bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Point Insulin Sensitivity Estimator in Pediatric Non-Alcoholic Fatty Liver Disease
Authors: Furthner Dieter , Anderwald Christian-Heinz , Bergsten Peter , Forslund Anders , Kullberg Joel , Ahlström Håkan , Manell Hannes , Ciba Iris , Mangge Harald , Maruszczak Katharina , Koren Pia , Schütz Sebastian , Brunner Susanne Maria , Schneider Anna Maria , Weghuber Daniel , Mörwald Katharina
Published: February 2022

Background

Attenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity.

Materials and Methods

Ninety-nine pubertal subjects with obesity (13.5 ± 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 ± 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (≤5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5.

Results

SPISE was lower in NAFLD (male: 4.8 ± 1.2, female: 4.5 ± 1.1) than in non-NAFLD group (male 6.0 ± 1.6, female 5.6 ± 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%).

Conclusion

SPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.
Do Green Credit Affect Green Total Factor Productivity? Empirical Evidence from China
Authors: Hu Qingqing , Li Xue , Feng Yanhong
Published: February 2022

Understanding the effects of green credit on green total factor productivity (GTFP) is conductive to promoting the sustainable economy development. This paper examines the total effects, influence mechanism, and heterogeneous impacts of green credit on GTFP based on GTFP data of 30 provinces in China from 2008 to 2017. The findings show that, firstly, on the whole, green credit significantly increases GTFP, which is tested by the panel regression model. Secondly, according to the result of the panel quantile model, the increasing effect of green credit on GTFP is strengthened by the improvement of GTFP. Thirdly, green credit has heterogeneous impact on GTFP, which is reflected in economic development with different level, especially for different degrees of environmental regulation. Fourthly, under the full samples, green credit impacts GTFP through green technology innovation, but it has no effect on energy consumption structure. Besides, the influence mechanism is heterogeneous in the variation of sample characteristics. Finally, some significant policy recommendations are provided for policymakers based on these conclusions.
Characterizing the Ectomycorrhizal Fungal Community of Whitebark Pine in Interior British Columbia: Mature Trees, Natural Regeneration and Planted Seedlings
Authors: Southam Hanno , Stafl Natalie , Guichon Shannon H. A. , Simard Suzanne W.
Published: February 2022

Whitebark pine (Pinus albicaulis Engelm.; WBP) is an endangered subalpine tree species and requires associations with ectomycorrhizal fungi (ECMF) for survival and growth. Despite this obligate dependence, there are gaps in the identification of ECMF that associate with WBP. In addition, ECMF rarely feature in assessments of recovery actions and little is known about the relationship between ECMF and the insects and pathogens affecting WBP. We used next-generation sequencing to characterize ECMF occurring in soil and mycorrhizal root tip samples from naturally occurring mature WBP trees and seedlings as well as planted WBP seedlings in the Columbia Mountains of Interior British Columbia, Canada. ECMF data was paired with data on tree age, tree health and soil conditions. Thirty-three species and twenty-one genera of ECMF were identified with medium or high confidence from mycorrhizal root tip samples. Major groups were: generalist ascomycetes [Cenococcum, Meliniomyces (=Hyaloscypha)], Atheliales (Piloderma, Amphinema, Tylospora), non-ascomycetous generalists (e.g., Amphinema), associates of high-elevation conifers (species of Cortinarius, Russula) and Suilloids (Suillus, Rhizopogon). Differences in WBP ECMF with other, drier and southerly regions that have been studied previously, were consistent with a distinct forest type and an endemism hypothesis. Soil at the planting site and planted seedlings hosted a reduced ECMF community or were non-ectomycorrhizal, which can be explained by site factors and is expected to affect seedling survival. ECMF composition on mature trees was correlated with tree health, which may have implications for WBPs resistance to pathogens and signals that ECMF are affected by the decline of their host. Understanding the ecology of WBP ECMF and their relationship with tree performance is essential for WBP recovery efforts.
Renal Involvement in IPEX Syndrome With a Novel Mutation of FOXP3: A Case Report
Authors: Ke Ruijuan , Zhu Ying , Deng Fang , Xu Daliang
Published: February 2022

