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High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury.

Exposure to hypoxia disrupts energy metabolism and induces inflammation. However, the pathways and mechanisms underlying energy metabolism disorders caused by hypoxic conditions remain unclear. In the present study, a hypoxic animal model was created and transcriptomic and non-targeted metabolomics techniques were applied to further investigate the pathways and mechanisms of hypoxia exposure that disrupt energy metabolism. Transcriptome results showed that 3,007 genes were significantly differentially expressed under hypoxic exposure, and Gene Ontology annotation analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes (DEGs) were mainly involved in energy metabolism and were significantly enriched in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathway. The DEGs IDH3A , SUCLA2 , and MDH2 in the TCA cycle and the DEGs NDUFA3 , NDUFS7 , UQCRC1 , CYC1 and UQCRFS1 in the OXPHOS pathway were validated using mRNA and protein expression, and the results showed downregulation. The results of non-targeted metabolomics showed that 365 significant differential metabolites were identified under plateau hypoxia stress. KEGG enrichment analysis showed that the differential metabolites were mainly enriched in metabolic processes, such as energy, nucleotide and amino acid metabolism. Hypoxia exposure disrupted the TCA cycle and reduced the synthesis of amino acids and nucleotides by decreasing the concentration of cis-aconitate, α-ketoglutarate, NADH, NADPH and that of most amino acids, purines, and pyrimidines. Bioinformatics analysis was used to identify inflammatory genes related to hypoxia exposure and some of them were selected for verification. It was shown that the mRNA and protein expression levels of IL1B , IL12B , S100A8 and S100A9 in kidney tissues were upregulated under hypoxic exposure. The results suggest that hypoxia exposure inhibits the TCA cycle and the OXPHOS signalling pathway by inhibiting IDH3A , SUCLA2 , MDH2 , NDUFFA3 , NDUFS7 , UQCRC1 , CYC1 and UQCRFS1 , thereby suppressing energy metabolism, inducing amino acid and nucleotide deficiency and promoting inflammation, ultimately leading to kidney damage., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Gao et al.)

High altitude pulmonary edema (HAPE) is a common respiratory disease in the high altitude area, which is rapid and harmful. We firstly conducted a case-control study to assess the potential association of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population. The study recruited 238 patients with HAPE and 230 healthy controls in Northwest China. Genomic DNA was extracted from blood samples, and gene polymorphisms were detected using the Agena MassARRAY platform. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-value were used to evaluate the relationship between HAPE risk and CYP4F2 gene polymorphisms. Multi-factor dimension reduction (MDR) was used to assess the optimal interaction of CYP4F2 gene polymorphisms on HAPE risk. We found rs3093193 was shown to reduce the risk of HAPE (OR = 0.70, 95% CI = 0.52-0.93, P = 0.014), while rs12459936 was increased the susceptibility to HAPE (OR = 2.08, 95% CI = 1.33-3.26, P = 0.001). Age stratified analysis revealed that rs3093193 and rs12459936 were correlated with HAPE risk in people at age > 32 years old, and rs3093193 and rs3093110 were correlated with the HAPE risk in people at age ≤ 32 years old. Gender stratification analysis was found that rs3093193, rs12459936, and rs3093110 were all related to HAPE risk in males. A combination of rs12459936 and rs3093110 was the best multi-loci model with the highest testing accuracy. Our study is the first to provide the association between CYP4F2 gene polymorphisms and HAPE risk in the Chinese Han population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright: © 2023 Si et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

