Evaluation of circulating plasma proteins in prostate cancer using mendelian randomization.

BACKGROUND: The proteome is an important resource for exploring potential diagnostic and therapeutic targets for cancer. This study aimed to investigate the causal associations between plasma proteins and prostate cancer (PCa), and to explore the downstream phenotypes that plasma proteins may influence and potential upstream intervening factors. METHODS: Proteome-wide Mendelian randomization was used to investigate the causal effects of plasma proteins on PCa. Colocalization analysis examined the common causal variants between plasma proteins and PCa. Summary-statistics-based Mendelian Randomization (SMR) analyses identified associations between the expression of protein-coding genes and PCa. Phenome-wide association study was performed to explore the effect of target proteins on downstream phenotypes. Finally, a systematic Mendelian randomization analysis between lifestyle factors and plasma proteins was performed to assess upstream intervening factors for plasma proteins. RESULTS: The findings revealed a positive genetic association between the predicted plasma levels of nine proteins and an elevated risk of PCa, while four proteins exhibited an inverse association with PCa risk. SMR analyses revealed ZG16B, PEX14 in blood and ZG16B, NAPG in prostate tissue were potential drug targets for PCa. The genetic association of PEX14 with PCa was further supported by colocalization analysis. Further Phenome-wide association study showed possible side effects of ZG16B, PEX14 and NAPG as drug targets. 10 plasma proteins (RBP7, TPST1, NFASC, LAYN, HDGF, SERPIMA5, DLL4, EFNA3, LIMA1, and CCL27) could be modulated by lifestyle-related factors. CONCLUSION: This study explores the genetic associations between plasma proteins and PCa, provides evidence that plasma proteins serve as potential drug targets and enhances the understanding of the molecular etiology, prevention and treatment of PCa.

Is diet related to skin condition? A Mendelian randomization study.

Observational studies have revealed associations between various dietary factors and skin conditions. However, the causal relationship between diet and skin condition is still unknown. Data on 17 dietary factors were obtained from the UK Biobank. Data on four skin conditions were derived from the UK Biobank and another large-scale GWAS study. Genetic predictions suggested that the intake of oily fish was associated with a lower risk of skin aging (OR: 0.962, P = 0.036) and skin pigmentation (OR: 0.973, P = 0.033); Tea intake was associated with a lower risk of skin pigmentation (OR: 0.972, P = 0.024); Salad/raw vegetables intake was associated with a lower risk of keratinocyte skin cancer (OR: 0.952, P = 0.007). Coffee intake was associated with increased risk of skin aging (OR: 1.040, P = 0.028); Pork intake was associated with increased risk of skin aging (OR: 1.134, P = 0.020); Beef intake was associated with increased risk of cutaneous melanoma (OR: 1.013, P = 0.016); Champagne plus white wine intake was associated with increased risk of cutaneous melanoma (OR: 1.033, P = 0.004); Bread intake was associated with increased risk of keratinocyte skin cancer (OR: 1.026, P = 0.013). Our study results indicate causal relationships between genetically predicted intake of oily fish, tea, salad/raw vegetables, coffee, pork, beef, champagne plus white wine, and bread and skin conditions.

Designing Efficient Non-Precious Metal Electrocatalysts for High-Performance Hydrogen Production: A Comprehensive Evaluation Strategy.

Developing abundant Earth-element and high-efficient electrocatalysts for hydrogen production is crucial in effectively reducing the cost of green hydrogen production. Herein, a strategy by comprehensively considering the computational chemical indicators for H* adsorption/desorption and dehydrogenation kinetics to evaluate the hydrogen evolution performance of electrocatalysts is proposed. Guided by the proposed strategy, a series of catalysts are constructed through a dual transition metal doping strategy. Density Functional Theory (DFT) calculations and experimental chemistry demonstrate that cobalt-vanadium co-doped Ni3N is an exceptionally ideal catalyst for hydrogen production from electrolyzed alkaline water. Specifically, Co,V-Ni3N requires only 10 and 41 mV in alkaline electrolytes and alkaline seawater, respectively, to achieve a hydrogen evolution current density of 10 mA cm-2. Moreover, it can operate steadily at a large industrial current density of 500 mA cm-2 for extended periods. Importantly, this evaluation strategy is extended to single-metal-doped Ni3N and found that it still exhibits significant universality. This study not only presents an efficient non-precious metal-based electrocatalyst for water/seawater electrolysis but also provides a significant strategy for the design of high-performance catalysts of electrolyzed water.

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling.

Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒Gs, GPR161‒Gs and GPR174‒Gs complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent manner. Moreover, GPR174 adopts a non-canonical Gs coupling mode. The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands.