Enrichment Patterns Research Articles

A bibliometric analysis of the psychologization of human resource management

Despite years of discussion, whether and to what extent human resource management (HRM) has been psychologized remains controversial. We consider HRM psychologization as indicated by a disciplinary (i.e., the relative contribution of psychology and other fields to HRM research) and an inter-disciplinary component (i.e., knowledge integration of psychology and other fields in HRM research). Accordingly, we apply two bibliometric methods (i.e., citation and co-citation analysis) to a sample of 6,709 articles published in six HRM journals from 2000 to 2021. Overall, psychology became more influential as a citation source in HRM research but integrated more closely with other intellectual sources in the period examined. In addition, HRM psychologization was contingent on HRM journals, the first authors’ countries, and HRM subdomains. This study presents an enriched pattern of psychologization as well as substantial quantitative evidence that confirms, counters, or extends prior findings.

Single Cell Transcriptomic Analysis of the Bone Marrow Microenvironment Uncovers a Role for Antigen Presentation Processes in MDS/AML Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Background: Bone marrow (BM) diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by a poor overall survival with allogeneic hematopoietic stem cell transplantation (allo-HSCT) often representing the only curative treatment option. However, patient mortality even after allo-HSCT remains high, mainly due to relapse. Previous studies showed involvement of immune escape processes in relapsed patients via downregulation of human leukocyte antigen class II (HLA-II) genes on leukemic blasts, or T cell exhaustion. Nevertheless, other components of the BM microenvironment (BMME) including mesenchymal stromal cells (MSC), endothelial cells and immune cells from the innate and adaptive immune system might play a role in relapse after allo-HSCT. This role remains unclear and needs further characterization. Therefore, we performed single cell transcriptomic analysis of different subpopulations of the BMME in MDS/AML patients who either achieved a long-term complete remission (CR) or relapsed after allo-HSCT. Methods: Patient BM aspirates were obtained before and after 3-6 months post allo-HSCT after written informed consent, and mononuclear cells were stored in liquid nitrogen. To reduce confounding factors (i.e., pre-conditioning treatment, age, sex, diagnosis, graft versus host disease), "best-matched" patient pairs in CR or relapse were established. Subsequently, 2 pairs of matched CR/relapse patients were chosen for further evaluation (Table 1). From each patient, 6 different BM subpopulations were FACS-sorted to enrich for rare cell populations: hematopoietic stem and progenitor cells (HSPC, CD45dim/CD34+), MSC (CD45-/CD271+), endothelial cells (CD45-/CD31+), monocytes (CD45dim/CD14+), granulocytes (CD45dim/CD11b+), T cells (SSClow/CD45hi/CD3+) and NK cells (SSClow/CD45hi/CD3-/CD56+/CD16+). A maximum number of 5x103 cells from each of these 6 cell populations from a single patient and time point were pooled back together in one lane of a 10X Genomics chip for single cell RNA sequencing library preparation. Data analysis was performed in R. Results: After UMAP clustering, 15 groups of cells could be identified by their conserved expression patterns, recapitulating the different input sorted subpopulations. Gene set enrichment analysis comparing cell types from patients in CR and relapse revealed enrichment in immune related pathways in many clusters from relapsing patients both before and after allo-HSCT. In contrast, this pathway enrichment was only observed in classical monocytes from patients in CR after allo-HSCT. Further gene expression analysis showed that within these pathways, the most significantly differentially expressed genes were HLA class I (HLA-I) and HLA-II genes, as well as the transcription factor STAT1. Of note, STAT1 expression was increased 1.2 to 2.3 fold in several cell types from patients in relapse compared to patients in CR. Similarly, the known STAT1 target genes HLA-A and HLA-C showed a 1.2 to 7.5 fold higher expression in several cell types from relapsed patients. Importantly, upregulations were observed in progenitor cells as well as in lymphocytes both before and after allo-HSCT, suggesting that STAT1 upregulation might trigger HLA-I genes expression and play a role in and/or serve as predictive marker of post-transplant relapse. Interestingly, HLA-II gene enrichment patterns were more heterogeneous. Indeed, before transplantation, genes such as HLA-DRA, HLA-DPB1 or CD74 were upregulated 1.4 to 3.0 fold in most cell types of patients in relapse, while after allo-HSCT a downregulation of 1.5 to 3.5 fold was observed in progenitor cells from patients in relapse, and was even more prominent in classical monocytes showing a 2 to 8 fold downregulation (Figure 1). This observation suggests that by preventing T cell activation via HLA-II antigen presentation, monocytes might also play a role in relapse mechanisms after allo-HSCT. Conclusions: Altogether, our results suggest that antigen presentation processes in the BMME via HLA-I and HLA-II could be involved in relapse mechanisms. Their expression level even before transplantation might be used as a predictor of relapse after allo-HSCT. Further analyses are ongoing to confirm our preliminary findings including functional analyses linking relapse with those observed differences in gene expression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Multi-Cohort Gene Expression Classifier (ALLCatchR) Identifies B-Precursor ALL Subtypes and Their Developmental Trajectories across Age Groups

The molecular landscape of B cell precursor acute lymphoblastic leukemia (BCP-ALL) describes >20 disease subtypes defined by initiating genomic alterations and corresponding gene expression signatures. Some subtypes represent phenocopies with shared gene expression signatures but distinct or absent genomic drivers. The majority of BCP-ALL subtypes have been acknowledged as diagnostic entities by the currently revised classifications of hematologic malignancies (WHO-HAEM5 / International Consensus Classification). Thus, unified diagnostic approaches are needed to systematically identify subtypes in individual BCP-ALL cases in clinical routine. Gene expression signatures represent the shared functional equivalent of heterogeneous genomic driver alterations. Therefore, we established a gene expression-based classifier to identify BCP-ALL subtypes and related clinical and biological phenotypes. We analyzed a total of n=3477 BCP-ALL gene expression profiles obtained from transcriptome sequencing of adult (n=1253) and pediatric patients (n=2224) including publicly available (n=2074; Gu Z et al. Nat. Genet. 2019; Schmidt B. et al. Blood Adv. 2022) and own data sets (n=1403) from adult and pediatric European study groups (GMALL, AIEOP-BFM, CELL). Raw read counts from 6 cohorts representing heterogeneous library preps (i.e., stranded/unstranded; mRNA/total RNA), sequencing platforms/depths, and gene count quantifications were included. All samples had been previously allocated to molecular BCP-ALL subtypes based on integration of independent genomic profiling, gene fusion calling and gene expression. For classification, data with defined subgroup allocation were randomly split into training (n=1831; 70%) and testing sets (n=785; 30%) and two hold-out studies (n=305). To define gene expression signatures of 21 BCP-ALL subtypes, we used training set samples and extracted specific gene sets employing different feature selection algorithms as well as ranking of genes in individual subtypes. Based on these definitions we established a BCP-ALL subtype classifier (ALLCatchR), which integrates machine learning models (support vector machines) and nearest-neighbors associations of single sample gene set enrichment analyses (Fig. A). ALLCatchR performed molecular subtype allocation for the testing set at high sensitivity (0.934±0.165) and specificity (0.997±0.005) on average across subtypes. A similar performance was achieved in the two hold-out cohorts despite completely independent data structures which have not been shown to the classifier (sensitivity: 0.946±0.097 / specificity: 0.996±0.007). Overall accuracies of 0.952 and 0.92 for testing and hold-out-data sets indicate that ALLCatchR reliably identifies molecular BCP-ALL subtypes in mixed adult / pediatric cohorts based on gene expression profiles alone (Fig. A, below). Among n=44/1090 (4%) samples of the combined hold-out/testing set with ambiguous subtype allocation (deemed 'unclassified'), ALLCatchR provides candidate subtype allocations (sensitivity: 0.671±0.393 / specificity: 0.978±0.036) for confirmation based on genomic driver alterations. In addition, we modified our classifier to predict baseline variables such as patient's sex (accuracy: 0.991), immunophenotype (accuracy: 0.935) or blast count (R=0.633). To define the corresponding B cell differentiation stage of origin, we compared BCP-ALL subtypes to differentiation stage-specific gene sets extracted from 7 FACS-sorted lymphopoietic subsets from healthy bone marrow donors (n=4). We observed defined BCP-ALL subtype-specific enrichment patterns which can be grouped along 4 major differentiation stages (Pro-B to Pre-B-II-Large, Fig. 1B) with a high degree of similarity in independent adult and pediatric cohorts. Thus, B cell developmental trajectories underlying BCP-ALL subtypes are dissected at high resolution by gene expression profiling and differentiation stages may favor the selection of specific leukemogenic drivers. ALLCatchR is a gene expression classifier for 21 established BCP-ALL molecular subtypes, which performs at independently validated cohorts with an accuracy of >90% and allows imputation of clinical baseline variables as well as underlying B cell developmental trajectories. It provides a reliable basis for systematic diagnostic approaches in pediatric and adult BCP-ALL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NIMG-106. WHAT’S BEHIND TSPO PET LABELLING: DIGGING FOR THE HISTOLOGICAL, CELLULAR AND MOLECULAR CORRELATES

Abstract TSPO is frequently upregulated in glioblastoma. Despite its use as an imaging biomarker for PET in glioma, the interpretation is challenging due to the heterogeneity of cell populations that could contribute to the TSPO-PET signal. We therefore dissected TSPO labelling in connection with the underlying histopathological and molecular features in biopsy samples from glioma patients. Comparing regions of high and low TSPO-PET signal in 58 patients, we assessed TSPO protein expression and expression of cell differentiation markers by use of immunohistochemistry on consecutive sections and by multiplex stains. Our results suggest that apart from microglia and macrophages the glial tumor cells relevantly contribute to the overall TSPO signal in glioma patients. To identify hallmarks and GO terms associated with TSPO labelling/expression we next performed RNAseq in 33 patients. Using DESeq2 followed by FUMA and Reactome as well as GSEA with normalized counts, we identified three TSPO-dependent functional clusters, i.e. apoptosis/DNA repair, extracellular matrix organization and immune system. On the DNA level, we analyzed the TSPO promoter by direct bisulfite sequencing suggesting that a loss of TSPO methylation may mechanistically contribute to the TSPO overexpression observed in high-grade gliomas. Exceeding our investigations on glioma biopsies we stained tissue microarrays (130 individuals) for TSPO that cover a broader spectrum of both human brain pathologies (13 different entities) and non-neoplastic tissues (14 different brain regions). We here found a high degree of heterogeneity of TSPO expression between entities and regions. Merging this information with TSPO-PETs from respective patients/brain regions allows to generate a map of TSPO expression in healthy and diseased brain for clinical use. Altogether, our approach of integrating histological, molecular and imaging data will provide unique insights into TSPO-PET enrichment patterns which may help to better understand and to comprehensively describe the clinical relevance of this novel imaging biomarker.

Commercial ChIP-Seq Library Preparation Kits Performed Differently for Different Classes of Protein Targets.

Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) is a powerful method commonly used to study global protein-DNA interactions including both transcription factors and histone modifications. We have found that the choice of ChIP-Seq library preparation protocol plays an important role in overall ChIP-Seq data quality. However, very few studies have compared ChIP-Seq libraries prepared by different protocols using multiple targets and a broad range ofinput DNA levels. In this study, we evaluated the performance of 4 ChIP-Seq library preparation protocols (New England Biolabs [NEB] NEBNext Ultra II, Roche KAPA HyperPrep, Diagenode MicroPlex, and Bioo [now PerkinElmer] NEXTflex) on 3 target proteins, chosen to represent the 3 typical signal enrichment patterns in ChIP-Seq experiments: sharp peaks (H3K4me3), broad domains (H3K27me3), and punctate peaks with a protein binding motif (CTCF). We also tested a broad range of different input DNA levels from 0.10 to 10 ng for H3K4me3 and H3K27me3 experiments. Our results suggest that the NEB protocol may be better for preparing H3K4me3 (and potentially other histone modifications with sharp peak enrichment) libraries; the Bioo protocol may be better for preparing H3K27me3 (and potentially other histone modifications with broad domain enrichment) libraries, and the Diagenode protocol may be better for preparing CTCF (and potentially other transcription factors with well-defined binding motifs) libraries. For ChIP-Seq experiments using novel targets without a known signal enrichment pattern, the NEB protocol might be the best choice, as it performed well for each of the 3 targets we tested across a wide array of input DNA levels.

Identification of CAMTA Gene Family in Heimia myrtifolia and Expression Analysis under Drought Stress.

Calmodulin-binding transcription factor (CAMTA) is an important component of plant hormone signal transduction, development, and drought resistance. Based on previous transcriptome data, drought resistance genes of the Heimia myrtifolia CAMTA transcription factor family were predicted in this study. The physicochemical characteristics of amino acids, subcellular localization, transmembrane structure, GO enrichment, and expression patterns were also examined. The results revealed that H. myrtifolia has a total of ten members (HmCAMTA1~10). Phylogenetic tree analysis of the HmCAMTA gene family revealed four different branches. The amino acid composition of CAMTA from H. myrtifolia and Punica granatum was quite similar. In addition, qRT-PCR data showed that the expression levels of HmCAMTA1, HmCAMTA2, and HmCAMTA10 genes increased with the deepening of drought, and the peak values appeared in the T4 treatment. Therefore, it is speculated that the above four genes are involved in the response of H. myrtifolia to drought stress. Additionally, HmCAMTA gene expression was shown to be more abundant in roots and leaves than in other tissues according to tissue-specific expression patterns. This study can be used to learn more about the function of CAMTA family genes and the drought tolerance response mechanism in H. myrtifolia.

Epigenetic Reprogramming of Kaposi's Sarcoma-Associated Herpesvirus during Hypoxic Reactivation.

The biphasic life cycle (latent and lytic) of Kaposi's sarcoma-associated Herpesvirus (KSHV) is regulated by epigenetic modification of its genome and its associated histone proteins. The temporal events driving epigenetic reprogramming of the KSHV genome on initial infection to establish latency has been well studied, but the reversal of these epigenetic changes during lytic replication, especially under physiological conditions such as hypoxia, has not been explored. In this study, we investigated epigenetic reprogramming of the KSHV genome during hypoxic reactivation. Hypoxia induced extensive enrichment of both transcriptional activators and repressors on the KSHV genome through H3K4Me3, H3K9Me3, and H3K27Me3, as well as histone acetylation (H3Ac) modifications. In contrast to uniform quantitative enrichment with modified histones, a distinct pattern of RTA and LANA enrichment was observed on the KSHV genome. The enrichment of modified histone proteins was due to their overall higher expression levels, which was exclusively seen in KSHV-positive cells. Multiple KSHV-encoded factors such as LANA, RTA, and vGPCR are involved in the upregulation of these modified histones. Analysis of ChIP-sequencing for the initiator DNA polymerase (DNAPol1α) combined with single molecule analysis of replicated DNA (SMARD) demonstrated the involvement of specific KSHV genomic regions that initiate replication in hypoxia.

