Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models.

The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.

Essential Functions of Calmodulin and Identification of Its Proximal Interacting Proteins in Tachyzoite-Stage Toxoplasma gondii via BioID Technology.

Toxoplasma gondii (T. gondii) is a pathogen belonging to the apicomplexan phylum, and it threatens human and animal health. Calcium ions, a critical second messenger in cells, can regulate important biological processes, including parasite invasion and egress. Calmodulin (CaM) is a small, highly conserved, Ca2+-binding protein found in all eukaryotic cells. After binding to Ca2+, CaM can be activated to interact with various proteins. However, little is known about CaM's function and its interacting proteins in T. gondii. In this study, we successfully knocked down CaM in the T. gondii parent strain TATI using a tetracycline-off system with the Toxoplasma CaM promoter. The results indicated that CaM was required for tachyzoite proliferation, invasion, and egress and that CaM depletion resulted in apicoplast loss, thus threatening parasite survival in the next lytic cycle. In the tachyzoite stage, CaM loss caused significant anomalies in the parasite's basal constriction, motility, and parasite rosette-like arrangement in the parasitophorous vacuole (PV). These phenotypic defects caused by CaM depletion indicate the importance of CaM in T. gondii. Therefore, it is important to identify the CaM-interacting proteins in T. gondii. Applying BioID technology, more than 300 CaM's proximal interacting proteins were identified from T. gondii. These CaM partners were broadly distributed throughout the parasite. Furthermore, the protein interactome and transcriptome analyses indicated the potential role of CaM in ion binding, cation binding, metal ion binding, calcium ion binding, and oxidation-reduction. Our findings shed light on the CaM function and CaM-interactome in T. gondii and other eukaryotes. IMPORTANCE Toxoplasma gondii is an intracellular pathogen that threatens human and animal health. This unicellular parasite is active in many biological processes, such as egress and invasion. The implementation efficiency of T. gondii biological processes is dependent on signal transmission. Ca2+, as a second messenger, is essential for the parasite's life cycle. Calmodulin, a ubiquitous Ca2+ receptor protein, is highly conserved and mediates numerous Ca2+-dependent events in eukaryotes. Few CaM functions or regulated partners have been characterized in T. gondii tachyzoites. Here, we reported the essential functions of calmodulin in T. gondii tachyzoite and the identification of its interacting partners using BioID technology, shedding light on the CaM function and CaM-interactome in Toxoplasma gondii and other eukaryotes.

Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasis.

BACKGROUND: Hydrogen Sulfide (H2S), a third member of gasotransmitter family along with nitric oxide (NO) and carbon monoxide (CO), exerts a wide range of cellular and molecular actions in our body. There is a large body of evidence suggesting that H2S plays an important role in cancer metastasis; however, the molecular mechanisms of H2S-mediated acceleration of cancer metastasis remain unknown. METHODS: We examined the promote effects of H2S on phenotype of gastric cancer (GC) cells (including those of express wild type CD36 and mutant CD36) in vitro and in vivo. GC patients' samples were used for clinical translational significance evaluation. FINDINGS: H2S triggered lipid metabolism reprogramming by significantly up-regulating the expression of the fatty-acid receptor CD36 (CD36) and directly activating CD36 in GC cells. Mechanistically, a disulfide bond located between cysteine (Cys)333 and Cys272 within the CD36 protein structure that was labile to H2S-mediated modification. The long chain-fatty acid (LC-FA) binding pocket was capped by a turn in the CD36 protein, located between helical and sheet structures that were stabilized by the Cys333-Cys272. This limited the secondary binding between LC-FAs and lysine (Lys)334. Breaking the Cys333-Cys272 disulfide bond restored the second LC-FA binding conformation of CD36. Targeting CD36 in vivo blocked H2S-promoted metastasis and improved animal survival. INTERPRETATION: These findings identify that the Cys333-Cys272 disulfide bond disrupted the integrity of the second LC-FA binding conformation of CD36. Therefore, CD36 can directly activate LC-FA access to the cytoplasm by acting as a direct target molecule for H2S.

Detection of the spatial patterns of water storage variation over China in recent 70 years.

Terrestrial water storage (TWS) variation is crucial for global hydrological cycles and water resources management under climatic changes. In the previous studies, changes in water storage of some part of China have been studied with GRACE data in recent ten years. However, the spatial pattern of changes in water storage over China may be different in a long period. Here, we aimed to present long-term spatial patterns of TWS over China between 1948 to 2015 by unique Global Land Data Assimilation System Version 2 data and identify possible factors to water storage changes. The results revealed that the inner-annual variations in TWS of China exhibited remarkable downward trends with decreased rate of 0.1 cm/yr. Meanwhile, we found that spatial patterns of TWS in China can be divided into three distinct sub-regions of TWS region with increased, TWS region with decreased, TWS region with insignificant variation. The Northeast had decreased trends (-0.05 cm/yr) due to climate change and anthropogenic activities. Urban expansion is a non-ignorable factor to TWS reduction in Jing-Jin-Ji region (r = 0.61); the west had increased from 1948 to 2015 (0.03 cm/yr) due to precipitation increased and recharge by glacier melt; the south had insignificant trends and TWS varied with precipitation (r = 0.78).

Quantitative and detailed spatiotemporal patterns of drought in China during 2001-2013.

Investigation of spatiotemporal patterns of drought is essential to understand the mechanism and influencing factors of drought occurrence and development. Due to the differences in designation of various drought indices, it remains a great challenge to obtain an accurate result in spatiotemporal patterns investigation of drought. In this study, a quantitative drought monitoring index (i.e., Integrated Surface Drought Index, ISDI) was used to identify spatiotemporal patterns of drought and the drought variation trend at the pixel level during 2001-2013 over China. Eco-geographical regionalization was used as an evaluation unit to distinguish the ecological and climatic background of drought over the whole country. The results showed that the spatial distribution of drought intensity has a strong correlation with eco-geographical regionalization in China. The severe drought areas were mainly concentrated in sub-humid regions and semi-arid regions of medium temperate zones, and humid regions of middle subtropical zones. The regions with higher drought probabilities were most distributed in the south and north of China, while the regions in central and western China exhibited lower drought probabilities. The most obvious decreasing trend of ISDI from 2001 to 2013 was located in the northeast of China and south of the Yangtze River. This decrease in ISDI over time indicates a trend for progressive aggravation of drought severity in these areas. This study shows great promise in informing the future drought prevention measures and management policies under the background of more frequent extreme climate events.