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genetic disease characterized by multiple immune disorders. Different mutations of the FOXP3 gene may lead to distinct clinical manifestations. Here, we present a rare case of IPEX syndrome caused by a novel variant of FOXP3. Clinical manifestations include autoimmune hemolysis, bronchiectasis, diarrhea, and proteinuria but without diabetes or other endocrine disorders. The diagnosis of IPEX syndrome was confirmed by whole-exon sequencing. Supportive treatment did not ameliorate the patient’s symptoms, while immunosuppressive therapy showed a promising efficacy. The patient we reported will improve the understanding of renal manifestations in IPEX syndrome.
Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci
Authors: Bellomo Tiffany R. , Bone William P. , Chen Brian Y. , Gawronski Katerina A. B. , Zhang David , Park Joseph , Levin Michael , Tsao Noah , Klarin Derek , Lynch Julie , Assimes Themistocles L. , Gaziano J. Michael , Wilson Peter W. , Cho Kelly , Vujkovic Marijana , the VA Million Veteran Program  , O’Donnell Christopher J. , Chang Kyong-Mi , Tsao Philip S. , Rader Daniel J. , Ritchie Marylyn D. , Damrauer Scott M. , Voight Benjamin F.
Published: February 2022

Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.
N6-Methyladenosine-Related lncRNAs Are Potential Prognostic Biomarkers and Correlated With Tumor Immune Microenvironment in Osteosarcoma
Authors: Zheng Di , Yu Ling , Wei Zhun , Xia Kezhou , Guo Weichun
Published: February 2022

N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play vital roles in the prognostic value and immune microenvironment of malignant tumors. Here, we constructed a m6A-related lncRNA signature in osteosarcoma samples from TCGA dataset and analyzed the association of the signature with tumor immune microenvironment. m6A-related lncRNAs were identified by performing Pearson’s correlation analysis and were used to construct a novel m6A-related lncRNA signature in osteosarcoma. Validation in testing and entire cohorts confirmed the satisfactory accuracy of the risk signature. Principal-component analysis verifies the grouping ability of the risk signature. Functional enrichment analyses connected immune with the risk signature based on the six m6A-related lncRNAs. When patients were separated into high- and low-risk group based on their risk scores, we found that patients in the high-risk group had lower stromal scores, immune scores, and ESTIMATE scores, while the tumor purity was higher in the high-risk group than that in the low-risk group. As for immune cell infiltration, the proportion of monocytes was significantly higher in the low-risk group than that in the high-risk group. Of the six lncRNAs, AC004812.2 was a protective factor in osteosarcoma and low expression of AC004812.2 predicted worse overall survival. Overexpression of AC004812.2 inhibited 143B cell proliferation and increased the expression levels of IGF2BP1 and YTHDF1. In all, our m6A-related lncRNA signature was a potential prognostic biomarker and correlated with tumor immune microenvironment and immune cell infiltration, and AC004812.2 might be an important regulator of m6A modification and a promising therapeutic target in osteosarcoma.
Clinical and Biological Significance of DNA Methylation-Driven Differentially Expressed Genes in Biochemical Recurrence After Radical Prostatectomy
Authors: Luo Chao , He Songzhe , Zhang Haibo , He Shuhua , Qi Huan , Wei Anyang
Published: February 2022

Background: Biochemical recurrence (BCR) after radical prostatectomy indicates poor prognosis in patients with prostate cancer (PCA). DNA methylation (DNAm) is a critical factor in tumorigenesis and has attracted attention as a biomarker for the diagnosis, treatment, and prognosis of PCA. However, the predictive value of DNAm-derived differentially expressed genes (DMGs) in PCA with BCR remains elusive.

Methods: We filtered the methylated genes and the differentially expressed genes (DGEs) for more than 1,000 clinical samples from the TCGA cohort using the chAMP and DESeq2 packages of R language, respectively. Next, we integrated the DNAm beta value and gene expression data with the Mithymix package of R language to obtain the DMGs. Then, 1,000 times Cox LASSO regression with 10-fold cross validation was performed to screen signature DMGs and establish a predictive classifier. Univariate and multivariate cox regressive analyses were used to identify the prognostic factors to build a predictive model, and its performance was measured by receiver operating characteristic, calibration curves, and Harrell’s concordance index (C-index). Additionally, a GEO dataset was used to validate the prognostic classifier.

Results: One hundred DMGs were mined using the chAMP and Methymix packages of R language. Of these, seven DMGs (CCK, CD38, CYP27A1, EID3, HABP2, LRRC4, and LY6G6D) were identified to build the prognostic classifier (Classifier) through LASSO analysis. Moreover, univariate and multivariate Cox regression analysis determined that the Classifier and pathological T stage (pathological_T) were independent predictors of BCR (hazard ratio (HR 2.2), (95% CI 1.4–3.5), p < 0.0012, and (HR 1.8), (95% CI 1.0–3.2), p < 0.046). A nomogram based on the Classifier was constructed, with high prediction accuracy for BCR-free survival in TCGA and GEO datasets. GSEA enrichment analysis showed that the DMGs were mainly enriched in the metabolism pathways.