High altitude hypoxia stress is the key cause of high-altitude pulmonary edema and spleen contraction. The molecular mechanism of immune response of various tissue systems to hypoxia stress remains lacking. In this study, we applied proteomics combined with metabolomics to explore the key molecular profilings involved in high altitude hypoxia response in the spleen of mice. The results showed that 166 proteins were significantly up-regulated, and only 39 proteins were down-regulated. Bioinformatics analysis showed that mineral absorption, neuroactive ligand-receptor interaction, arachidonic acid metabolism, IL-17 signaling pathway and NOD-like preceptor signaling pathway were significantly enriched in the list of 166 upregulated differentially expressed proteins (DEPs). Among these metabolic pathways, the former three pathways were co-identified in KEGG terms from LC-MS/MS based metabolic analysis. We further found that both arachidonate 15-lipoxygenase and hematopoietic prostaglandin D synthase were upregulated by around 30% and 80% for their protein levels and mRNA levels, respectively. Most downstream metabolites were upregulated accordingly, such as prostaglandin A2 and D2. This study provides important evidence that arachidonic acid metabolism potentially promotes spleen hypoxia response through a combined analysis of proteomics and metabolism, which could bring new insights for the spleen targeted rational design upon arachidonic acid metabolism of new therapies.

High-altitude pulmonary edema (HAPE) is a common acute altitude sickness. This study was designed to investigate the effect of MIR17HG polymorphisms on HAPE risk in the Chinese population. The Agena MassARRAY platform was used to genotype six single-nucleotide polymorphisms (SNPs) in the MIR17HG gene in 244 HAPE patients and 243 non-HAPE controls. The odds ratio (OR) and 95% confidence interval were used to evaluate the association between each MIR17HG polymorphisms and the risk of HAPE under a polygenetic model. Statistical analysis was performed using the χ 2 test. Multifactor dimensionality reduction (MDR) analysis was used to analyze the impacts of SNP-SNP interactions on the risk of HAPE. According to the allele model, the HAPE risk of people with the rs7318578 A allele of MIR17HG was lower than that of people with the C allele (OR 0.74, p = 0.036).Logistic regression analysis of four models for all selected MIR17HG SNPs showed significant differences in the frequencies of rs7318578 (OR 0.74, p = 0.037) and rs17735387 (OR 1.51, p = 0.036) between cases and controls. The results of the sex stratification analysis showed that among males, rs17735387 in the MIR17HG gene is associated with an increased risk of HAPE. MDR analysis showed that the best combination model was a three-locus model incorporating rs72640334, rs7318578, and rs7336610. This study revealed the correlations between rs7318578 and rs17735387 on the MIR17HG gene and the risk of HAPE in the Chinese population, providing a theoretical basis for the early screening, prevention, and diagnosis of HAPE in high-risk populations., (© 2022. The Author(s).)

Halophilic Archaea are widely distributed globally in hypersaline environments. However, little is known of how dominant halophilic archaeal genera are distributed across environments and how they may co-associate across ecosystems. Here, the archaeal community composition and diversity from hypersaline environments (> 300 g/L salinity; total of 33 samples) in the Qaidam Basin of China were investigated using high-throughput Illumina sequencing of 16S rRNA genes. The archaeal communities (total of 3,419 OTUs) were dominated by the class Halobacteria (31.7-99.6% relative abundances) within the phylum Euryarchaeota (90.8-99.9%). Five predominant taxa, including Halorubrum, Halobacterium, Halopenitus, Methanothrix, and Halomicrobium, were observed across most samples. However, several distinct genera were associated with individual samples and were inconsistently distributed across samples, which contrast with previous studies of hypersaline archaeal communities. Additionally, co-occurrence network analysis indicated that five network clusters were present and potentially reflective of interspecies interactions among the environments, including three clusters (clusters II, III, and IV) comprising halophilic archaeal taxa within the Halobacteriaceae and Haloferacaceae families. In addition, two other clusters (clusters I and V) were identified that comprised methanogens. Finally, salinity comprising ionic concentrations (in the order of Na +  > Ca 2+  > Mg 2+ ) and pH were most correlated with taxonomic distributions across sample sites.

