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Book
Escalating global exposure to compound heat-humidity extremes with warming
Heat stress harms human health, agriculture, the economy, and the environment more broadly. Exposure to heat stress is increasing with rising global temperatures. While most studies assessing future heat stress have focused on surface air temperature, compound extremes of heat and humidity are key drivers of heat stress. Here, we use atmospheric reanalysis data and a large initial-condition ensemble of global climate model simulations to evaluate future changes in daily compound heat-humidity extremes as a function of increasing global-mean surface air temperature (GSAT). The changing frequency of heat-humidity extremes, measured using wet bulb globe temperature (WBGT), is strongly related to GSAT and, conditional upon GSAT, nearly independent of forcing pathway. The historical ∼1°C of GSAT increase above preindustrial levels has already increased the population annually exposed to at least one day with WBGT exceeding 33°C (the reference safety value for humans at rest per the ISO-7243 standard) from 97 million to 275 million. Maintaining the current population distribution, this exposure is projected to increase to 508 million with 1.5°C of warming, 789 million with 2.0°C of warming, and 1.22 billion with 3.0°C of warming (similar to late-century warming projected based on current mitigation policies).
Journal Article
Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer
Background
Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown.
Methods
Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages.
Results
In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells.
Conclusions
These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.
Journal Article
Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.
Journal Article
The Paris Climate Agreement and future sea-level rise from Antarctica
The Paris Agreement aims to limit global mean warming in the twenty-first century to less than 2 degrees Celsius above preindustrial levels, and to promote further efforts to limit warming to 1.5 degrees Celsius
1
. The amount of greenhouse gas emissions in coming decades will be consequential for global mean sea level (GMSL) on century and longer timescales through a combination of ocean thermal expansion and loss of land ice
2
. The Antarctic Ice Sheet (AIS) is Earth’s largest land ice reservoir (equivalent to 57.9 metres of GMSL)
3
, and its ice loss is accelerating
4
. Extensive regions of the AIS are grounded below sea level and susceptible to dynamical instabilities
5
–
8
that are capable of producing very rapid retreat
8
. Yet the potential for the implementation of the Paris Agreement temperature targets to slow or stop the onset of these instabilities has not been directly tested with physics-based models. Here we use an observationally calibrated ice sheet–shelf model to show that with global warming limited to 2 degrees Celsius or less, Antarctic ice loss will continue at a pace similar to today’s throughout the twenty-first century. However, scenarios more consistent with current policies (allowing 3 degrees Celsius of warming) give an abrupt jump in the pace of Antarctic ice loss after around 2060, contributing about 0.5 centimetres GMSL rise per year by 2100—an order of magnitude faster than today
4
. More fossil-fuel-intensive scenarios
9
result in even greater acceleration. Ice-sheet retreat initiated by the thinning and loss of buttressing ice shelves continues for centuries, regardless of bedrock and sea-level feedback mechanisms
10
–
12
or geoengineered carbon dioxide reduction. These results demonstrate the possibility that rapid and unstoppable sea-level rise from Antarctica will be triggered if Paris Agreement targets are exceeded.
An observationally calibrated ice sheet–shelf model suggests that global warming of 3 °C will trigger rapid Antarctic ice loss, contributing about 0.5 cm per year of sea-level rise by 2100.
Journal Article
Genome evolution and diversity of wild and cultivated potatoes
Potato (
Solanum tuberosum
L.) is the world’s most important non-cereal food crop, and the vast majority of commercially grown cultivars are highly heterozygous tetraploids. Advances in diploid hybrid breeding based on true seeds have the potential to revolutionize future potato breeding and production
1
–
4
. So far, relatively few studies have examined the genome evolution and diversity of wild and cultivated landrace potatoes, which limits the application of their diversity in potato breeding. Here we assemble 44 high-quality diploid potato genomes from 24 wild and 20 cultivated accessions that are representative of
Solanum
section
Petota
, the tuber-bearing clade, as well as 2 genomes from the neighbouring section,
Etuberosum
. Extensive discordance of phylogenomic relationships suggests the complexity of potato evolution. We find that the potato genome substantially expanded its repertoire of disease-resistance genes when compared with closely related seed-propagated solanaceous crops, indicative of the effect of tuber-based propagation strategies on the evolution of the potato genome. We discover a transcription factor that determines tuber identity and interacts with the mobile tuberization inductive signal SP6A. We also identify 561,433 high-confidence structural variants and construct a map of large inversions, which provides insights for improving inbred lines and precluding potential linkage drag, as exemplified by a 5.8-Mb inversion that is associated with carotenoid content in tubers. This study will accelerate hybrid potato breeding and enrich our understanding of the evolution and biology of potato as a global staple food crop.
High-quality diploid assemblies of potato genomes from 24 wild and 20 cultivated potatoes provide insights into the complex evolution and diversity of potatoes, and could have applications in the breeding of hybrid potatoes.
