bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-step genomic BLUP with many metafounders
Authors: Kudinov Andrei A. , Koivula Minna , Aamand Gert P. , Strandén Ismo , Mäntysaari Esa A. 
Published: November 2022

Single-step genomic BLUP (ssGBLUP) model for routine genomic prediction of breeding values is developed intensively for many dairy cattle populations. Compatibility between the genomic (G) and the pedigree (A) relationship matrices remains an important challenge required in ssGBLUP. The compatibility relates to the amount of missing pedigree information. There are two prevailing approaches to account for the incomplete pedigree information: unknown parent groups (UPG) and metafounders (MF). unknown parent groups have been used routinely in pedigree-based evaluations to account for the differences in genetic level between groups of animals with missing parents. The MF approach is an extension of the UPG approach. The MF approach defines MF which are related pseudo-individuals. The MF approach needs a Γ matrix of the size number of MF to describe relationships between MF. The UPG and MF can be the same. However, the challenge in the MF approach is the estimation of Γ having many MF, typically needed in dairy cattle. In our study, we present an approach to fit the same amount of MF as UPG in ssGBLUP with Woodbury matrix identity (ssGTBLUP). We used 305-day milk, protein, and fat yield data from the DFS (Denmark, Finland, Sweden) Red Dairy cattle population. The pedigree had more than 6 million animals of which 207,475 were genotyped. We constructed the preliminary gamma matrix (Γpre) with 29 MF which was expanded to 148 MF by a covariance function (Γ148). The quality of the extrapolation of the Γpre matrix was studied by comparing average off-diagonal elements between breed groups. On average relationships among MF in Γ148 were 1.8% higher than in Γpre. The use of Γ148 increased the correlation between the G and A matrices by 0.13 and 0.11 for the diagonal and off-diagonal elements, respectively. [G]EBV were predicted using the ssGTBLUP and Pedigree-BLUP models with the MF and UPG. The prediction reliabilities were slightly higher for the ssGTBLUP model using MF than UPG. The ssGBLUP MF model showed less overprediction compared to other models.
Distinct clinical pattern of colorectal cancer patients with POLE mutations: A retrospective study on real-world data
Authors: Jiang Miao , Jia Yongliang , Han Jinming , Shi Jianxiang , Su Chang , Zhang Rui , Xing Menglu , Jin Shuiling , Zong Hong 
Published: November 2022

Objective: Studies have demonstrated an association between somatic POLE exonuclease domain mutations (EDMs) and the prognosis of colorectal cancer (CRC). However, the prognostic value of POLE non-EDMs remains unclear. This retrospective study aimed to explore the possible relationships between POLE mutation subtypes and CRC prognosis.Methods: The 272 CRC patients from the First Affiliated Hospital of Zhengzhou University (ZZ cohort) and 499 CRC patients from The Cancer Genome Atlas database (TCGA cohort) were retrospectively collected. The cases were divided into subgroups based on POLE mutation sites and microsatellite instability (MSI) status. The continuous variables were compared among three subgroups with Kruskal-Wallis tests. Pairwise comparisons between three groups were performed by Bonferroni correction method, and adjusted p &lt; 0.05 was considered statistically significant. The categorical variables were compared with Chi-square test and Fisher’s exact test. The Kaplan—Meier curves and Cox regression models were conducted to evaluate prognostic values of POLE mutations.Results: In the ZZ cohort, POLE EDMs (2.6%) were significantly associated with younger age (p = 0.018) and localized in the left colon (p = 0.001). POLE non-EDMs were significantly associated with MSI-high status (p &lt; 0.001) and localization in the right colon (p = 0.001). In the TCGA cohort, the tumor mutation burden (TMB) of both POLE EDM tumors (p &lt; 0.001) and POLE non-EDM tumors (p &lt; 0.001) was significantly higher than that of POLE wild-type (WT) tumors. A similar trend was observed in the ZZ cohort, although there were no significant differences. In the ZZ cohort, the POLE EDM group had higher progression-free survival (PFS) (p = 0.002) and overall survival (OS) (p = 0.042) than the POLE non-EDM group and POLE WT group. We also report one CRC patient harboring a germline POLE mutation who received camrelizumab and exhibited long-term stable disease.Conclusion: Both POLE-EDMs and POLE non-EDMs were associated with significantly increased TMB in CRC and may be biomarkers for CRC treatment and prognosis. Current evidence does not support an effect of POLE non-EDMs on PFS and OS. A significant association between POLE EDMs and improved PFS and OS may exist, but future studies with larger sample sizes are needed. Entire coding region of the POLE gene should be screened.
The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective
Authors: Hu Xueqing , Zhang Yingru , Yu Hao , Zhao Yiyang , Sun Xiaoting , Li Qi , Wang Yan 
Published: November 2022