Speciation and leaching characteristics of heavy metals from municipal solid waste incineration fly ash

• Characteristics of heavy metals in MSWI fly ash were investigated. • Coarse and fine particles MSWI fly ash can enrich more heavy metals. • Long-term environmental risk was low for As and Cr, but high for Pb and Hg. • CaO can effectively inhibit the leaching of As and Pb from MSWI fly ash. Fly ash from municipal solid waste incineration (MSWI) is classified as hazardous waste because it is rich in heavy metals (HMs), dioxins and other hazardous substances. In this paper, four kinds of MSWI fly ash were selected and tested to understand their physical and chemical properties, HM enrichment pattern, HM fugacity pattern and leaching toxicity. The results show that the main mineral components of MSWI fly ash are chlorine minerals and calcium minerals (NaCl, NaSO 4 , KCl, CaClOH, CaCO 3 , CaSO 4 , etc.), while only NaSO 4 and NaCl exist in MSWI fly ash without CaO injection. The HM contents in MSWI fly ash were As (25.8–922.0 μg/g), Cr (26.9–173.3 μg/g), Pb (988.8–1259.4 μg/g) and Hg (7.29–8.47 μg/g) and showed a trend of an initial decrease and later increase as the MSWI fly ash particle size decreased. The major species of As and Cr in the four MSWI fly ash samples were As(V) and Cr(III); Pb mainly existed as PbCl 2 and PbSO 4 . The injection of CaO could make the fly ash alkaline and promote the formation of Ca 3 (AsO 4 ) 2 , CaCrO 4 and PbCl 2 , which reduced the leaching rate of As and Pb to<10 % and 15 %, respectively. Hg exists mainly in the species of Hg 0 , Hg-OM, HgCl 2 , HgO and HgSO 4 , and its distribution is mainly influenced by the flue gas components. These results can provide a basis for studying the escape mode and leaching toxicity of HMs in MSWI fly ash.

Tracing Carbon Metabolism with Stable Isotope Metabolomics Reveals the Legacy of Diverse Carbon Sources in Soil.

Tracking the metabolic activity of whole soil communities can improve our understanding of the transformation and fate of carbon in soils. We used stable isotope metabolomics to trace 13C from nine labeled carbon sources into the water-soluble metabolite pool of an agricultural soil over time. Soil was amended with a mixture of all nine sources, with one source isotopically labeled in each treatment. We compared changes in the 13C enrichment of metabolites with respect to carbon source and time over a 48-day incubation and contrasted differences between soluble sources (glucose, xylose, amino acids, etc.) and insoluble sources (cellulose and palmitic acid). Whole soil metabolite profiles varied singularly by time, while the composition of 13C-labeled metabolites differed primarily by carbon source (R2 = 0.68) rather than time (R2 = 0.07), with source-specific differences persisting throughout incubations. The 13C labeling of metabolites from insoluble carbon sources occurred slower than that from soluble sources but yielded a higher average atom percent (atom%) 13C in metabolite markers of biomass (amino acids and nucleic acids). The 13C enrichment of metabolite markers of biomass stabilized between 5 and 15 atom% 13C by the end of incubations. Temporal patterns in the 13C enrichment of tricarboxylic acid cycle intermediates, nucleobases (uracil and thymine), and by-products of DNA salvage (allantoin) closely tracked microbial activity. Our results demonstrate that metabolite production in soils is driven by the carbon source supplied to the community and that the fate of carbon in metabolites do not generally converge over time as a result of ongoing microbial processing and recycling. IMPORTANCE Carbon metabolism in soil remains poorly described due to the inherent difficulty of obtaining information on the microbial metabolites produced by complex soil communities. Our study demonstrates the use of stable isotope probing (SIP) to study carbon metabolism in soil by tracking 13C from supplied carbon sources into metabolite pools and biomass. We show that differences in the metabolism of sources influence the fate of carbon in soils. Heterogeneity in 13C-labeled metabolite profiles corresponded with compositional differences in the metabolically active populations, providing a basis for how microbial community composition correlates with the quality of soil carbon. Our study demonstrates the application of SIP-metabolomics in studying soils and identifies several metabolite markers of growth, activity, and other aspects of microbial function.

Enrichment of Residual Carbon in Coal Gasification Fine Slag via Wet Sieving Separation with Ultrasonic Pretreatment.

To overcome the environmental and economic challenges posed by the increasing amounts of the coal gasification slag, here, a simple and efficient method for enriching the residual carbon from the coal gasification fine slag was proposed. The residual carbon enrichment pattern in the particle size distribution of coal gasification fine slags after the ultrasonic pretreatment was mainly enriched toward the 500-250 μm and 250-125 μm particle size classes by analyzing the changes in the particle size distribution and apparent morphology. The pulp pretreatment at the ultrasonic output power of 270 W for 4 min was determined as the optimal experimental condition with respect to the yield, ash content, and ash rejection of the concentrates. Compared to the conventional wet sieving separation, the yield and ash content of the final concentrates were reduced by 7.99 and 14.96%, respectively. Moreover, the ash rejection of the final concentrates was as high as 88.51%, indicating an increment of 11.63% than the conventional wet sieving separation. Furthermore, thermogravimetric analysis confirmed that the final concentrates exhibited the lowest reactivity; however, these demonstrated had the highest carbon content (nearly 70%) with 27.27% ash content. The combustion characteristics analysis showed that the wet screening concentrate after ultrasonic pretreatment had the highest composite combustion characteristic index (S) of 3.17 × 10-8, as compared to the raw and conventional sieving concentrates.

Transcriptome analysis of floral bud development and function analysis of a novel CO gene in Paeonia × lemoinei ‘High Noon’

Paeonia × lemoinei 'High Noon' is one of the most important cultivars in tree peony (Paeonia sect. Moutan), a traditional horticultural plant in China, with a re-blooming characteristic which was quite different from other cultivars. So, the genetic resources in 'High Noon' were incredibly valuable in flowering-time-modified molecular breeding in tree peony. However, the molecular mechanism underlying the floral bud formation of 'High Noon' was not clear yet. To explore the molecular mechanism in this process, the transcriptomes of three stages during floral bud development were deeply analyzed in this study. As a result, a total of 5816 differentially expressed genes (DEGs) were identified between the three developmental stages, and pathways including ''DNA replication'', ''metabolic pathways'', ''circadian rhythm'', and ''plant hormone signal transduction'' were mostly enriched in the functional enrichment and expression pattern analysis. Furthermore, a total of 584 genes related to the photoperiod pathway were further identified and a novel CO homolog gene PlCO was identified to be a stable hydrophilic protein, which contained both CCT domain and B-box domain. Over-expression of PlCO in Arabidopsis resulted in early flowering, which suggested a promotion role of flowering. The PlCO protein localized in nucleus and possessed a transcription activity ability, which implied that PlCO might function as a transcription factor. The transcriptome analysis revealed pathways involved in floral bud development in tree peony and provided new insight into the regulatory network underlying the floral bud development. The gene identification in 'High Noon' provided new valuable candidate genes for flowering-time-modified molecular breeding in tree peony.

Deconstructing Allograft Adipose and Fascia Matrix: Fascia Matrix Improves Angiogenesis, Volume Retention, and Adipogenesis in a Rodent Model.

Autologous fat grafting is commonly used for soft-tissue repair (approximately 90,000 cases per year in the United States), but outcomes are limited by volume loss (20% to 80%) over time. Human allograft adipose matrix (AAM) stimulates de novo adipogenesis in vivo, but retention requires optimization. The extracellular matrix derived from superficial fascia, interstitial within the adipose layer, is typically removed during AAM processing. Thus, fascia, which contains numerous important proteins, might cooperate with AAM to stimulate de novo adipogenesis, improving long-term retention compared to AAM alone. Human AAM and fascia matrix proteins (back and upper leg regions) were identified by mass spectrometry and annotated by gene ontology. A three-dimensional in vitro angiogenesis assay was performed. Finally, AAM and/or fascia (1 mL) was implanted into 6- to 8-week-old male Fischer rats. After 8 weeks, the authors assessed graft retention by gas pycnometry and angiogenesis (CD31) and adipocyte counts (hematoxylin and eosin) histologically. Gene ontology annotation revealed an angiogenic enrichment pattern unique to the fascia, including lactadherin, collagen alpha-3(V) chain, and tenascin-C. In vitro, AAM stimulated 1.0 ± 0.17 angiogenic sprouts per bead. The addition of fascia matrix increased sprouting by 88% (2.0 ± 0.12; P < 0.001). A similar angiogenic response (CD31) was observed in vivo. Graft retention volume was 25% (0.25 ± 0.13) for AAM, significantly increasing to 60% (0.60 ± 0.14) for AAM/fascia ( P < 0.05). De novo adipogenesis was 12% (12.4 ± 7.4) for AAM, significantly increasing to 51% (51.2 ± 8.0) for AAM/fascia ( P < 0.001) by means of adipocyte quantification. Combining fascia matrix with AAM improves angiogenesis and adipogenesis compared to AAM alone in rats. These preliminary in vitro and pilot animal studies should be further validated before definitive clinical adoption. When producing an off-the-shelf adipose inducing product by adding a connective tissue fascial component (that is normally discarded) to the mix of adipose matrix, vasculogenesis is increased and, thus, adipogenesis and graft survival is improved. This is a significant advance in this line of product.

Evolutionary responses of a reef-building coral to climate change at the end of the last glacial maximum.

Climate change threatens the survival of coral reefs on a global scale, primarily through mass bleaching and mortality as a result of marine heatwaves. While these short-term effects are clear, predicting the fate of coral reefs over the coming century is a major challenge. One way to understand the longer-term effect of rapid climate change is to examine the response of coral populations to past climate shifts. Coastal and shallow-water marine ecosystems such as coral reefs have been reshaped many times by sea-level changes during the Pleistocene, yet few studies have directly linked this with its consequences on population demographics, dispersal, and adaptation. Here we use powerful analytical techniques, afforded by haplotype-phased whole-genomes, to establish such links for the reef-building coral, Acropora digitifera. We show that three genetically distinct populations are present in northwestern Australia, and that their rapid divergence since the last glacial maximum (LGM) can be explained by a combination of founder-effects and restricted gene flow. Signatures of selective sweeps, too strong to be explained by demographic history, are present in all three populations and overlap with genes that show different patterns of functional enrichment between inshore and offshore habitats. In contrast to rapid divergence in the host, we find that photosymbiont communities are largely undifferentiated between corals from all three locations, spanning almost 1000 km, indicating that selection on host genes, and not acquisition of novel symbionts, has been the primary driver of adaptation for this species in northwestern Australia.

Transcriptional signatures of the BCL2 family for individualized acute myeloid leukaemia treatment

BackgroundAlthough anti-apoptotic proteins of the B-cell lymphoma-2 (BCL2) family have been utilized as therapeutic targets in acute myeloid leukaemia (AML), their complicated regulatory networks make individualized therapy difficult. This study aimed to discover the transcriptional signatures of BCL2 family genes that reflect regulatory dynamics, which can guide individualized therapeutic strategies.MethodsFrom three AML RNA-seq cohorts (BeatAML, LeuceGene, and TCGA; n = 451, 437, and 179, respectively), we constructed the BCL2 family signatures (BFSigs) by applying an innovative gene-set selection method reflecting biological knowledge followed by non-negative matrix factorization (NMF). To demonstrate the significance of the BFSigs, we conducted modelling to predict response to BCL2 family inhibitors, clustering, and functional enrichment analysis. Cross-platform validity of BFSigs was also confirmed using NanoString technology in a separate cohort of 47 patients.ResultsWe established BFSigs labeled as the BCL2, MCL1/BCL2, and BFL1/MCL1 signatures that identify key anti-apoptotic proteins. Unsupervised clustering based on BFSig information consistently classified AML patients into three robust subtypes across different AML cohorts, implying the existence of biological entities revealed by the BFSig approach. Interestingly, each subtype has distinct enrichment patterns of major cancer pathways, including MAPK and mTORC1, which propose subtype-specific combination treatment with apoptosis modulating drugs. The BFSig-based classifier also predicted response to venetoclax with remarkable performance (area under the ROC curve, AUROC = 0.874), which was well-validated in an independent cohort (AUROC = 0.950). Lastly, we successfully confirmed the validity of BFSigs using NanoString technology.ConclusionsThis study proposes BFSigs as a biomarker for the effective selection of apoptosis targeting treatments and cancer pathways to co-target in AML.

Molecular diversity and phenotypic pleiotropy of ancient genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their contemporary impacts on pathophysiology of Modern Humans

Timelines of population-level effects of viruses on humans varied from the evolutionary scale of million years to contemporary spread of viral infections. Correspondingly, these events are exemplified by: (i) emergence of human endogenous retroviruses (HERVs) from ancient germline infections leading to stable integration of viral genomes into human chromosomes; and (ii) wide-spread viral infections reaching a global pandemic state such as the COVID-19 pandemic. Despite significant efforts, understanding of HERV’s roles in governance of genomic regulatory networks, their impacts on primate evolution and development of human-specific physiological and pathological phenotypic traits remains limited. Remarkably, present analyses revealed that expression of a dominant majority of genes (1696 of 1944 genes; 87%) constituting high-confidence down-steam regulatory targets of defined HERV loci was significantly altered in cells infected with the SARS-CoV-2 coronavirus, a pathogen causing the global COVID-19 pandemic. This study focused on defined sub-sets of DNA sequences derived from HERVs that are expressed at specific stages of human preimplantation embryogenesis and exert regulatory actions essential for self-renewal and pluripotency. Evolutionary histories of LTR7/HERVH and LTR5_Hs/HERVK were charted based on evidence of the earliest presence and expansion of highly conserved (HC) LTR sequences. Sequence conservation analyses of most recent releases 17 primate species’ genomes revealed that LTR7/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage, while LTR5_Hs/HERVK successfully colonized primates’ germlines after the segregation of Gibbons’ species. Subsequently, both LTR7 and LTR5_Hs undergo a marked ~ fourfold–fivefold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies. Consistent with previous reports, identified in this study, 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of naïve and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS-LTRs manifest regulatory connectivity to genes encoding markers of 12 distinct cells’ populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia. Granular interrogations of genes linked with 11 distinct LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout ~ 30 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including Autosomal Dominant (92 genes) and Autosomal Recessive (93 genes) Inheritance. LTR7 regulatory elements appear linked with genes implicated in functional and morphological features of central nervous system, including synaptic transmission and protein–protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked genes identified significantly enriched gene sets encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus. Identification and characterization of 1944 genes comprising high-confidence down-steam regulatory targets of LTR7 and/or LTR5_Hs loci validated and extended these observations by documenting marked enrichments for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimer’s, schizophrenia, and other brain disorders. Overall, genes representing down-stream regulatory targets of ancient retroviral LTRs exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. This is exemplified by altered expression of 93% high-confidence LTR targets in cells infected by contemporary viruses, revealing a convergence of virus-inflicted aberrations on genomic regulatory circuitry governed by ancient retroviral LTR elements and interference with human cells’ differentiation programs.

A scalable Bayesian functional GWAS method accounting for multivariate quantitative functional annotations with applications for studying Alzheimer disease.

SummaryExisting methods for integrating functional annotations in genome-wide association studies (GWASs) to fine-map and prioritize potential causal variants are limited to using non-overlapped categorical annotations or limited by the computation burden of modeling genome-wide variants. To overcome these limitations, we propose a scalable Bayesian functional GWAS method to account for multivariate quantitative functional annotations (BFGWAS_QUANT), accompanied by a scalable computation algorithm enabling joint modeling of genome-wide variants. Simulation studies validated the performance of BFGWAS_QUANT for accurately quantifying annotation enrichment and improving GWAS power. Applying BFGWAS_QUANT to study five Alzheimer disease (AD)-related phenotypes using individual-level GWAS data (n = ∼1,000), we found that histone modification annotations have higher enrichment than expression quantitative trait locus (eQTL) annotations for all considered phenotypes, with the highest enrichment in H3K27me3 (polycomb regression). We also found that cis-eQTLs in microglia had higher enrichment than eQTLs of bulk brain frontal cortex tissue for all considered phenotypes. A similar enrichment pattern was also identified using the International Genomics of Alzheimer’s Project (IGAP) summary-level GWAS data of AD (n = ∼54,000). The strongest known APOE E4 risk allele was identified for all five phenotypes, and the APOE locus was validated using the IGAP data. BFGWAS_QUANT fine-mapped 32 significant variants from 1,073 genome-wide significant variants in the IGAP data. We also demonstrated that the polygenic risk scores (PRSs) using effect size estimates by BFGWAS_QUANT had a similar prediction accuracy as other methods assuming a sparse causal model. Overall, BFGWAS_QUANT is a useful GWAS tool for quantifying annotation enrichment and prioritizing potential causal variants.

Phosphorylation of β-catenin at Serine552 correlates with invasion and recurrence of non-functioning pituitary neuroendocrine tumours

Non-functioning pituitary tumours (NF-PitNETs) are common intracranial benign neoplasms that can exhibit aggressive behaviour by invading neighbouring structures and, in some cases, have multiple recurrences. Despite resulting in severe co-morbidities, no predictive biomarkers of recurrence have been identified for NF-PitNETs. In this study we have used high-throughput mass spectrometry-based analysis to examine the phosphorylation pattern of different subsets of NF-PitNETs. Based on histopathological, radiological, surgical and clinical features, we have grouped NF-PitNETs into non-invasive, invasive, and recurrent disease groups. Tumour recurrence was determined based on regular clinical and radiological data of patients for a mean follow-up of 10 years (SD ± 5.4 years). Phosphoproteomic analyses identified a unique phosphopeptide enrichment pattern which correlates with disease recurrence. Candidate phosphorylated proteins were validated in a large cohort of NF-PitNET patients by western blot and immunohistochemistry. We identified a cluster of 22 phosphopeptides upregulated in recurrent NF-PitNETs compared to non-invasive and invasive subgroups. We reveal significant phosphorylation of the β-catenin at Ser552 in recurrent and invasive NF-PitNETs, compared to non-invasive/non-recurrent NF-PitNET subgroup. Moreover, β-catenin pSer552 correlates with the recurrence free survival among 200 patients with NF-PitNET. Together, our results suggest that the phosphorylation status of β-catenin at Ser552 could act as potential biomarker of tumour recurrence in NF-PitNETs.

Nature and evolution of diagenetic fluids in the deeply buried Cambrian Xiaoerbulake Formation, Tarim Basin, China

Significant amounts of petroleum are found in the deeply buried Cambrian Xiaoerbulake Formation in the Tarim Basin. However, limited understanding of origin of diagenetic fluids hampers petroleum exploration. In this study, petrological and high-resolution geochemical methods have been performed to understand the origin and evolution of diagenetic fluids, and their effects on the formation of dolostone reservoir. The Xiaoerbulake Formation is characterised by microbialites. The matrix is characterised by modern seawater-like rare earth element and yttrium (REY) patterns and δ18O values of −6.02 ± 2.11‰ Vienna Pee Dee Belemnite (VPDB). Fine-crystalline dolomite cements have similar δ13C values and heavy rare earth element enrichment patterns to that of matrix dolomite, yet with lower δ18O values of −7.47 ± 1.2‰ VPDB. In the deep-burial regimes, medium- to coarse-crystalline dolomite cements and saddle dolomites were precipitated at temperatures of 90–120 and 130–190 °C, respectively, lower δ18O values, distinct middle rare earth element enrichment, and high Fe and Mn contents compared with matrix and fine-crystalline dolomite cements. These imply thermochemical reduction of Fe- or Mn-rich oxides and/or hydrothermal fluids. Compared with other types of dolomite cements, calcite cements are characterised by low δ13C values (as low as −6‰ VPDB), light rare earth elements enrichment and significantly elevated Y/Ho ratios (86 ± 59.3), likely related to the oxidation of organic matter during thermochemical sulfate reduction (TSR). Consequently, diagenetic fluid may have evolved from: Cambrian seawater, meteoric water, shallow-buried seawater-dominated pore water, medium-deep-buried ferrous-rich pore water, lately high-salinity hydrothermal fluid-dominated pore water and finally to acidic fluids related to TSR dissolution. Reservoir quality is enhanced by hydrothermal pulses and TSR in deep-burial settings. This study is significant for those concerned with the formation of deep-buried carbonate reservoirs.

Identification of the key immune-related genes in aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a major cause of death and morbidity worldwide, often due to rupture of intracranial aneurysms (IAs). Immune infiltration and inflammatory activation play key roles in the process of aneurysmal SAH (aSAH). This study aimed to elaborate the immune infiltration and identify related biomarkers both in blood and tissue samples from patients with aSAH. Expression data of aSAH and healthy control samples were obtained from gene expression omnibus (GEO) database. Overall, a blood sample dataset GSE36791 and a tissue sample dataset GSE122897 were included. Differentially expressed genes (DEGs) between aSAH and healthy samples were explored. We applied GO biological and Gene Set Enrichment Analyses (GSEA) processes to access the functional enrichment. Then feature elimination algorithms based on random forest were used to screen and verify the biomarkers of aSAH. We performed three computational algorithms including Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), Microenvironment Cell Populations-counter (MCPcounter), and xcell to evaluate the immune cell infiltration landscape to identify the unique infiltration characteristics associated with rupturing. We found 2,220 DEGs (856 upregulated and 1,364 downregulated) in the original dataset. Functional analysis revealed most of these genes are enriched in immunological process, especially related with neutrophil response. Similar signaling pathway enrichment patterns were observed in tissue sample dataset and ClueGo. Analysis of immune microenvironment infiltration suggested neutrophils were abnormally upregulated in aSAH compared with those in the control group. Key gene SRPK1 was then filtered based on feature elimination algorithms, and transcription factor (TF) ZNF281 is assumed to participate in immunomodulation by regulating expression of SRPK1. Several immunomodulators such as CXCR1 and CXCR2 also appear to be involved in the progression of aSAH. In the present study, we performed a comprehensive stratification and quantification of the immune infiltration status of aSAH. By exploring the potential mechanism for aSAH based on several computational algorithms, key genes including SRPK1 and ZNF281 were filtered. This study may be of benefit to patients who are at high risk of suffering aSAH which allows for early diagnosis and potential therapy.

Can microplastics in offshore waters reflect plastic emissions from coastal regions?

Marine microplastic pollution is a major environmental challenge that threatens marine ecosystems and human health. Several models have been used to calculate and predict the theoretical amount of plastic waste discharged into the sea by coastal countries. Unlike earlier theoretical models of source discharge, we used the method of data normalisation to focus on the actual distribution of microplastics and their potential ecological risk in offshore surface waters. Our findings indicate that the average normalised abundance of microplastics in near-shore region of Bohai Sea was greater than the average normalised abundance of microplastics in the seas near the Yangtze River Delta urban agglomeration and the Pearl River Delta urban agglomeration. Moreover, the average amount of plastic waste discharged from terrestrial sources to the ocean per kilometre exhibited the following order: Bohai Rim urban agglomeration (150.90) (tonnes km−1) < the Pearl River Delta urban agglomeration (274.30) (tonnes km−1) < Yangtze River Delta urban agglomeration (577.44) (tonnes km−1). Further, the average microplastics abundance in offshore areas of different countries and the amount of plastic discharged per kilometre of the coastline were significantly negatively correlated, implying that microplastics were not necessarily abundant in coastal areas where large amounts of plastic are discharged into the sea. Hydrodynamic conditions had the greatest influence on the distribution of microplastics in offshore surface waters. The transport of nutrient salts from terrestrial areas to offshore waters was also influenced by hydrodynamics, with enrichment patterns in offshore areas exhibiting similar to those of microplastics. Therefore, when the offshore microplastic accumulation area overlapped with the nutrient salt enrichment zone, the health risk associated with the consumption of edible fish from offshore communities increased. In view of these findings, coastal countries must implement policies to reduce marine plastic waste emissions and develop management strategies based on their local pollution levels.