Conclusion: We identified and validated the nomogram of BCR-free survival for PCA patients, which has the potential to guide treatment decisions for patients at differing risks of BCR. Our study deepens the understanding of DMGs in the pathogenesis of PCA.
Cdc42/Rac Interactive Binding Containing Effector Proteins in Unicellular Protozoans With Reference to Human Host: Locks of the Rho Signaling
Authors: Umarao Preeti , Rath Pragyan Parimita , Gourinath Samudrala
Published: February 2022

Small GTPases are the key to actin cytoskeleton signaling, which opens the lock of effector proteins to forward the signal downstream in several cellular pathways. Actin cytoskeleton assembly is associated with cell polarity, adhesion, movement and other functions in eukaryotic cells. Rho proteins, specifically Cdc42 and Rac, are the primary regulators of actin cytoskeleton dynamics in higher and lower eukaryotes. Effector proteins, present in an inactive state gets activated after binding to the GTP bound Cdc42/Rac to relay a signal downstream. Cdc42/Rac interactive binding (CRIB) motif is an essential conserved sequence found in effector proteins to interact with Cdc42 or Rac. A diverse range of Cdc42/Rac and their effector proteins have evolved from lower to higher eukaryotes. The present study has identified and further classified CRIB containing effector proteins in lower eukaryotes, focusing on parasitic protozoans causing neglected tropical diseases and taking human proteins as a reference point to the highest evolved organism in the evolutionary trait. Lower eukaryotes’ CRIB containing proteins fall into conventional effector molecules, PAKs (p21 activated kinase), Wiskoit-Aldrich Syndrome proteins family, and some have unique domain combinations unlike any known proteins. We also highlight the correlation between the effector protein isoforms and their selective specificity for Cdc42 or Rac proteins during evolution. Here, we report CRIB containing effector proteins; ten inDictyosteliumandEntamoeba, fourteen inAcanthamoeba, one inTrypanosomaandGiardia. CRIB containing effector proteins that have been studied so far in humans are potential candidates for drug targets in cancer, neurological disorders, and others. Conventional CRIB containing proteins from protozoan parasites remain largely elusive and our data provides their identification and classification for further in-depth functional validations. The tropical diseases caused by protozoan parasites lack combinatorial drug targets as effective paradigms. Targeting signaling mechanisms operative in these pathogens can provide greater molecules in combatting their infections.
MoGCN: A Multi-Omics Integration Method Based on Graph Convolutional Network for Cancer Subtype Analysis
Authors: Li Xiao , Ma Jie , Leng Ling , Han Mingfei , Li Mansheng , He Fuchu , Zhu Yunping
Published: February 2022

In light of the rapid accumulation of large-scale omics datasets, numerous studies have attempted to characterize the molecular and clinical features of cancers from a multi-omics perspective. However, there are great challenges in integrating multi-omics using machine learning methods for cancer subtype classification. In this study, MoGCN, a multi-omics integration model based on graph convolutional network (GCN) was developed for cancer subtype classification and analysis. Genomics, transcriptomics and proteomics datasets for 511 breast invasive carcinoma (BRCA) samples were downloaded from the Cancer Genome Atlas (TCGA). The autoencoder (AE) and the similarity network fusion (SNF) methods were used to reduce dimensionality and construct the patient similarity network (PSN), respectively. Then the vector features and the PSN were input into the GCN for training and testing. Feature extraction and network visualization were used for further biological knowledge discovery and subtype classification. In the analysis of multi-dimensional omics data of the BRCA samples in TCGA, MoGCN achieved the highest accuracy in cancer subtype classification compared with several popular algorithms. Moreover, MoGCN can extract the most significant features of each omics layer and provide candidate functional molecules for further analysis of their biological effects. And network visualization showed that MoGCN could make clinically intuitive diagnosis. The generality of MoGCN was proven on the TCGA pan-kidney cancer datasets. MoGCN and datasets are public available at https://github.com/Lifoof/MoGCN. Our study shows that MoGCN performs well for heterogeneous data integration and the interpretability of classification results, which confers great potential for applications in biomarker identification and clinical diagnosis.
Clonally Expanded Virus-Specific CD8 T Cells Acquire Diverse Transcriptional Phenotypes During Acute, Chronic, and Latent Infections
Authors: Kuhn Raphael , Sandu Ioana , Agrafiotis Andreas , Hong Kai-Lin , Shlesinger Danielle , Neimeier Daniel , Merkler Doron , Oxenius Annette , Reddy Sai T. , Yermanos Alexander
Published: February 2022