Journal Article
A multi-dimensional approach to unravel the intricacies of lactylation related signature for prognostic and therapeutic insight in colorectal cancer
Background
Lactylation, a novel contributor to post-translational protein modifications, exhibits dysregulation across various tumors. Nevertheless, its intricate involvement in colorectal carcinoma, particularly for non-histone lactylation and its intersection with metabolism and immune evasion, remains enigmatic.
Methods
Employing immunohistochemistry on tissue microarray with clinical information and immunofluorescence on colorectal cell lines, we investigated the presence of global lactylation and its association with development and progression in colorectal cancer as well as its functional location. Leveraging the AUCell algorithm alongside correlation analysis in single-cell RNA sequencing data, as well as cox-regression and lasso-regression analysis in TCGA dataset and confirmed in GEO dataset, we identified a 23-gene signature predicting colorectal cancer prognosis. Subsequently, we analyzed the associations between the lactylation related gene risk and clinical characteristics, mutation landscapes, biological functions, immune cell infiltration, immunotherapy responses, and drug sensitivity. Core genes were further explored for deep biological insights through bioinformatics and in vitro experiments.
Results
Our study innovatively reveals a significant elevation of global lactylation in colorectal cancer, particularly in malignant tumors, confirming it as an independent prognostic factor for CRC. Through a comprehensive analysis integrating tumor tissue arrays, TCGA dataset, GEO dataset, combining in silico investigations and in vitro experiments, we identified a 23-gene Lactylation-Related Gene risk model capable of predicting the prognosis of colorectal cancer patients. Noteworthy variations were observed in clinical characteristics, biological functions, immune cell infiltration, immune checkpoint expression, immunotherapy responses and drug sensitivity among distinct risk groups.
Conclusions
The Lactylation-Related Gene risk model exhibits significant potential for improving the management of colorectal cancer patients and enhancing therapeutic outcomes, particularly at the intersection of metabolism and immune evasion. This finding underscores the clinical relevance of global lactylation in CRC and lays the groundwork for mechanism investigation and targeted therapeutic strategies given the high lactate concentration in CRC.
Journal Article
Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2
Pyruvate kinase M2 isoform （PKM2） catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms under- lying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine （T） 69. This phosphoryla- tion prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90al, is required for this function of PKM2. HSP90al＇s ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bci2. Replacement of wild-type Bcl2 with phosphorylation-de- ficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor for- mation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-BcI2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phos- phorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma.
Journal Article
Advances in understanding multifunctionality of Barley stripe mosaic virus γb protein
Plant viruses usually encode versatile but limited number of proteins to reshape the cellular microenvironment, suppress or co-opt host pathways and proteins for their own benefit. Barley stripe mosaic virus (BSMV, Hordeivirus hordei ) is a positive single-stranded RNA virus that infects both monocots and dicots. Among its seven encoded proteins, the γb protein exhibits remarkable multifunctionality despite being the smallest one. By interacting with various viral and host proteins, γb acts as a master regulator participating in almost all steps of the viral life cycle, including replication, movement, virion morphogenesis and vertical transmission, in addition to counteracting several layers of host defenses. In this review, we systematically summarize current understanding of the γb protein multifunctionality and discuss its implications in the ongoing co-evolutionary battle between host plants and invading viruses.
Journal Article
Optimized paired‐sgRNA/Cas9 cloning and expression cassette triggers high‐efficiency multiplex genome editing in kiwifruit
Summary Kiwifruit is an important fruit crop; however, technologies for its functional genomic and molecular improvement are limited. The clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein (Cas) system has been successfully applied to genetic improvement in many crops, but its editing capability is variable depending on the different combinations of the synthetic guide RNA (sgRNA) and Cas9 protein expression devices. Optimizing conditions for its use within a particular species is therefore needed to achieve highly efficient genome editing. In this study, we developed a new cloning strategy for generating paired‐sgRNA/Cas9 vectors containing four sgRNAs targeting the kiwifruit phytoene desaturase gene (AcPDS). Comparing to the previous method of paired‐sgRNA cloning, our strategy only requires the synthesis of two gRNA‐containing primers which largely reduces the cost. We further compared efficiencies of paired‐sgRNA/Cas9 vectors containing different sgRNA expression devices, including both the polycistronic tRNA‐sgRNA cassette (PTG) and the traditional CRISPR expression cassette. We found the mutagenesis frequency of the PTG/Cas9 system was 10‐fold higher than that of the CRISPR/Cas9 system, coinciding with the relative expressions of sgRNAs in two different expression cassettes. In particular, we identified large chromosomal fragment deletions induced by the paired‐sgRNAs of the PTG/Cas9 system. Finally, as expected, we found both systems can successfully induce the albino phenotype of kiwifruit plantlets regenerated from the G418‐resistance callus lines. We conclude that the PTG/Cas9 system is a more powerful system than the traditional CRISPR/Cas9 system for kiwifruit genome editing, which provides valuable clues for optimizing CRISPR/Cas9 editing system in other plants.
Journal Article