Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers.

BACKGROUND: The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs. METHODS: The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein-protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications. RESULTS: This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86-0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65-0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94-0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10-1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03-1.06), GSTP1 (OR: 0.82, 95% CI 0.74-0.90), and CTSS (OR: 0.91, 95% CI 0.88-0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80-0.91), ISLR2 (OR: 0.87, 95% CI 0.82-0.93), and CTSF (OR: 1.14, 95% CI 1.08-1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91-0.95), ICAM5 (OR: 0.95, 95% CI 0.93-0.97), and FLRT3 (OR: 1.10, 95% CI 1.05-1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment. CONCLUSIONS: This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

The association between ACE inhibitors and psoriasis based on the drug-targeted Mendelian randomization and real-world pharmacovigilance analyses.

BACKGROUND: Although a growing number of observational studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) intake may be a risk factor for psoriasis, evidence is still insufficient to draw definitive conclusions. RESEARCH DESIGN AND METHODS: Drug-targeted Mendelian randomization (DTMR) was used to analyze the causality between genetic proxied ACEIs and psoriasis. Furthermore, we performed a disproportionality analysis based on the FDA adverse event reporting system (FAERS) database to identify more suspicious subclasses of ACEIs. RESULTS: Using two kinds of genetic proxy instruments, the present DTMR research identified genetic proxied ACEIs as risk factors for psoriasis. Furthermore, our disproportionality analysis revealed that ramipril, trandolapril, perindopril, lisinopril, and enalapril were associated with the risk of psoriasis, which validates and refines the findings of the DTMR. CONCLUSIONS: Our integrative study verified that ACEIs, especially ramipril, trandolapril, perindopril, lisinopril, and enalapril, tended to increase the risk of psoriasis statistically.

Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization.

BACKGROUND: Despite growing knowledge regarding the pathogenesis of autoimmune diseases (ADs) onset, the current treatment remains unsatisfactory. This study aimed to identify innovative therapeutic targets for ADs through various analytical approaches. RESEARCH DESIGN AND METHODS: Utilizing Mendelian randomization, Bayesian co-localization, phenotype scanning, and protein-protein interaction network, we explored potential therapeutic targets for 14 ADs and externally validated our preliminary findings. RESULTS: This study identified 12 circulating proteins as potential therapeutic targets for six ADs. Specifically, IL12B was judged to be a risk factor for ankylosing spondylitis (p = 1.61E - 07). TYMP (p = 6.28E - 06) was identified as a protective factor for ulcerative colitis. For Crohn's disease, ERAP2 (p = 4.47E - 14), HP (p = 2.08E - 05), and RSPO3 (p = 6.52E - 07), were identified as facilitators, whereas FLRT3 (p = 3.42E - 07) had a protective effect. In rheumatoid arthritis, SWAP70 (p = 3.26E - 10), SIGLEC6 (p = 2.47E - 05), ISG15 (p = 3.69E - 05), and FCRL3 (p = 1.10E - 10) were identified as risk factors. B4GALT1 (p = 6.59E - 05) was associated with a lower risk of Type 1 diabetes (T1D). Interestingly, CTSH was identified as a protective factor for narcolepsy (p = 1.58E - 09) but a risk factor for T1D (p = 7.36E - 11), respectively. External validation supported the associations of eight of these proteins with three ADs. CONCLUSIONS: Our integrated study identified 12 potential therapeutic targets for ADs and provided novel insights into future drug development for ADs.

Impact of urban tree arrangement on pedestrian exposure to the size-fractional particulate matter in a city boulevard.

Trees act as natural filters that mitigate roadside air pollution. However, the filtration impact of different tree arrangements on traffic pollutants with different particle diameters has rarely been analysed in real street canyon environments. To quantify how roadside tree arrangements impact pedestrian exposure to particle number concentrations (PNCs) of different diameters (0.25-32 µm), in situ field measurements were carried out in a boulevard-type street canyon in the city of Xi'an, China. This study analysed the experimental data of PNCs collected along segments of a pedestrian lane under four typical tree arrangements: open space without trees, a sparse-spaced tree arrangement, a medium-spaced tree arrangement, and a dense-spaced tree arrangement in a street canyon. Our results reveal that the effect of tree arrangement on PNCs depended on the particle diameter. In general, trees can significantly reduce coarse PNC (particles with diameters >2.5 µm) but not the fine PNC. Quantitative analysis showed that a medium-spaced tree arrangement, in which tree crowns are adjacent to each other but do not overlap, is the most capable of reducing PNC, followed by a sparse-spaced tree arrangement, while a the dense-spaced tree arrangement has the least impact. The attenuation effect of trees on the PNCs increased with increasing particle diameter. Moreover, the presence of trees altered the local microclimate, which also affected how exposure to PNCs changed. Our empirical findings further highlight the complexity of how trees affect particulate pollutants in street canyons and provide timely insights for enhancing tree-planning management in cities from the perspective of air quality improvement.

The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis.

Background: Growing evidence shows a significant association between intestinal flora and allergic diseases, specifically atopic dermatitis (AD), allergic rhinitis (AR), and allergic asthma (AA). However, the causality has not yet been clarified. Objective: We conducted a bidirectional two-sample Mendelian randomization (TSMR) analysis to study the causal relationships between intestinal flora classification and AD, AR, or AA. Materials and methods: We obtained summary data of intestinal flora, AD, AR, and AA from a genome-wide association research. The inverse-variance weighted method is the primary method for analyzing causality in the TSMR analysis. Several sensitivity analyses were conducted to examine the stability of TSMR results. Reverse TSMR analysis was also performed to assess whether there was a reverse causality. Results: A total of 7 bacterial taxa associated with AD, AR, and AA were identified by the current TSMR analysis. Specifically, the genus Dialister(P=0.034)and genus Prevotella(P=0.047)were associated with a higher risk of AD, whereas class Coriobacteriia (P=0.034) and its child taxon, order Coriobacteriales (P=0.034) and family Coriobacteriaceae (P=0.034), all had a protective effect on AR. In addition, the family Victivallaceae (P=0.019) was identified as a risk factor for AR. We also noticed a positive association between the genus Holdemanella (P=0.046) and AA. The reverse TSMR analysis didn't suggest any evidence of reverse causality from allergic diseases to the intestinal flora. Conclusion: We confirmed the causal relationship between intestinal flora and allergic diseases and provided an innovative perspective for research on allergic diseases: targeted regulation of dysregulation of specific bacterial taxa to prevent and treat AD, AR, and AA.

Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study.

Background: Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods: Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results: At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion: Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".

Genetic evidence supporting the causal role of gut microbiota in chronic kidney disease and chronic systemic inflammation in CKD: a bilateral two-sample Mendelian randomization study.

Background: The association of gut microbiota (GM) and chronic kidney disease (CKD), and the relevancy of GM and chronic systemic inflammation in CKD, were revealed on the basis of researches on gut-kidney axis in previous studies. However, their causal relationships are still unclear. Objective: To uncover the causal relationships between GM and CKD, as well as all known GM from eligible statistics and chronic systemic inflammation in CKD, we performed two-sample Mendelian randomization (MR) analysis. Materials and methods: We acquired the latest and most comprehensive summary statistics of genome-wide association study (GWAS) from the published materials of GWAS involving GM, CKD, estimated glomerular filtration rate (eGFR), c-reactive protein (CRP) and urine albumin creatine ratio (UACR). Subsequently, two-sample MR analysis using the inverse-variance weighted (IVW) method was used to determine the causality of exposure and outcome. Based on it, additional analysis and sensitivity analysis verified the significant results, and the possibility of reverse causality was also assessed by reverse MR analysis during this study. Results: At the locus-wide significance threshold, IVW method and additional analysis suggested that the protective factors for CKD included family Lachnospiraceae (P=0.049), genus Eubacterium eligens group (P=0.002), genus Intestinimonas (P=0.009), genus Streptococcu (P=0.003) and order Desulfovibrionales (P=0.001). Simultaneously, results showed that genus LachnospiraceaeUCG010 (P=0.029) was a risk factor for CKD. Higher abundance of genus Desulfovibrio (P=0.048) was correlated with higher eGFR; higher abundance of genus Parasutterella (P=0.018) was correlated with higher UACR; higher abundance of class Negativicutes (P=0.003), genus Eisenbergiella (P=0.021), order Selenomonadales (P=0.003) were correlated with higher CRP levels; higher abundance of class Mollicutes (0.024), family Prevotellaceae (P=0.030), phylum Tenericutes (P=0.024) were correlated with lower levels of CRP. No significant pleiotropy or heterogeneity was found in the results of sensitivity analysis, and no significant causality was found in reverse MR analysis. Conclusion: This study highlighted associations within gut-kidney axis, and the causal relationships between GM and CKD, as well as GM and chronic systemic inflammation in CKD were also revealed. Meanwhile, we expanded specific causal gut microbiota through comprehensive searches. With further studies for causal gut microbiota, they may have the potential to be new biomarkers for targeted prevention of CKD and chronic systemic inflammation in CKD.