IntroductionDysregulation of the Hippo signaling pathway has been implicated in multiple pathologies, including cancer, and YAP1 is the major effector of the pathway. In this study, we assessed the role of YAP1 in prognostic value, immunomodulation, and drug response from a pan-cancer perspective.MethodsWe compared YAP1 expression between normal and cancerous tissues and among different pathologic stages survival analysis and gene set enrichment analysis were performed. Additionally, we performed correlation analyses of YAP1 expression with RNA modification-related gene expression, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint regulator expression, and infiltration of immune cells. Correlations between YAP1 expression and IC50s (half-maximal inhibitory concentrations) of drugs in the CellMiner database were calculated.ResultsWe found that YAP1 was aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications, particularly m6A methylation. High expression of YAP1 was associated with poor survival outcomes in ACC, BLCA, LGG, LUAD, and PAAD. YAP1 expression was negatively correlated with the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, and positively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in pan-cancer. Higher YAP1 expression showed upregulation of TGF-β signaling, Hedgehog signaling, and KRAS signaling. IC50s of FDA-approved chemotherapeutic drugs capable of inhibiting DNA synthesis, including teniposide, dacarbazine, and doxorubicin, as well as inhibitors of hypoxia-inducible factor, MCL-1, ribonucleotide reductase, and FASN in clinical trials were negatively correlated with YAP1 expression.DiscussionIn conclusion, YAP1 is aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications. High expression of YAP1 is associated with poor survival outcomes in certain cancer types. YAP1 may promote tumor progression through immunosuppression, particularly by suppressing the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, as well as recruiting MDSCs and CAFs in pan-cancer. The tumor-promoting activity of YAP1 is attributed to the activation of TGF-β, Hedgehog, and KRAS signaling pathways. AZD2858 and varlitinib might be effective in cancer patients with high YAP1 expression.
Epigenetic-related gene mutations serve as potential biomarkers for immune checkpoint inhibitors in microsatellite-stable colorectal cancer
Authors: Liu Chao , Xiao Huiting , Cui Luying , Fang Lin , Han Shuling , Ruan Yuli , Zhao Wenyuan , Zhang Yanqiao 
Published: November 2022

BackgroundCombination therapy with immune checkpoint inhibitors (ICIs) may benefit approximately 10-20% of microsatellite-stable colorectal cancer (MSS-CRC) patients. However, there is a lack of optimal biomarkers. This study aims to understand the predictive value of epigenetic-related gene mutations in ICIs therapy in MSS-CRC patients.MethodsWe analyzed DNA sequences and gene expression profiles from The Cancer Genome Atlas (TCGA) to examine their immunological features. The Harbin Medical University Cancer Hospital (HMUCH) clinical cohort of MSS-CRC patients was used to validate the efficacy of ICIs in patients with epigenetic-related gene mutations (Epigenetic_Mut).ResultsIn TCGA, 18.35% of MSS-CRC patients (78/425) had epigenetic-related gene mutations. The Epigenetic_Mut group had a higher tumor mutation burden (TMB) and frameshift mutation (FS_mut) rates. In all MSS-CRC samples, Epigenetic_Mut was elevated in the immune subtype (CMS1) and had a strong correlation with immunological features. Epigenetic_Mut was also associated with favorable clinical outcomes in MSS-CRC patients receiving anti-PD-1-based therapy from the HMUCH cohort. Using immunohistochemistry and flow cytometry, we demonstrated that Epigenetic_Mut samples were associated with increased anti-tumor immune cells both in tumor tissues and peripheral blood.ConclusionMSS-CRC patients with epigenetic regulation impairment exhibit an immunologically active environment and may be more susceptible to treatment strategies based on ICIs.
Preparing for the next pandemic: Simulation-based deep reinforcement learning to discover and test multimodal control of systemic inflammation using repurposed immunomodulatory agents
Authors: Cockrell Chase , Larie Dale , An Gary 
Published: November 2022