Background: Esophageal cancer (EC) is the leading cause of cancer-related mortality worldwide. The underlying genetic risk factors remain unclear. The association between gene growth hormone receptor (GHR) and phospholipase C epsilon 1 (PLCE1) polymorphisms and the EC risk were identified in this study., Methods: A total of 506 EC cases and 507 controls were included in this research. Two SNPs (rs6898743 of GHR and rs2274223 of PLCE1) were selected and genotyped. The associations between gene polymorphisms and the EC risk were assessed by logistic regression analysis. The databases RegulomeDB, GTEx, and UALCAN were used for functional annotations., Results: In the allelic frequencies analysis, the rs6898743 of GHR was associated with decreased susceptibility of EC (OR = 0.83, 95% CI: 0.70-1.00, p = 0.049), while rs2274223 of PLCE1 was associated with increased 0.25-fold EC risk (OR = 1.25, 95% CI: 1.02-1.53, p = 0.037). The "GC" genotype of rs6898743 was associated with a 0.24-fold decreased risk of EC under co-dominant model (OR = 0.76, 95% CI: 0.58-0.99, p = 0.046), and the "GA" genotype of rs2274223 was associated with increased EC risk under co-dominant model (OR = 1.36, 95% CI: 1.04-1.77, p = 0.023). Using GTEx database, rs2274223 was found to be significant associated with increased PLCE1 expression (p = 4.1 × 10 -7 ) in esophagus muscularis. The UALCAN database demonstrated that the GHR gene was under-expressed in esophageal cancer tissues (p = 0.017)., Conclusion: The gene GHR and PLCE1 polymorphisms are associated with EC in the general population and the results need to be verified in future., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Hypersaline lakes and saltern areas are important industrial and biodiversity resources in the Qaidam Basin of China that reside at > 2600 m asl. Most hypersaline environments in this area are characterized by saturated salinity (~ 300 g/L salinity), nearly neutral pH, intense ultraviolet radiation, and extremely variable temperature fluctuations. The core bacterial communities associated with these stressful environments have nevertheless remained uninvestigated. 16S rRNA gene Illumina sequencing analyses revealed that the bacterial communities were dominated by core lineages including the Proteobacteria (39.4-64.6%) and the Firmicutes (17.0-42.7%). However, the relative abundances of common lineages, and especially the five most abundant taxa of Pseudomonas, Lactococcus, Anoxybacillus, Acinetobacter, and Brevundimonas, were highly variable across communities and closely associated with hypersaline characteristics in the samples. Network analysis revealed the presence of co-occurrence high relative abundance taxa (cluster I) that were highly correlated across all hypersaline samples. Additionally, temperature, total organic carbon, K + , and Mg 2+ correlated highest with taxonomic distributions across communities. These results highlight the potential mechanisms that could underlie survival and adaptation to these extreme hypersaline ecosystems.

Puma Yumco Lake (PYL) is an ultraoligotrophic freshwater lake that sits an altitude of 5030 m within the Qinghai-Tibet Plateau of China. The bacterial and archaeal diversity of the lake remains poorly understood, despite their potential to inform on biogeochemical cycling and environment-microbial associations in these unique environments. Here, the bacterial and archaeal communities of PYL were investigated using high-throughput sequencing analysis of community 16S rRNA gene sequences. Further, the relationships among dominant taxa and environmental factors were comprehensively evaluated. Bacterial diversity comprised 31 phyla and 371 genera (10,645 operational taxonomic units [OTUs], Shannon index values of 5.21-6.16) and was significantly higher than that of Archaea (five phyla and 24 genera comprising 1141 OTUs and Shannon index values of 1.18-3.28). The bacterial communities were dominated by Proteobacteria (48.42-59.97% relative abundances), followed by Bacteroidetes (12.5-32.51%), Acidobacteria (2.07-11.56%), Firmicutes (0.65-6.32%), Planctomycetes (0.99-3.56%), Gemmatimonadetes (0.38-3.57%), Actinobacteria (1.67-3.52%), Verrucomicrobia (0.87-2.01%), and Chloroflexi (0.5-1.17%). In addition, archaeal communities were dominated by Thaumarchaeota (33.22-93.00%), followed by Euryarchaeota (2.89-35.47%), Woesearchaeota (0.99-31.04%), and Pacearchaeota (0.01-1.14%). The most abundant bacterial genus was Rhodoferax (5.73-26.62%) and the most abundant archaeal genus was the ammonia-oxidizing Nitrososphaera (29.18-91.46%). These results suggest that the Rhodoferax and Nitrososphaera are likely to participate in biogeochemical cycles in these environments through photoheterotrophy and nitrification, respectively. Taken together, these results provide valuable data for better understanding microbial interactions with each other and with these unique environments., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Association of Microbiologists of India 2020.)

Nanoparticles (NPs) have found a wide range of applications in clinical therapeutic and diagnostic fields. However, currently most NPs are still in the preclinical evaluation phase with few approved for clinical use. Microfluidic systems can simulate dynamic fluid flows, chemical gradients, partitioning of multi-organs as well as local microenvironment controls, offering an efficient and cost-effective opportunity to fast screen NPs in physiologically relevant conditions. Here, in this review, we are focusing on summarizing key microfluidic platforms promising to mimic in vivo situations and test the performance of fabricated nanoparticles. Firstly, we summarize the key evaluation parameters of NPs which can affect their delivery efficacy, followed by highlighting the importance of microfluidic-based NP evaluation. Next, we will summarize main microfluidic systems effective in evaluating NP haemocompatibility, transport, uptake and toxicity, targeted accumulation and general efficacy respectively, and discuss the future directions for NP evaluation in microfluidic systems. The combination of nanoparticles and microfluidic technologies could greatly facilitate the development of drug delivery strategies and provide novel treatments and diagnostic techniques for clinically challenging diseases.

Keke Salt Lake is located in the Qaidamu Basin of China. It is a unique magnesium sulfate-subtype hypersaline lake that exhibits a halite domain ecosystem, yet its microbial diversity has remained unstudied. Here, the microbial community structure and diversity was investigated via high-throughput sequencing of the V3-V5 regions of 16S rRNA genes. A high diversity of operational taxonomic units was detected for Bacteria and Archaea (734 and 747, respectively), comprising 21 phyla, 43 classes, and 201 genera of Bacteria and 4 phyla, 4 classes, and 39 genera of Archaea. Salt-saturated samples were dominated by the bacterial genera Bacillus (51.52%-58.35% relative abundance), Lactococcus (9.52%-10.51%), and Oceanobacillus (8.82%-9.88%) within the Firmicutes phylum (74.81%-80.99%), contrasting with other hypersaline lakes. The dominant Archaea belonged to the Halobacteriaceae family, and in particular, the genera (with an abundance of >10% of communities) Halonotius, Halorubellus, Halapricum, Halorubrum, and Natronomonas. Additionally, we report the presence of Nanohaloarchaeota and Woesearchaeota in Qinghai-Tibet Plateau lakes, which has not been previously documented. Total salinity (especially Mg 2+ , Cl - , Na + , and K + ) mostly correlated with taxonomic distribution across samples. These results expand our understanding of microbial resource utilization within hypersaline lakes and the potential adaptations of dominant microorganisms that allow them to inhabit such environments.

The moderately halophilic bacterium Halomonas sp. QHL1 was identified as a member of the genus Halomonas by 16S rRNA gene sequencing. HPLC analysis showed that strain QHL1 synthesizes ectoine in its cytoplasm. The genes involved in the ectoine biosynthesis pathway were identified on the chromosome in the order ectABC. Subsequently, the ectB gene from this strain was amplified by PCR, and the entire ectABC gene cluster (3,580 bp) was cloned using genome walking. Analysis showed that the ectA (579 bp), ectB (1269 bp), and ectC (390 bp) genes were organized in a single transcriptional unit and were predicted to encode three peptides of 21.2 kDa, 46.4 kDa, and 14.7 kDa, respectively. Two putative promoters, a δ(70)-dependent promoter and a δ(38)-controlled promoter, as well as several conserved motifs with unknown function were identified. Individual ectA, ectB, and ectC genes, and the entire ectABC gene cluster were inserted into the expression plasmid pET-28a(+) to generate the recombinant plasmids pET-28a(+)-ectA, pET-28a(+)-ectB, pET-28a(+)-ectC and pET-28a(+)-ectABC, respectively. Heterologous expression of these proteins in Escherichia coli BL21 (DE3) was confirmed by SDS-PAGE. The recombinant E. coli strain BL21 (pET-28a (+)-ectABC) displayed a higher salt tolerance than native E. coli cells but produced far less ectoine than the wild-type QHL1 strain.