Patients' Expectancies to Acupuncture: A Systematic Review.

Objective: This systematic review aimed to document and describe how and when to assess patients' expectancies to acupuncture and the relationship between patients' expectancies and clinical effects. Materials and Methods: Three English databases, including PubMed, Cochrane Central Register of Controlled Trials, and EMBASE, and four Chinese databases, including the Chinese Biomedicine Literature Database, Chinese Journal Full-text Database, Chinese Scientific Journal Full-text Database, and Wanfang Database, were searched up to February 2020. Studies involving patients' expectancies to acupuncture were included. Based on the detailed situations of patients' expectancies, we made a standardized data extraction table that included the basic information of articles, study design details, and measurement of expectations. Based on the data, a descriptive analysis was performed, covering the characteristics of studies, measuring methods of expectations and the relationship between patients' expectancies and clinical effects. Methodology quality assessment was also performed by the risk of bias and the standards for reporting interventions in controlled trials of acupuncture. Results: There were 61 randomized controlled trials included in our analysis. The number of articles increased gradually over time and grew significantly after 2008. About half of trials focused on pain alleviation. Expectancies were measured before the treatment (N = 43), after the treatment (N = 3), and both before and after the treatment (N = 10), and five studies did not mention it. The measurement of expectancies used self-made questionnaires or scales (N = 27), the Acupuncture Expectations Scale (N = 6), and other scales (N = 11), while 17 studies did not describe what scale they used. The used questionnaires or scales mostly tried to ascertain the strength of confidence that acupuncture would help. Patients' expectancies and clinical effects were relevant in 19 studies, irrelevant in 21 studies, and were not mentioned in 21 studies. Conclusions: Patients' expectations to acupuncture have received increasing attention in recent years, but there is still no recognized measurement time and methods. It is critical to develop questions and answers regarding patients' expectations with better discrimination and reliability to accurately assess expectations and to explore the relationship between patients' expectations and acupuncture outcomes in future trials.

Solvent-Diluent Interaction-Mediated Solvation Structure of Localized High-Concentration Electrolytes.

The latest developments of localized high-concentration electrolytes (LHCEs) shed light on stabilizing the high-energy-density lithium (Li) metal batteries. It is generally considered that the nonsolvating diluents introduced into the LHCEs improve the viscosity and wettability of high-concentration electrolytes (HCEs) without changing their inner solvation structures, thus maintaining the highly coordinated contact ion pairs (CIPs) and ionic aggregates (AGGs) of the precursor HCEs with limited free solvent numbers and high Coulombic efficiency (CE) of Li metal anodes. Herein, we show an unexpected effect of the diluent amount on the solvation structures of the LHCEs: as the diluent amount increases, the proportions of free solvent molecules and CIPs rise up simultaneously. The latter is probably due to the partial splits of the AGGs via the dipole-dipole interactions between the diluent and solvent molecules. Accordingly, a moderately diluted LHCE shows the best Coulombic efficiency of Li metal anodes (99.6%), compared with the precursor HCE (97.4%) or highly diluted LHCE (99.0%). This work reveals a new criterion of the LHCE chemical formulation for the designing of advanced electrolytes for high-energy-density batteries.

Potential therapeutic effects of natural compounds targeting autophagy to alleviate podocyte injury in glomerular diseases.

