fractional shortening. The measurements from the students’ exams had a variation coefficient of 14.8% compared to the reference. The calculated deviation of the insonation angle was above 25° for both E and A-wave mitral valve blood flow velocity measurements. Images acquired by guidance through smartphone videoconference were of lower quality than those obtained using the designated remote guidance software.

Conclusion
Real-time remote-guided echocardiography performed by medical students has limited value for clinical screening but could be useful for educational purposes.

Graphical Abstract
PHDs-seq: a large-scale phenotypic screening method for drug discovery through parallel multi-readout quantification
Authors: Li Jun , Chi Jun , Yang Yang , Song Zhongya , Yang Yong , Zhou Xin , Liu Yang , Zhao Yang 
Published: June 2023

AbstractHigh-throughput phenotypic screening is a cornerstone of drug development and the main technical approach for stem cell research. However, simultaneous detection of activated core factors responsible for cell fate determination and accurate assessment of directional cell transition are difficult using conventional screening methods that focus on changes in only a few biomarkers. The PHDs-seq (Probe Hybridization based Drug screening by sequencing) platform was developed to evaluate compound function based on their transcriptional effects in a wide range of signature biomarkers. In this proof-of-concept demonstration, several sets of markers related to cell fate determination were profiled in adipocyte reprogramming from dermal fibroblasts. After validating the accuracy, sensitivity and reproducibility of PHDs-seq data in molecular and cellular assays, a panel of 128 signalling-related compounds was screened for the ability to induce reprogramming of keloid fibroblasts (KF) into adipocytes. Notably, the potent ATP-competitive VEGFR/PDGFR inhibitor compound, ABT869, was found to promote the transition from fibroblasts to adipocytes. This study highlights the power and accuracy of the PHDs-seq platform for high-throughput drug screening in stem cell research, and supports its use in basic explorations of the molecular mechanisms underlying disease development.
Modelling renewable energy communities: assessing the impact of different configurations, technologies and types of participants
Authors: Belmar Francisco , Baptista Patrícia , Neves Diana 
Published: June 2023

Abstract
Background
Energy communities (ECs) have emerged as a solution to support governments mitigating climate change and comply with decarbonization goals, while introducing end-users on the energy value chain. In this paradigm, citizens have an active role in reducing electricity demand from the utility grid, by generating, sharing and/or trading locally generated renewable energy, such as solar energy. However, the economic and environmental outputs of energy communities are dependent on a variety of factors, such as technology features (renewable energy generation, existence of flexible equipment and/or energy storage systems), types of participants (consumers and prosumers with different electricity intensity and load profiles), and electricity sharing/trading agreements. As such, assessing the impact these will have on delivering benefits to the energy community and its participants is of paramount importance.

Methods
This work models different energy communities’ design typologies in Lisbon, Portugal considering different types of consumers with heterogenous electricity demand profiles and willingness to participate, multiple technology deployment scenarios (solar systems installation, batteries, and electric vehicles), and electricity trading (collective self-consumption versus peer-to-peer trading).

Results
Results demonstrate community electricity cost savings are up to 42%, with self-sufficiency rate up to 12.5%, which is considerably low due to the participation of high demanding sectors (such as industry or retail). At participants’ individual level, electricity costs savings can reach 48% and 53%, for residential consumers and prosumers, respectively, while for high-demanding participants are slightly lower: 43% for hotel, 44% for retail, 13% for industry and 5% for university. Individual self-sufficiency rates register highest results for the residential prosumers (35% for PV prosumers, 28% for PV + electric vehicles and 54% with PV + batteries) while for other participants results fall between 6% (retail) and 26% (industry).

Conclusions
We conclude that for ECs deployment, individual PV self-consumption assets are not sufficient, thus greater PV sizes and higher adoption rates should be considered, according to consumer and prosumers shares. The share/trade of PV surplus, paired with competitive aggregation tariffs results in positive economic and environmental outputs, for the majority of both consumers and prosumers.
Entrepreneurial leadership, learning organization and organizational culture relationship: a systematic literature review
Authors: Shiferaw Robson Mekonnin , Birbirsa Zerihun Ayenew , Werke Shimels Zewdie 
Published: June 2023

AbstractThe purpose of this study is to examine the relations between organizational culture, learning organizations, and entrepreneurial leadership. The study concentrated on how organizational culture, learning organizations, and entrepreneurial leadership are measured in the literature. The study used a systematic literature review methodology analysis that was published in reputable and peer-reviewed English research journals to look at how organizational culture, learning organizations, and entrepreneurial leadership are related to one another. The study used content analysis on 27 peer-reviewed journal articles that were discovered in various journals examined in the databases, which was based on a systematic examination of the literature. This study offers a comprehensive view of entrepreneurial leadership that has been linked to learning organizations and organizations in various enterprises and nations. The study looked at research approaches, sample sizes, data gathering tools, implications, and limits from the body of literature. The study is also one of the first of its kind to review the research on the connection between entrepreneurial leadership, learning organizations, and organizational culture. The outcomes of this study help the scientific community underline the connection between entrepreneurial leadership, learning organizations, and organizational culture for upcoming policy makers.
Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program
Authors: Wendt Frank R. , Pathak Gita A. , Vahey Jacqueline , Qin Xuejun , Koller Dora , Cabrera-Mendoza Brenda , Haeny Angela , Harrington Kelly M. , Rajeevan Nallakkandi , Duong Linh M. , Levey Daniel F. , De Angelis Flavio , De Lillo Antonella , Bigdeli Tim B. , Pyarajan Saiju ,   VA Million Veteran Program, Gaziano John Michael , Gelernter Joel , Aslan Mihaela , Provenzale Dawn , Helmer Drew A. , Hauser Elizabeth R. , Polimanti Renato ,   Department of Veteran Affairs Cooperative Study Program (#2006)
Published: June 2023

Abstract
Background
The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]).

Results
Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen’s d < 0.259, p < 7.80 × 10−4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics.

Conclusions
This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.
X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease
Authors: Gromova Anastasia , Cha Byeonggu , Robinson Erica M. , Strickland Laura M. , Nguyen Nhat , ElMallah Mai K. , Cortes Constanza J. , La Spada Albert R. 
Published: June 2023

AbstractX-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally.