Recent advancements in spatial transcriptomic technologies have enabled the measurement of whole transcriptome profiles with preserved spatial context. However, limited by spatial resolution, the ...measured expressions at each spot are often from a mixture of multiple cells. Computational deconvolution methods designed for spatial transcriptomic data rarely make use of the valuable spatial information as well as the neighboring similarity information. Here, we propose SONAR, a Spatially weighted pOissoN-gAmma Regression model for cell-type deconvolution with spatial transcriptomic data. SONAR directly models the raw counts of spatial transcriptomic data and applies a geographically weighted regression framework that incorporates neighboring information to enhance local estimation of regional cell type composition. In addition, SONAR applies an additional elastic weighting step to adaptively filter dissimilar neighbors, which effectively prevents the introduction of local estimation bias in transition regions with sharp boundaries. We demonstrate the performance of SONAR over other state-of-the-art methods on synthetic data with various spatial patterns. We find that SONAR can accurately map region-specific cell types in real spatial transcriptomic data including mouse brain, human heart and human pancreatic ductal adenocarcinoma. We further show that SONAR can reveal the detailed distributions and fine-grained co-localization of immune cells within the microenvironment at the tumor-normal tissue margin in human liver cancer.
Summary Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung ...cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.
The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic ...immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
The origin and evolution of the domestic dog remains a controversial question for the scientific community, with basic aspects such as the place and date of origin, and the number of times dogs were ...domesticated, open to dispute. Using whole genome sequences from a total of 58 canids （12 gray wolves, 27 primitive dogs from Asia and Africa, and a collection of 19 diverse breeds from across the world）, we find that dogs from southern East Asia have significantly higher genetic diversity compared to other populations, and are the most basal group relating to gray wolves, indicating an ancient origin of domestic dogs in southern East Asia 33 000 years ago. Around 15 000 years ago, a subset of ancestral dogs started migrating to the Middle East, Africa and Europe, arriving in Europe at about 10 000 years ago. One of the out of Asia lineages also migrated back to the east, creating a series of admixed populations with the endemic Asian lineages in northern China before migrating to the New World. For the first time, our study unravels an extraordinary journey that the domestic dog has traveled on earth.
In situ immobilization of heavy metals in contaminated soils using industrial by-products is an attractive remediation technique. In this work, titanium gypsum (TG) was applied at two levels (TG-L: ...0.15% and TG-H: 0.30%) to simultaneously reduce the uptake of cadmium (Cd), lead (Pb) and arsenic (As) in rice grown in heavy metal contaminated paddy soils. The results showed that the addition of TG significantly decreased the pH and dissolved organic carbon (DOC) in the bulk soil. TG addition significantly improved the rice plants growth and reduced the bioavailability of Cd, Pb and As. Particularly, bioavailable Cd, Pb and As decreased by 35.2%, 38.1% and 38.0% in TG-H treatment during the tillering stage, respectively. Moreover, TG application significantly reduced the accumulation of Cd, Pb and As in brown rice. Real-time PCR analysis demonstrated that the relative abundance of sulfate-reducing bacteria increased with the TG application, but not for the iron-reducing bacteria. In addition, 16S rRNA sequencing analysis revealed that the relative abundances of heavy metal-resistant bacteria such as Bacillus, Sulfuritalea, Clostridium, Sulfuricella, Geobacter, Nocardioides and Sulfuricurvum at the genus level significantly increased with the TG addition. In conclusion, the present study implied that TG is a potential and effective amendment to immobilize metal(loid)s in soil and thereby reduce the exposure risk of metal(loid)s associated with rice consumption.
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•Titanium gypsum addition decreased the bioavailability of Cd, Pb and As in soil.•Titanium gypsum addition reduced the accumulation of Cd, Pb and As in brown rice.•Titanium gypsum addition enhanced the abundance of sulfate-reducing bacteria and metal-resistant bacteria in soil.•Titanium gypsum is a potential and effective amendment to immobilize metals in soil.
Titanium gypsum is a potential and effective amendment to immobilize Cd, Pb and As in paddy soils.
Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) ...in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.
Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure. Enterovirus B (EV-B) consists of several subgroups according to receptor ...usage, among which echovirus 30 (E30), a leading causative agent for human aseptic meningitis, utilizes FcRn as an uncoating receptor. However, receptors for many EVs remain unknown. Here we analyzed the atomic structures of E30 mature virion, empty- and A-particles, which reveals serotype-specific epitopes and striking conformational differences between the subgroups within EV-Bs. Of these, the VP1 BC loop markedly distinguishes E30 from other EV-Bs, indicative of a role as a structural marker for EV-B. By obtaining cryo-electron microscopy structures of E30 in complex with its receptor FcRn and CD55 and comparing its homologs, we deciphered the underlying molecular basis for receptor recognition. Together with experimentally derived viral receptor identifications, we developed a structure-based in silico algorithm to inform a rational prediction for EV receptor usage.
Phenotypic plasticity facilitates organismal invasion of novel environments, and the resultant phenotypic change may later be modified by genetic change, so called 'plasticity first.' Herein, we ...quantify gene expression plasticity and regulatory adaptation in a wild bird (Eurasian Tree Sparrow) from its original lowland (ancestral stage), experimentally implemented hypoxia acclimation (plastic stage), and colonized highland (colonized stage). Using a group of co-expressed genes from the cardiac and flight muscles, respectively, we demonstrate that gene expression plasticity to hypoxia tolerance is more often reversed than reinforced at the colonized stage. By correlating gene expression change with muscle phenotypes, we show that colonized tree sparrows reduce maladaptive plasticity that largely associated with decreased hypoxia tolerance. Conversely, adaptive plasticity that is congruent with increased hypoxia tolerance is often reinforced in the colonized tree sparrows. Genes displaying large levels of reinforcement or reversion plasticity (i.e. 200% of original level) show greater genetic divergence between ancestral and colonized populations. Overall, our work demonstrates that gene expression plasticity at the initial stage of high-elevation colonization can be reversed or reinforced through selection-driven adaptive modification.
Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, ...using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.
Microbial transformation of arsenic (As) plays a key role in As biogeochemical cycling and affects the mobility, bioavailability, and toxicity of As. This study aims to investigate the accumulation ...of As in marine sediments at different water depths in the East China Sea and reveal the abundance and diversity of the aioA, arrA, arsC, and arsM genes through quantitative real-time polymerase chain reaction (qPCR) and high-throughput sequencing. Results showed that the As content in sediments ranged from 5.53 mg kg−1 to 17.70 mg kg−1, which decreased with water depth. Abundant As biotransformation genes with low diversity were identified in these sediments, of which arsM and arrA were the most abundant. Significant positive correlation exists between the arsM and arrA gene abundance and between arsC and aioA, indicating the co-occurrence of the As biotransformation genes in microbes in marine sediments. Metagenomics analysis revealed that arsM gene was mainly distributed in Alphaproteobacteria, Solibacteres, Deltaproteobacteria, Clostridia, and Bacilli in these sediments. Among the sediment properties, total N, total S, C/N, and TOC were important factors that shaped the abundance profile of the genes involved in As transformation. This study provides a picture of As biotransformation genes in marine sediments from the East China Sea, which may affect As transformation and the ultimate fate of As in a marine environment.
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•As content in marine sediments from the East China Sea decreased with water depth.•As biotransformation genes were analyzed by metagenomics in marine sediments.•arsM and arrA were abundant and co-existed in marine sediments.•α-, δ-Proteobacteria, Solibacteres, Clostridia, were main microbes carrying arsM.•Total N, S, C/N and TOC were important factors shaping the diversity of these genes.
This study depicts the As distribution and its biotransformation genes in marine sediments from the East China Sea.
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