CD8+ T cells play a crucial role in the control and resolution of viral infections and can adopt a wide range of phenotypes and effector functions depending on the inflammatory context and the duration and extent of antigen exposure. Similarly, viral infections can exert diverse selective pressures on populations of clonally related T cells. Technical limitations have nevertheless made it challenging to investigate the relationship between clonal selection and transcriptional phenotypes of virus-specific T cells. We therefore performed single-cell T cell receptor (TCR) repertoire and transcriptome sequencing of virus-specific CD8 T cells in murine models of acute, chronic and latent infection. We observed clear infection-specific populations corresponding to memory, effector, exhausted, and inflationary phenotypes. We further uncovered a mouse-specific and polyclonal T cell response, despite all T cells sharing specificity to a single viral epitope, which was accompanied by stereotypic TCR germline gene usage in all three infection types. Persistent antigen exposure during chronic and latent viral infections resulted in a higher proportion of clonally expanded T cells relative to acute infection. We furthermore observed a relationship between transcriptional heterogeneity and clonal expansion for all three infections, with highly expanded clones having distinct transcriptional phenotypes relative to less expanded clones. Together our work relates clonal selection to gene expression in the context of viral infection and further provides a dataset and accompanying software for the immunological community.
Case Report: Preemptive Treatment With Low-Dose PD-1 Blockade and Azacitidine for Molecular Relapsed Acute Myeloid Leukemia With RUNX1-RUNX1T1 After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Tang Yutong , Zhou Zhenyang , Yan Han , You Yong
Published: February 2022

Acute myeloid leukemia (AML) patients who develop hematological relapse (HR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally have dismal clinical outcomes. Measurable residual disease (MRD)-directed preemptive interventions are effective approaches to prevent disease progression and improve prognosis for molecular relapsed patients with warning signs of impending HR. In this situation, boosting the graft-vs-leukemia (GVL) effect with immune checkpoint inhibitors (ICIs) might be a promising prevention strategy, despite the potential for causing severe graft-vs-host disease (GVHD). In the present study, we reported for the first time an AML patient with RUNX1-RUNX1T1 who underwent preemptive treatment with the combined application of tislelizumab (an anti-PD-1 antibody) and azacitidine to avoid HR following allo-HSCT. On day +81, molecular relapse with MRD depicted by RUNX1-RUN1T1-positivity as well as mixed donor chimerism occurred in the patient. On day +95, with no signs of GVHD and an excellent eastern cooperative oncology group performance status (ECOG PS), the patient thus was administered with 100 mg of tislelizumab on day 1 and 100 mg of azacitidine on days 1-7. After the combination therapy, complete remission was successfully achieved with significant improvement in hematologic response, and the MRD marker RUNX1-RUNX1T1 turned negative, along with a complete donor chimerism in bone marrow. Meanwhile, the patient experienced moderate GVHD and immune-related adverse events (irAEs), successively involving the lung, liver, lower digestive tract and urinary system, which were well controlled by immunosuppressive therapies. As far as we know, this case is the first one to report the use of tislelizumab in combination with azacitidine to prevent post-transplant relapse in AML. In summary, the application of ICIs in MRD positive patients might be an attractive strategy for immune modulation in the future to reduce the incidence of HR in the post-transplant setting, but safer clinical application schedules need to be explored.
Progesterone Inhibits the Establishment of Activation-Associated Chromatin During TH1 Differentiation
Authors: Rundquist Olof , Nestor Colm E. , Jenmalm Maria C. , Hellberg Sandra , Gustafsson Mika
Published: February 2022

TH1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human TH1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during TH1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.
Occurrence and Distribution of Microplastics in Soils and Intertidal Sediments at Fildes Bay, Maritime Antarctica
Authors: Perfetti-Bolaño Alessandra , Araneda Alberto , Muñoz Katherine , Barra Ricardo O.
Published: February 2022