BackgroundPreparation to address the critical gap in a future pandemic between non-pharmacological measures and the deployment of new drugs/vaccines requires addressing two factors: 1) finding virus/pathogen-agnostic pathophysiological targets to mitigate disease severity and 2) finding a more rational approach to repurposing existing drugs. It is increasingly recognized that acute viral disease severity is heavily driven by the immune response to the infection (“cytokine storm” or “cytokine release syndrome”). There exist numerous clinically available biologics that suppress various pro-inflammatory cytokines/mediators, but it is extremely difficult to identify clinically effective treatment regimens with these agents. We propose that this is a complex control problem that resists standard methods of developing treatment regimens and accomplishing this goal requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training successful game-playing artificial intelligences (AIs). This proof-of-concept study determines if simulated sepsis (e.g. infection-driven cytokine storm) can be controlled in the absence of effective antimicrobial agents by targeting cytokines for which FDA-approved biologics currently exist.MethodsWe use a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. DRL training used a Deep Deterministic Policy Gradient (DDPG) approach with a clinically plausible control interval of 6 hours with manipulation of six cytokines for which there are existing drugs: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Interleukin-4 (IL-4), Interleukin-8 (IL-8), Interleukin-12 (IL-12) and Interferon-γ(IFNg).ResultsDRL trained an AI policy that could improve outcomes from a baseline Recovered Rate of 61% to one with a Recovered Rate of 90% over ~21 days simulated time. This DRL policy was then tested on four different parameterizations not seen in training representing a range of host and microbe characteristics, demonstrating a range of improvement in Recovered Rate by +33% to +56%DiscussionThe current proof-of-concept study demonstrates that significant disease severity mitigation can potentially be accomplished with existing anti-mediator drugs, but only through a multi-modal, adaptive treatment policy requiring implementation with an AI. While the actual clinical implementation of this approach is a projection for the future, the current goal of this work is to inspire the development of a research ecosystem that marries what is needed to improve the simulation models with the development of the sensing/assay technologies to collect the data needed to iteratively refine those models.
Seasonal dynamics of major phytoplankton functional types in the coastal waters of the west coast of Canada derived from OLCI Sentinel 3A
Authors: Vishnu Perumthuruthil Suseelan , Xi Hongyan , Belluz Justin Del Bel , Hussain Midhun Shah , Bracher Astrid , Costa Maycira 
Published: November 2022

Monitoring the spatial distribution and seasonal dynamics of phytoplankton functional types (PFTs) in coastal oceans is essential for understanding fisheries production, changes in water quality, and carbon export to the deep ocean. The launch of new generation ocean color sensors such as OLCI (Ocean Land Color Instrument) onboard Sentinel 3A provides an unprecedented opportunity to study the surface dynamics of PFTs at high spatial (300 m) and temporal (daily) resolution. Here we characterize the seasonal dynamics of the major PFTs over the surface waters of the west coast of Canada using OLCI imagery and Chemical Taxonomy (CHEMTAX, v1.95) software. The satellite-based approach was adapted from a previously proven Empirical Orthogonal Function (EOF)-based algorithm by using a local matchup dataset comprising CHEMTAX model output and EOF scores derived from OLCI remote sensing reflectance. The algorithm was developed for the following PFTs: diatoms, dinoflagellates, dictyochophytes, haptophytes, green algae, cryptophytes, cyanobacteria, raphidophytes, and total chlorophyll-a (TChla) concentration. Of these PFTs, first level evaluation of the OLCI-derived retrievals showed reliable performance for diatoms and raphidophytes. The second level of validation showed that TChla had the best performance, and green algae, cryptophytes, and diatoms followed seasonal trends of a high temporal resolution in situ CHEMTAX time-series. Somewhat reduced correspondence was observed for raphidophytes. Due to their low contribution to the phytoplankton community (26%) and low range of variation, weak performance was noted for haptophytes, dictyochophytes, cyanobacteria, and dinoflagellates. The EOF-based PFT maps from daily OLCI imagery showed seasonal spring and fall diatom blooms with succession from spring blooms to high diversity flagellate dominated summer conditions. Furthermore, strong localized summer raphidophyte blooms (Heterosigma akashiwo) were observed, which are a regionally important harmful species. Overall, this study demonstrates the potential of the OLCI in deriving the surface dynamics of major PFTs of the Strait of Georgia (SoG), a critical habitat for the juvenile Pacific Salmon.
Metagenomics and metabolomics analysis to investigate the effect of Shugan decoction on intestinal microbiota in irritable bowel syndrome rats
Authors: Hang Lu , Wang Enkang , Feng Ya , Zhou Yan , Meng Yangyang , Jiang Fengru , Yuan Jianye 
Published: November 2022

BackgroundThe effect of Shugan Decoction (SGD) on intestinal motility and visceral hypersensitivity in Water avoid stress (WAS)-induced diarrhea predominant irritable bowel syndrome (IBS-D) model rats has been confirmed. However, the mechanisms of its action involved in the treatment of IBS-D need to be further studied. Intestinal microbiota plays an important role in maintaining intestinal homeostasis and normal physiological function. Changes in the intestinal microbiota and its metabolites are thought to participate in the pathophysiological process of IBS.AimThis study aimed to analyze the influence of SGD on intestinal microbiota and fecal metabolites in IBS-D rats by multiple omics techniques, including metagenomic sequencing and metabolomics.MethodsWe measured the intestinal motility and visceral sensitivity of three groups of rats by fecal pellets output and colorectal distension (CRD) experiment. In addition, metagenome sequencing analysis was performed to explore the changes in the number and types of intestinal microbiota in IBS-D model rats after SGD treatment. Finally, we also used untargeted metabolomic sequencing to screen the metabolites and metabolic pathways closely related to the therapeutic effect of SGD.ResultsWe found that compared with the rats in the control group, the fecal pellets output of the rats in the WAS group increased and the visceral sensitivity threshold was decreased (P &lt; 0.05). Compared with the rats in the WAS group, the fecal pellets output of the SGD group was significantly decreased, and the visceral sensitivity threshold increased (P &lt; 0.05). Besides, compared with the rats in the WAS group, the relative abundance of Bacteroidetes increased in SGD group, while that of Firmicutes decreased at the phylum level, and at the species level, the relative abundance of Bacteroides sp. CAG:714, Lactobacillus reuteri and Bacteroides Barnesiae in SGD group increased, but that of bacterium D42-87 decreased. In addition, compared with the WAS group, several metabolic pathways were significantly changed in SGD group, including Taurine and hypotaurine metabolism, Purine metabolism, Sulfur metabolism, ABC transporters, Arginine and proline metabolism and Bile secretion.ConclusionSGD can regulate specific intestinal microbiota and some metabolic pathways, which may explain its effect of alleviating visceral hypersensitivity and abnormal intestinal motility in WAS-induced IBS-D rats.
Enhancing erythritol production from crude glycerol in a wild-type Yarrowia lipolytica by metabolic engineering
Authors: Yang Shuling , Pan Xuewei , Wang Qiang , Lv Qinglan , Zhang Xian , Zhang Rongzhen , Rao Zhiming 
Published: November 2022

Background: Erythritol is a zero-calorie sweetener that is widely used in the food, pharmaceutical, and medical industries. Crude glycerol is the main by-product of biodiesel, and the effective utilization of crude glycerol will help to improve biodiesel viability. Previous studies on the production of erythritol from Y. lipolytica using crude glycerol as a carbon source have focused on optimizing the fermentation process of the mutant Y. lipolytica Wratislavia K1, while metabolic engineering has not been successfully applied.Results: To this end, we engineered the yeast Y. lipolytica to increase the productivity of this strain. Wild strains tolerant to high concentrations of crude glycerol were screened and identified. A series of rational metabolic approaches were employed to improve erythritol production. Among them, the engineered strain Y-04, obtained by tandem overexpression of GUT1 and GUT2, significantly increased glycerol assimilation by 33.3%, which was consistent with the results of RT-qPCR analysis. The effects of tandem overexpression of GUT1, GUT2, TKL1, and TAL1 on erythritol synthesis were also evaluated. The best results were obtained using a mutant that overexpressed GUT1, GUT2, and TKL1 and knocked out EYD1. The final Y-11 strain produced 150 g/l erythritol in a 5-L bioreactor with a yield and productivity of 0.62 g/g and 1.25 g/l/h, respectively. To the best of our knowledge, this is the highest erythritol yield and productivity from crude glycerol ever reported in Y. lipolytica.Conclusion: This work demonstrated that overexpression of GUT1, GUT2, and TKL1 and knockdown of EYD1 could be used to improve crude glycerol utilization and erythritol synthesis in Y. lipolytica. The process parameters such as erythritol yield and productivity were significantly elevated, which is valuable for industrial applications. Crude glycerol, as a carbon source, could efficiently restrict the synthesis of by-products while enhancing the generation of erythritol, compared to glucose. This indicates considerable potential for synthesizing value-added products from crude glycerol by Y. lipolytica.
Identification of metabolic fingerprints in severe obstructive sleep apnea using gas chromatography–Mass spectrometry
Authors: Mohit  , Tomar Manendra Singh , Araniti Fabrizio , Pateriya Ankit , Singh Kushwaha Ram Awadh , Singh Bhanu Pratap , Jurel Sunit Kumar , Singh Raghuwar Dayal , Shrivastava Ashutosh , Chand Pooran 
Published: November 2022

