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Colorectal cancer (CRC) is a prevalent malignancy with significant mortality rates globally. Understanding the genetic and molecular mechanisms underlying CRC development is crucial for improving therapeutic strategies. In this study, we utilized cis-eQTL summary data to identify genes potentially causally associated with CRC. The expression levels of candidate genes in tumor and normal tissues were compared using the GEPIA2 database. The correlations between FUT8 expression and cellular functions, tumor mutation burden, immune checkpoint genes, and immune infiltration were analyzed. Molecular docking was performed to identify potential drugs targeting FUT8, and the effects of the selected drug on cell proliferation were evaluated using the MTT assay. Additionally, the cellular thermal shift assay (CETSA) was employed to assess the interaction between the drug and the target protein. We identified 19 genes with eQTLs potentially associated with CRC, among which six eQTLs were associated with increased CRC risk, including FUT8. FUT8 was significantly overexpressed in CRC tumor tissues and correlated with various cellular functions such as stemness, invasion, EMT, and metastasis. Higher FUT8 expression was associated with higher tumor mutation burden and significant correlations with multiple immune checkpoint genes. Molecular docking identified VE-822 as a promising drug candidate targeting FUT8, which demonstrated inhibitory effects on CRC cell proliferation. The CETSA results indicated that VE ‒ 822 could bind to FUT8 and improve its thermal stability. FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8.

Climate change has broadly impacted on the China areas. There will be severe challenges due to the variations of precipitation and temperature in the future. Therefore, a comprehensive understanding of the future climate change over China areas is desired. In this study, future annual precipitation and annual mean temperature under two SSPs over China areas were projected through multiple global climate models. Meanwhile, to explore the sources of uncertainty in projecting future climate change, the multi-factorial analysis was conducted through GCMs (five levels) and SSPs (two levels). This study can help us understand the possible changes in precipitation, temperature, and the potential extreme climate events over the China area. The results indicate that China would have more annual precipitation and higher annual mean temperature in the future. Compared with the historical period, the annual mean temperature would face a continuously increasing trend under SSPs. Regardless of SSP245 or SSP585, the growth rate of annual precipitation and annual mean temperature increase in the northern region (e.g., Northeast China, North China, and Northwest China) are higher than those in the southern parts (e.g., East China, South China, and Central China). The future temperature rise may increase the frequency of heat-related extreme climate events, which needs to be focused on in future research. Moreover, GCM was the main contributing factor to the sources of uncertainty in projecting future precipitation and SSP was the main factor for future temperature. Overall, climate change is an indisputable fact in China. The annual precipitation and annual mean temperature would increase to varying degrees in the future. Reducing the systemic bias of the climate model itself will undoubtedly be the top priority, and it would help to improve the projection and evaluation effects of relevant climate variables.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY‐box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6+/ALDH1A1+) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT‐rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT‐rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co‐expressing AEP‐truncated Sox6 and ALDH1A1 fragments in 3‐month‐old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP‐resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone‐induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD. The Gut‐to‐brain propagation of pathologic α‐Syn via vagus nerve‐DMVN‐LC‐SN initiates PD. SNpc DA neurons form stronger connections with the LC than the VTA. AEP is subsequently activated by α‐Syn fibrils in the SNpc, leading to cleavage of Sox6 and ALDH1A1 in SNpc DA neurons, contributing to the vulnerability of dopaminergic neurons in Parkinson's disease.

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC. [Display omitted] •Pyr regulates mitophagy by interfering with autophagosome-lysosome formation.•Pyr blocks autolysosomes formation by inhibiting SNAP29-VAMP8 interactions.•Pyr upregulates BNIP3 and induces the interaction of SNAP29 with BNIP3.•Restoration of the interaction between SNAP29 and VAMP8 by BNIP3 depletion.•Pyr enhances the sensitivity of HCC to Sora in vitro and in vivo.

Significant increases in both heatwaves and heavy precipitation were reported under global warming, leading to detrimental social, economic, and environmental impacts. However, future variations of such compound heatwave and heavy precipitation events (CHWHPs) were barely analyzed in Guangdong. Therefore, a downscaled compound heatwave-precipitation analysis approach (DCHP) was developed to explore the spatio-temporal variations of CHWHPs in Guangdong under two shared socioeconomic pathways (i.e., SSPs). Potential changes in four parameters (i.e., the occurrence frequency, the average duration, the total intensity, and the longest duration) of projected CHWHPs for the future (i.e., 2025–2054 and 2066–2095) and historical (i.e., 1985–2014) periods were analyzed based on the multi-model ensemble of 15 global climate models (GCMs) from the Coupled Model Intercomparison Projected Phase 6 (CMIP6). Additionally, the effects of multiple impact factors (GCM, SSP, and their interactions) on the compound events were investigated through a multilevel factorial analysis approach. The results showed that the majority of Guangdong would undergo a significant increasing trend in the projected temperature and precipitation (e.g., 0.43–0.61 °C per decade and − 7.79 to 43.02 mm per decade under SSP5–8.5). Spatial changes and interannual trends suggested that Guangdong would suffer more CHWHP events in the future, especially for 2066–2095 under SSP5–8.5. The variations of four parameters are projected to increase by 13.86 events, 2.27 days per event, 55.32 °C, and 7.13 days during 2066–2095 under SSP5–8.5, respectively; the MK test of four parameters are statistically significant and the Sen’s slopes are 0.0125%, 0.0027%, 0.1946%, and 0.0097% per decade, respectively. The higher increases in such parameters are expected to be concentrated in western, northwestern, and northeastern Guangdong. The factorial analysis results indicate that the GCM choice is a major impacting factor on the projected CHWHP parameters in two future periods; the contribution of such factor would decrease slightly from 2025–2054 to 2066–2095. The results can help support informed decision-making to mitigate and adapt to potential risks from compound events in multiple sectors under climate change, such as human health and agriculture.