Increased human activity on the Antarctic Peninsula has generated microplastic contamination in marine systems; however, less attention has been paid to soils so far. We investigated the occurrence of microplastics in 11 surface soils and intertidal sediments collected from Fildes Bay, King George Island. A transect of soils at Antarctic stations until Fildes Bay was made (i.e., S1–S5). Intertidal sediments along the shore (i.e., IS1–IS5) and a reference sample from Ardley Island (i.e., IS6) were also collected. All samples were stored at 4°C and analyzed for the organic matter content, particle size, and pH. Plastic particles were counted and classified by shape using metal dissecting forceps and a stereomicroscope and further analyzed by Fourier-transform infrared spectroscopy (FT-IR). They were classified by length as fibers (length: 500–2,000 μm) and fragments (length: 20–500 μm). In soil, fragments reached an average of 13.6 particles/50 ml sample, while in intertidal sediments, no fragments were found, but a fiber abundance of 1.5 particles/50 ml sample was observed. The principal component analysis shows a relationship between fibers and intertidal sediments, whereas fragments present a relationship with soils. There were differences between the numbers of fragments found in soils and intertidal sediments (p = 0.003), with a high abundance of fragments at site S5, but no significant differences were observed for fibers. The physicochemical soil analysis revealed that larger particle sizes were observed in intertidal sediments (average = 706.94 ± 230.51 μm) than in soils (p = 0.0007). The organic matter content was higher in soil than in intertidal sediments (p = 0.006) reaching an average of 6.0%. Plastic fragments and organic matter were significantly correlated (r = 0.779, p = 0.005), while fibers were positively correlated with particle size (r = 0.713, p = 0.014). The fragments were composed of phenoxy resin with the same appearance, shape, and bright orange color as the coatings of the facilities. According to the FT-IR analysis, the fibers had different colors and were composed of polyethylene terephthalate (PET). Cotton was also present at the sites surrounding the sampling site close to the base effluent. The presence of fiber on Ardley Island (i.e., control) may indicate that microplastic contamination has reached protected areas. This is the first study to confirm the presence of plastic debris in Antarctic soils. Further studies should focus on the identification of plastic sources and on the management of human activities and their eventual effects on biota.
The MicroRNAs-Transcription Factors-mRNA Regulatory Network Plays an Important Role in Resistance to Cold Stress in the Pearl Gentian Grouper
Authors: Miao Ben-Ben , Niu Su-Fang , Wu Ren-Xie , Liang Zhen-Bang , Zhai Yun
Published: February 2022

Pearl gentian grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) is a hybrid fish with high commercial value. It is widely cultured on the Asian coast; however, it is not cold-tolerant. Although we have previously characterized the liver transcriptomic responses of this grouper to cold stress, the roles of miRNAs and transcription factors (TFs) in cold resistance and the underlying regulatory mechanisms are still unclear. In this study, we integrated miRNA and mRNA sequencing data for pearl gentian grouper under cold stress and constructed a miRNA-TF-mRNA regulatory network. Furthermore, we screened seven key miRNAs (i.e., gmo-miR-221-5p, ssa-miR-7132b-5p, ola-let-7c, ssa-miR-25-3-5p, ccr-miR-489, gmo-miR-10545-5p, ccr-miR-122) that regulated target genes (including TF ACSS2, TF PPARD, TF PPP4CB; CYP2J2, EHHADH, RXRs, NR1D2, PPP1CC-A, PPP2R1A, FOXK2, etc.). These miRNAs participated in several important pathways and biological processes by the direct or indirect regulation of target genes, such as antioxidation and membrane fluidity, glucose and lipid metabolism, circadian rhythm, DNA repair, and apoptosis. The key cold-related miRNAs, TFs, and genes and their potential regulatory relationships identified in this study provide a deeper understanding of the complex molecular basis of the response to low-temperature environments in the grouper. In particular, our results provide the first identification for the role of NR1D2 gene in the cold tolerance of fish via the regulation of circadian rhythm. Furthermore, the key miRNAs and genes provide a basis for the molecular breeding of new cold-tolerant varieties of the pearl gentian grouper.
A New Classification Tool and a Systematic Review of Macroalgal Studies Disentangle the Complex Interactive Effects of Warming and Nutrient Enrichment on Primary Production
Authors: Endo Hikaru , Gao Xu
Published: February 2022

In order to understand how global warming effects on ecosystem primary production may change depending on nutrient enrichment, a new classification is proposed to disentangle and recognize the combination of interactions among several factors, based on the effect direction (positive, negative, or neutral) and its changes induced in it by the other factor (synergizing, antagonizing, inducing no change, or changing it in some other way). Marine macroalgae were chosen (as primary producers for which there is the most experimental information available) to review the relevant studies on which this new classification can be tested. It was observed the positive effects of elevated temperature and nutrient enrichment often synergized each other within the temperature range between relatively low and optimal growth levels. However, the negative effect of further temperature elevation from optimal to higher levels was antagonized by nutrient enrichment in some studies but was synergized in others, depending on the range of temperature elevation. The positive effect of nutrient enrichment was antagonized (but still positive) by temperature increase above the optimum in many cases, although the effect sometimes switched to a negative effect depending on the magnitude of nutrient enrichment. These results predict that global warming will enhance bottom-up effects on primary production in cold seasons and areas, and there will be a negative warming effect on production in hot seasons and areas, but it may be possible to mitigate this effect by appropriate levels of nutrient enrichment.
Quorum Sensing Regulates Bacterial Processes That Play a Major Role in Marine Biogeochemical Cycles
Authors: Urvoy Marion , Labry Claire , L’Helguen Stéphane , Lami Raphaël
Published: February 2022