Objective: Obstructive sleep apnea (OSA) is considered a major sleep-related breathing problem with an increasing prevalence rate. Retrospective studies have revealed the risk of various comorbidities associated with increased severity of OSA. This study aims to identify novel metabolic biomarkers associated with severe OSA.Methods: In total, 50 cases of OSA patients (49.74 ± 11.87 years) and 30 controls (39.20 ± 3.29 years) were included in the study. According to the polysomnography reports and questionnaire-based assessment, only patients with an apnea–hypopnea index (AHI &gt;30 events/hour) exceeding the threshold representing severe OSA patients were considered for metabolite analysis. Plasma metabolites were analyzed using gas chromatography–mass spectrometry (GC-MS).Results: A total of 92 metabolites were identified in the OSA group compared with the control group after metabolic profiling. Metabolites and their correlated metabolic pathways were significantly altered in OSA patients with respect to controls. The fold-change analysis revealed markers of chronic kidney disease, cardiovascular risk, and oxidative stress-like indoxyl sulfate, 5-hydroxytryptamine, and 5-aminolevulenic acid, respectively, which were significantly upregulated in OSA patients.Conclusion: Identifying these metabolic signatures paves the way to monitor comorbid disease progression due to OSA. Results of this study suggest that blood plasma-based biomarkers may have the potential for disease management.
Cerebral blood flow regulation is not acutely altered after a typical number of headers in women footballers
Authors: Jack Jacob , Woodgates Alex , Smail Oliver , Brown Felix , Lynam Katie , Lester Alice , Williams Genevieve , Bond Bert 
Published: November 2022

BackgroundThe repeated act of heading has been implicated in the link between football participation and risk of neurodegenerative disease, and acutely alters cerebrovascular outcomes in men. This study assessed whether exposure to a realistic number of headers acutely influences indices of cerebral blood flow regulation in female footballers.MethodsNineteen female players completed a heading trial and seated control trial on two separate days. The heading trial involved six headers in 1 h (one every 10 min), with the ball traveling at 40 ± 5 km/h. Cerebrovascular reactivity to hypercapnia and hypocapnia was determined using serial breath holding and hyperventilation attempts. Dynamic cerebral autoregulation (dCA) was assessed by scrutinizing the relationship between cerebral blood flow and mean arterial blood pressure during 5 min of squat stand maneuvers at 0.05 Hz. Neurovascular coupling (NVC) was quantified as the posterior cerebral artery blood velocity response to a visual search task. These outcomes were assessed before and 1 h after the heading or control trial.ResultsNo significant time by trial interaction was present for the hypercapnic (P = 0.48, ηp2 = 0.05) and hypocapnic (P = 0.47, ηp2 = 0.06) challenge. Similarly, no significant interaction effect was present for any metric of dCA (P &gt; 0.12, ηp2 &lt; 0.16 for all) or NVC (P &gt; 0.14, ηp2 &lt; 0.15 for all).ConclusionThe cerebral blood flow response to changes in carbon dioxide, blood pressure and a visual search task were not altered following six headers in female footballers. Further study is needed to observe whether changes are apparent after more prolonged exposure.