Long non-coding RNA MALAT1 triggers ferroptosis via interaction with FUS to enhance ACSF2 mRNA stabilization in septic acute kidney injury.

Septic acute kidney injury (AKI) is a fatal disease in the intensive care unit, with ferroptosis playing a crucial role in its pathogenesis. Long non-coding RNA (LncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in septic-induced AKI inflammation and apoptosis. However, its regulatory role in ferroptosis and underlying mechanisms remain unclear. In vivo and in vitro models of septic AKI were established using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) challenge, respectively. Serum levels of creatinine (Cr), blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and inflammatory cytokine in kidney tissues were determined by ELISA kits. Histopathological alterations and apoptosis were evaluated by HE staining and TUNEL. Ferroptosis was accessed by measuring MDA, GSH, Fe2+, total and lipid ROS levels, and mitochondrial ultrastructure changes. Target molecular levels were determined using RT-qPCR, Western blotting, and immunofluorescence. Interactions among MALAT1, acyl-CoA synthetase family member 2 (ACSF2) and FUS RNA binding protein (FUS) were validated by RIP and RNA-pull down. MALAT1 level was significantly elevated in both in vivo and in vitro septic AKI models, of which knockdown impeded ferroptosis to alleviate septic AKI. Mechanistically, high MALAT1 expression increased ACSF2 mRNA stability via interaction with FUS. Rescue experiments showed that ACSF2 overexpression partially reversed the ferroptosis inhibition mediated by MALAT1 silencing. MALAT1 induces ferroptosis and exacerbates septic AKI by stabilizing ACSF2 mRNA with the assistance of FUS. These findings provide theoretical evidence for MALAT1 as a potential therapeutic target for septic AKI.

High-resolution mapping of age- and gender-specific risk of Clonorchis sinensis infection risk in Guangdong, China: a geostatistical modeling study.

BACKGROUND: The latest national survey on the distribution of human parasites in China demonstrated that Guangdong was among the endemic provinces with the highest Clonorchis sinensis infection rates. High-resolution, age- and gender-specific risk maps of the temporal and spatial distributions are essential for the targeted control work. METHODS: Disease data on the prevalence of C. sinensis infection from 1990 onwards, either age- and gender-specific or aggregated across age and gender, were collected through systematic review and four large-scale surveys in Guangdong Province. Environmental and socioeconomic variables were obtained from open-access databases and employed as potential predictors. A Bayesian geostatistical model was developed to estimate the C. sinensis infection risk at high spatial resolution. RESULTS: The final dataset included 606 surveys at 463 unique locations for C. sinensis infection. Our findings suggested that following an initial increase and stabilization, the overall population-adjusted prevalence had declined to 2.2% (95% Bayesian credible interval: 1.7-3.0%) in the period of 2015 onwards. From 2015 onwards, moderate and high infection risks were found in the northern regions (e.g. Heyuan and Shaoguan cities) and the southern Pearl River Delta (e.g. Foshan, Zhongshan, Zhuhai and Jiangmen cities), respectively. Age- and gender-specific risk maps revealed that males had a higher infection risk than females, and the infection risk was higher in adults compared to children. CONCLUSIONS: Our high-resolution risk maps of C. sinensis infection in Guangdong Province identified the spatial, temporal, age and gender heterogeneities, which can provide useful information assisting tailored control strategies.

The spatial-temporal distribution of soil-transmitted helminth infections in Guangdong Province, China: A geostatistical analysis of data derived from the three national parasitic surveys.

BACKGROUND: The results of the latest national survey on important human parasitic diseases in 2015-2016 showed Guangdong Province is still a moderately endemic area, with the weighted prevalence of soil-transmitted helminths (STHs) higher than the national average. High-resolution age- and gender-specific spatial-temporal risk maps can support the prevention and control of STHs, but not yet available in Guangdong. METHODOLOGY: Georeferenced age- and gender-specific disease data of STH infections in Guangdong Province was derived from three national surveys on important human parasitic diseases, conducted in 1988-1992, 2002-2003, and 2015-2016, respectively. Potential influencing factors (e.g., environmental and socioeconomic factors) were collected from open-access databases. Bayesian geostatistical models were developed to analyze the above data, based on which, high-resolution maps depicting the STH infection risk were produced in the three survey years in Guangdong Province. PRINCIPAL FINDINGS: There were 120, 31, 71 survey locations in the first, second, and third national survey in Guangdong, respectively. The overall population-weighted prevalence of STH infections decreased significantly over time, from 68.66% (95% Bayesian credible interval, BCI: 64.51-73.06%) in 1988-1992 to 0.97% (95% BCI: 0.69-1.49%) in 2015-2016. In 2015-2016, only low to moderate infection risk were found across Guangdong, with hookworm becoming the dominant species. Areas with relatively higher risk (>5%) were mostly distributed in the western region. Females had higher infection risk of STHs than males. The infection risk of A. lumbricoides and T. trichiura were higher in children, while middle-aged and elderly people had higher infection risk of hookworm. Precipitation, elevation, land cover, and human influence index (HII) were significantly related with STH infection risk. CONCLUSIONS/SIGNIFICANCE: We produced the high-resolution, age- and gender-specific risk maps of STH infections in the three national survey periods across nearly 30 years in Guangdong Province, which can provide important information assisting the control and prevention strategies.

A DGCR8-Independent Stable MicroRNA Expression Strategy Reveals Important Functions of miR-290 and miR-183-182 Families in Mouse Embryonic Stem Cells.

Dgcr8 knockout cells provide a great means to understand the function of microRNAs (miRNAs) in vitro and in vivo. Current strategies to study miRNA function in Dgcr8 knockout cells depend on transient transfection of chemically synthesized miRNA mimics, which is costly and not suitable for long-term study and genetic selection of miRNA function. Here, we developed a cost-effective DGCR8-independent stable miRNA expression (DISME) strategy based on a short hairpin RNA vector that can be precisely processed by DICER. Using DISME, we found that miR-294 promoted the formation of meso-endoderm lineages during embryonic stem cell differentiation. Furthermore, DISME allowed for a pooled screen of miRNA function and identified an miR-183-182 cluster of miRNAs promoting self-renewal and pluripotency in mouse embryonic stem cells. Altogether, our study demonstrates that DISME is a robust and cost-effective strategy that allows for long-term study and genetic selection of miRNA function in a Dgcr8 knockout background.