Bacteria play a crucial role in marine biogeochemistry by releasing, consuming and transforming organic matter. Far from being isolated entities, bacteria are involved in numerous cell–cell interactions. Among such interactions, quorum sensing (QS) allows bacteria to operate in unison, synchronizing their actions through chemical communication. This review aims to explore and synthesize our current knowledge of the involvement of QS in the regulation of bacterial processes that ultimately impact marine biogeochemical cycles. We first describe the principles of QS communication and the renewed interest in its study in marine environments. Second, we highlight that the microniches where QS is most likely to occur due to their high bacterial densities are also hotspots of bacterially mediated biogeochemical transformations. Many bacterial groups colonizing these microniches harbor various QS systems. Thereafter, we review relevant QS-regulated bacterial processes in marine environments, building on research performed in both complex marine assemblages and isolated marine bacteria. QS pathways have been shown to directly regulate organic matter degradation, carbon allocation and nutrient acquisition but also to structure the community composition by mediating colonization processes and microbial interactions. Finally, we discuss current limitations and future perspectives to better characterize the link between QS expression and the bacterial mediation of biogeochemical cycles. The picture drawn by this review highlights QS as one of the pivotal mechanisms impacting microbial composition and functions in the oceans, paving the way for future research to better constrain its impact on marine biogeochemical cycles.
Neutrophils in Bronchoalveolar Lavage Fluid Indicating the Severity and Relapse of Pulmonary Sarcoidosis
Authors: Feng Haoshen , Yan Lili , Zhao Yabin , Li Zhenhua , Kang Jian
Published: February 2022

Background

Pulmonary sarcoidosis is a highly heterogeneous granulomatous disease without any specific symptoms and manifestations. Neutrophils in bronchoalveolar lavage fluid (BALF) have been proposed to indicate the severity and prognosis of pulmonary sarcoidosis, but this needs confirmation in patients from different populations due to the heterogeneity of the disease. This study aimed to determine the characteristics of patients with pulmonary sarcoidosis in northeastern China and to explore the relationship between neutrophils in BALF and the severity of pulmonary sarcoidosis.

Methods

We enrolled 432 patients who were diagnosed with pulmonary sarcoidosis in this retrospective study. The symptoms, extrapulmonary involvement, forced vital capacity percentage predicted (FVC % pred), and diffusing capacity of the lung for carbon monoxide percentage predicted (DLco % pred) were recorded. BAL was performed in 319 patients, and the results of a cellular examination of BALF were collected. A total of 123 patients who received corticosteroid treatment were followed up for at least 12 months, and the outcomes were recorded.

Results

Cough was the most common symptom, and cutaneous involvement was the most common extrapulmonary manifestation in 304 (70.4%) and 82 (19.0%) patients, respectively. The percentages of patients with high neutrophil counts in BALF (>3%) were higher at Stages 2 and 3 compared with Stages 0 and 1 (33.2 vs. 19.4%, p = 0.007), although the percentages of neutrophils in BALF showed no difference between patients at Stages 0, 1, 2, and 3. Patients with high neutrophil counts in BALF had lower FVC % pred compared with the other patients (79.5 ± 18.2 vs. 84.9 ± 14.5%, p = 0.025) and were prone to relapse after corticosteroids were tapered. High neutrophil counts in BALF were independently associated with relapse after corticosteroids were tapered in a binary logistic regression analysis (p = 0.027).

Conclusions

Patients with pulmonary sarcoidosis lacked specific symptoms and manifestations. The neutrophil count in BALF could indicate the severity and outcomes of pulmonary sarcoidosis.
Comparison of Deep and Moderate Neuromuscular Blockade on Intestinal Mucosal Barrier in Laparoscopic Gastrectomy: A Prospective, Randomized, Double-Blind Clinical Trial
Authors: Huang He , Zhou Ling , Yu Yingying , Liu Shijiang , Xu Hao , Xu Zekuan , Yang Chun , Liu Cunming
Published: February 2022