In this study, the fifth generation ECMWF reanalysis (ERA5) reanalysis datasets and three global climate models (GCMs) were selected as the inputs of the stepwise-clustered heat stress downscaling (SCHSD) method to simulate the future heat stress indices in East China. The heat stress indices included the Heat Index ( HI ), Humidex ( HUMIDEX ) and the simplified Wet Bulb Globe Temperature ( sWBGT ). Three GCMs (i.e., CanESM5, INM-CM4-8 and MPI-ESM1-2-HR) under two Shared Socioeconomic Pathway (SSP245 and SSP585) were input into the SCHSD model to develop downscaled climate projections. To verify the SCHSD model, the reproduction results from three GCMs during the period of 1990–2014 were compared to daily observational data (i.e., HI , HUMIDEX and sWBGT ). The verification results suggest that the coefficient of determination ( R 2 ) of the stations in the northern part of East China mostly exceeds 0.8, while the R 2 of the stations in the southern part of East China is mostly in the range of 0.6 to 0.8. The projection results suggest that the future heat stress in East China would generally maintain an upward trend from 2021 to 2100. The largest change in heat stress is projected in June under the period of 2021–2100. The results also show that the highest average of days in the danger category is 78.9 in summer under the SSP585 scenario, accounting for 86% of the total summer (June, July and August). Highlights A stepwise-clustered heat stress downscaling (SCHSD) approach was developed to analyze the future changes in heat stress changes in East China. The coefficient of determination ( R 2 ) of the stations in the northern part of East China mostly exceeds 0.8, while the R 2 of the stations in the southern part of East China is mostly in the range of 0.8 to 0.6. The highest average of days in the danger category is 78.9 in summer under the SSP585 scenario, accounting for 86% of the total summer (June, July and August).

Millions of nerves, immune factors, and hormones in the circulatory system connect the gut and the brain. In bidirectional communication, the gut microbiota play a crucial role in the gut-brain axis (GBA), wherein microbial metabolites of the gut microbiota regulate intestinal homeostasis, thereby influencing brain activity. Dynamic changes are observed in gut microbiota as well as during brain development. Altering the gut microbiota could serve as a therapeutic target for treating abnormalities associated with brain development. Neurophysiological development and immune regulatory disorders are affected by changes that occur in gut microbiota composition and function. The molecular aspects relevant to the GBA could help develop targeted therapies for neurodevelopmental diseases. Herein, we review the findings of recent studies on the role of the GBA in its underlying molecular mechanisms in the early stages of brain development. Furthermore, we discuss the bidirectional regulation of gut microbiota from mother to infant and the potential signaling pathways and roles of posttranscriptional modifications in brain functions. Our review summarizes the role of molecular GBA in early brain development and related disorders, providing cues for novel therapeutic targets.

Non-small cell lung cancer (NSCLC) is a highly malignant tumor with a poor prognosis. Hypoxia conditions affect multiple cellular processes promoting the adaptation and progression of cancer cells via the activation of hypoxia-inducible factors (HIF) and subsequent transcription activation of their target genes. Preliminary studies have suggested that estrogen receptor β (ERβ) might play a promoting role in the progression of NSCLC. However, the precise mechanisms, particularly its connection to HIF-1α-mediated modulation under hypoxia, remain unclear. Our findings demonstrated that the overexpression of ERβ, not ERα, increased cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts. Tissue microarray staining revealed a strong correlation between the protein expression of HIF-1α and ERβ. HIF-1α induced ERβ gene transcription and protein expression in CoCl2-induced hypoxia, 1% O2 incubation, or HIF-1α overexpressing cells. ChIP identified HIF-1α binding to a hypoxia response element in the ESR2 promoter. The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the tumor growth, thus emphasizing the promising prospects of targeting HIF-1α and ERβ as a therapeutic approach for the treatment of NSCLC.Key messagesERβ, not ERα, increases cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts.A strong correlation exists between the protein expression of HIF-1α and ERβ.HIF-1α induced ERβ gene transcription and protein expression in hypoxic cells via binding to HRE in the ESR2 promoter.The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the NSCLC tumor growth.

Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.

The SIMILAR TO RCD-ONE (SROs) have been characterized as a group of plant-specific proteins which play important functions in stress responses and development. Here, we analyze the expression profiles of six SRO genes under different stress treatments in Arabidopsis. Our results revealed that RCD1 play an essential role in plant responses to various environmental stresses. SRO1 has partially overlapping functions with RCD1 in plant response to HgCl2 and H2O2 stress. Analysis of the transcriptional expression of SROs indicated that both of the RCD1 and SRO1 transcripts were up-regulated by HgCl2 and light, not by other stresses, and that of SRO5 was induced by salt. Expression of SRO3 and SRO4 were not influenced by stresses. The different effects of these stresses on the expression of the SRO genes indicate that the SRO family is regulated by multiple signaling pathways. Sequence analyses of the SRO proteins implicate a highly preserved protein structure and are specific to plants, which might have implications for functional conservation. The ubiquitous expression and nuclear localization of SRO family suggested that their function might be related to transcription factor regulation and complex formation. Taken together, SRO family is critical for proper plant development and multiple stress responses.