Deep neuromuscular blockade (NMB) improves the surgical conditions and is benefit for the postoperative recovery after laparoscopic surgery. However, the mechanisms of deep NMB in promoting the recovery of intestinal function have not been completely investigated. The objective of our study was to determine the impact of the deep NMB and moderate NMB strategy on the intestinal barrier function after laparoscopic gastrectomy. We collected patients undergoing elective laparoscopic gastrectomy. Patients were randomized to deep NMB (post-tetanic count 1–2) vs. moderate NMB (train-of-four count 1–2) during the surgery. Primary outcomes were time to flatus, serum diamine oxidase (DAO) and D-lactate, and gut microbiota. Other outcomes were surgical condition scores, postoperative visual analog pain scores, and length of hospital stay. Ninety patients in deep NMB group and sixty patients in moderate NMB group completed the study. Main results showed that the time to flatus was decreased in deep NMB group (74 ± 32 h) than that in moderate NMB group (93 ± 52 h, P = 0.006). The level of serum D-lactate was statistically increased in the moderate NMB group than that in the deep NMB group (1,209 ± 224 vs. 1,164 ± 185 ng/ml, p < 0.001). But no significant differences could be detected in the level of DAO between the groups. Additionally, the 16s rRNA analysis indicated that gut microbiota were similar in Alpha diversity but distinct in Beta diversity. Furthermore, the beneficial bacteria, such as genus Lactobacillus and Bifidobacterium, were more abundant in the deep NMB group, while the potentially harmful bacteria were more abundant in the moderate NMB group. Our findings suggested that the intestinal mucosal barrier and gut microbiota were better preserved in deep NMB, which greatly improved the postoperative recovery of intestinal function after laparoscopic gastrectomy.
Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases
Authors: Carey Jenny L. , Guo Lin
Published: February 2022

Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. We also review evidences that connect the phase separation property of TDP-43 and FUS to their functional roles in cells. Aberrant phase transition of TDP-43 and FUS leads to protein aggregation and disrupts their regular cell function. Therefore, restoration of functional protein phase of TDP-43 and FUS could be beneficial for neuronal cells. We discuss possible mechanisms for TDP-43 and FUS aberrant phase transition and aggregation while reviewing the methods that are currently being explored as potential therapeutic strategies to mitigate aberrant phase transition and aggregation of TDP-43 and FUS.
Predicted Cognitive Conversion in Guiding Early Decision-Tailoring on Patients With Cognitive Impairment
Authors: Zheng Yu , Liu Yin , Wu Jiawen , Xie Yi , Yang Siyu , Li Wanting , Sun Huaiqing , He Qing , Wu Ting
Published: February 2022

Background

Cognitive decline is the most dominant and patient-oriented symptom during the development of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This study was designed to test the feasibility of hybrid convolutional neural networks and long-short-term memory (CNN-LSTM) modeling driven early decision-tailoring with the predicted long-term cognitive conversion in AD and MCI.

Methods

Characteristics of patients with AD or MCI covering demographic features, clinical features, and time-dependent neuropsychological-related features were fused into the hybrid CNN-LSTM modeling to predict cognitive conversion based on a 4-point change in the AD assessment scale-cognition score. Treatment reassignment rates were estimated based on the actual and predicted cognitive conversion at 3 and 6 months according to the prespecified principle; that is if the ADAS-cog score of the patient declines less than 4 points or increases at either follow-up time point, the medical treatment recommended upon their diagnosis would be considered insufficient. Therefore, it is recommended to upgrade the medical treatment upon diagnosis. Actual and predicted treatment reassignment rates were compared in the general population and subpopulations categorized by age, gender, symptom severity, and the intervention subtypes.

Results

A total of 224 patients were included in the analysis. The hybrid CNN-LSTM model achieved the mean AUC of 0.735 (95% CI: 0.701–0.769) at 3 months and 0.853 (95% CI: 0.814–0.892) at 6 months in predicting cognitive conversion status. The AUC at 6 months was significantly impacted when data collected at 3 months were withdrawn. The predicted cognitive conversion suggested a revision of medical treatment in 46.43% (104/224) of patients at 3 months and 54.02% (121/224) at 6 months as compared with 62.05% (139/224) at 3 months (p = 0.001) and 62.50% (140/224) at 6 months (p = 0.069) according to their actual cognitive conversion. No significant differences were detected between treatment reassignment rates estimated based on actual and predicted cognitive conversion in all directions at 6 months.

Conclusion

Using the synergistic advances of deep learning modeling and featured longitudinal information, our hypothesis was preliminarily verified with the comparable predictive performance in cognitive conversion. Results provided the possibility of reassigned recommended treatment for those who may suffer from cognitive decline in the future. Considering the limited diversity of treatment strategies applied in this study, the real-world medical situation should be further simulated.
Distinct Age-Specific Effects on Olfactory Associative Learning in C57BL/6 Substrains
Authors: Chen Hung-Lun , Chen Chien-Fu F. , Huang Han-Bin
Published: February 2022

C57BL/6 is the most widely used mouse strain in the laboratories. Two substrains of C57BL/6, C57BL/6J (B6J), and C57BL/6N (B6N) are well-known backgrounds for genetic modification and have been shown difference in quite a few tests, including open field test, rotarod test, and Morris water maze. However, difference between these two substrains in olfaction-dependent behaviors remains unknown. Here, we used olfactory two-alternative choice task, which is modified to have two training stages, to evaluate animals’ ability in instrumental learning and olfactory association. In the first (rule learning) stage, the mice were trained to use the operant chamber to collect water rewards. An odor cue was provided in the procedure, with no indication about reward locations. In the following (discrimination learning) stage, two odor cues were provided, with each indicating a specific water port. The animals were rewarded upon correct port choices following cue deliveries. We found that during young adulthood (7–10 weeks old), proportionally more B6J than B6N mice were able to pass rule learning (58.3% vs. 29.2%) and ultimately acquire this task (54.2% vs. 25%), with the two substrains showing similar pass rates in discrimination learning (92.9% vs. 85.7%). Surprisingly, at a more mature age (17 weeks old), this substrain difference disappeared. Mature B6N mice had a significant improvement in pass percentages of rule learning and overall task, whereas similar improvement was not observed in the B6J counterparts. Instead, mature B6J mice had an improved speed in rule learning and overall task. We further examined behavioral patterns of 8-week-old B6J and B6N mice in the olfactory habituation or dishabituation test. We observed normal olfactory habituation from subjects of both substrains, with the B6J mice exhibiting stronger investigative responses to newly presented odorants. These results reveal for the first time that B6J and B6N mice are different in acquisition processes of a behavioral task that requires instrumental learning and olfactory association, and that maturation appears to employ different effects on these two substrains during these processes. Furthermore, young adult B6J and B6N mice might be similar in olfactory habituation but different in the olfactory aspects of novelty seeking.
The Effect of Statins on Mortality of Patients With Chronic Kidney Disease Based on Data of the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) and Korea National Health Insurance Claims Database
Authors: Kim Ji Eun , Choi Yun Jin , Oh Se Won , Kim Myung Gyu , Jo Sang Kyung , Cho Won Yong , Ahn Shin Young , Kwon Young Joo , Ko Gang-Jee
Published: February 2022

The role of statins in chronic kidney disease (CKD) has been extensively evaluated, but it remains controversial in specific population such as dialysis-dependent CKD. This study examined the effect of statins on mortality in CKD patients using two large databases. In data from the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) from two hospitals, CKD was defined as an estimated glomerular filtration rate < 60 mL/min/m2; we compared survival between patients with or without statin treatment. As a sensitivity analysis, the results were validated with the Korea National Health Insurance (KNHI) claims database. In the analysis of CDM datasets, statin users showed significantly lower risks of all-cause and cardiovascular mortality in both hospitals, compared to non-users. Similar results were observed in CKD patients from the KNHI claims database. Lower mortality in the statin group was consistently evident in all subgroup analyses, including patients on dialysis and low-risk young patients. In conclusion, we found that statins were associated with lower mortality in CKD patients, regardless of dialysis status or other risk factors.
Clinical Outcomes of Endovascular Treatment for Carotid Artery Dissection Without Intracranial Large Vessel Occlusion in Patients With Cerebral Ischemia Presentation
Authors: Kim Joong-Goo , Kang Chul-Hoo , Choi Jay Chol , Song Yunsun , Suh Dae Chul , Lee Deok Hee
Published: February 2022

Background and Purpose

We describe the clinical characteristics and outcomes (including the long-term patency of endovascular treatment [EVT]) of patients with acute ischemic strokes (AISs) featuring carotid artery dissection (CAD) but not intracranial large vessel occlusion.

Methods

We retrospectively reviewed patients who underwent EVT for spontaneous or post-traumatic AISs with CAD over a 13 year period from September 2005 to November 2018. The indications for EVT in patients with AIS-related CAD were a pretreatment diffusion-weighted imaging-Alberta Stroke Program early computed tomography (ASPECT) score > 6 and, clinical-diffusion mismatch. But, if the patients showed fluctuated ischemic symptoms, the joint decision by a stroke neurologist and neurointerventionist was done according to the onset-to-door time, symptoms, patient data, and the initial neuroimaging findings whether indicated that EVT was appropriate.

Results

Twenty-two dissected carotid arteries underwent balloon angioplasty and/or stent placement. The patients were 6 women and 16 men of median age 46 years. Twelve lacked any trauma history. Recombinant tissue plasminogen activator was prescribed for two (9.1%) patients. Four developed symptomatic intracranial hemorrhages (18.2%) but 86.4% exhibited modified Rankin scores ≤ 2.

Conclusions

Although attention to the hemorrhagic complication is required, EVT for selective patients with cerebral ischemia associated with CAD may be safe and acceptable treatment strategy for reconstruction of luminal patency, with good clinical outcomes. Prospective large-scale randomized studies are required to optimize EVT for CAD patients.