Podocyte injury is a common cause of proteinuric kidney diseases. Uncontrollable progressive podocyte loss accelerates glomerulosclerosis and increases the risk of end-stage renal disease. To date, owing to the complex pathological mechanism, effective therapies for podocyte injury have been limited. Accumulating evidence supports the indispensable role of autophagy in the maintenance of podocyte homeostasis. A variety of natural compounds and their derivatives have been found to regulate autophagy through multiple targets, including promotes nuclear transfer of transcription factor EB and lysosomal repair. Here, we reviewed the recent studies on the use of natural compounds and their derivatives as autophagy regulators and discussed their potential applications in ameliorating podocyte injury. Several known natural compounds with autophagy-regulatory properties, such as quercetin, silibinin, kaempferol, and artemisinin, and their medical uses were also discussed. This review will help in improving the understanding of the podocyte protective mechanism of natural compounds and promote their development for clinical use.

Oral Microbiota of Children Is Conserved across Han, Tibetan and Hui Groups and Is Correlated with Diet and Gut Microbiota.

The oral microbiota can be affected by several factors; however, little is known about the relationship between diet, ethnicity and commensal oral microbiota among school children living in close geographic proximity. In addition, the relationship between the oral and gut microbiota remains unclear. We collected saliva from 60 school children from the Tibetan, Han and Hui ethnicities for a 16S rRNA gene sequencing analysis and comparison with previously collected fecal samples. The study revealed that Bacteroidetes and Proteobacteria were the dominant phyla in the oral microbiota. The Shannon diversity was lowest in the Tibetan group. A PCA showed a substantial overlap in the distribution of the taxa, indicating a high degree of conservation among the oral microbiota across ethnic groups while the enrichment of a few specific taxa was observed across different ethnic groups. The consumption of seafood, poultry, sweets and vegetables was significantly correlated with multiple oral microbiotas. Furthermore, 123 oral genera were significantly associated with 191 gut genera. A principal coordinate analysis revealed that the oral microbiota clustered separately from the gut microbiota. This work extends the findings of previous studies comparing microbiota from human populations and provides a basis for the exploration of the interactions governing the tri-partite relationship between diet, oral microbiota and gut microbiota.

Transplantable Carbonaceous Li+ Filtrating Membrane for Lithium Metal Protection.

Utilization of the lithium (Li) metal anode is seriously prevented by the undesirable side reactions with electrolyte solvents due to their mismatched energy gaps and easily lacerated SEI layer. In this work, we develop a transplantable carbonaceous membrane with a particular ability of filtrating Li+ ions by blocking organic solvents and use it as an independent protective component to isolate lithium metal anode from the electrolytes. This graphene-supported N-doped membrane (GNM) can separate organic carbonates of dimethyl carbonate (DMC) and diethyl carbonate (DEC) from H2O-DMC/DEC mixtures by holding back the organic solvents. When this membrane is used in a Li-Cu cell, a high Li Coulombic efficiency (CE) of 98.5% is maintained in carbonate electrolyte over 400 cycles. Application of GNM in Li-O2 full cell provides a sustainable use of Li metal for more than 200 cycles (2000 h) by keeping its shiny metal luster. Our results demonstrate that the use of an independent component with Li+ filtrating ability, such as the transplantable membrane of GNM developed in this work, should be a feasible remedy to protect Li metal anode in practical Li metal batteries.

Suppressing Sponge-Like Li Deposition via AlN-Modified Substrate for Stable Li Metal Anode.

Sponge-like lithium (Li) deposition results in high-surface-area morphology that harmfully accelerates the side reactions between Li and electrolyte, arousing serious safety issues of next high energy density Li metal batteries (LMBs). Herein, we propose a strategy to suppress the sponge-like Li deposition by plating Li metal on aluminum nitride (AlN)-modified substrates. For a practical Li deposition of 4 mAh cm-2 on a AlN-modified copper (Cu) electrode, the roughness and thickness of the as-deposited Li layer are only ∼10% and ∼50% of those for the Li layer deposited on bare Cu. Only based on the compacted Li deposition layer without any other protective remedies, the AlN-modified Cu electrode could provide a Li cycling life of 5 times longer than that on bare Cu, and an AlN-modified carbon felt was proved as an efficient interlayer to boost the cycling stability of Li||LiFePO4 batteries. These results demonstrate the high importance of suppressing the sponge-like Li deposition for high energy density LMBs.

Unstable Allotetraploid Tobacco Genome due to Frequent Homeologous Recombination, Segmental Deletion, and Chromosome Loss.

The types of mutations and their corresponding frequencies are difficult to measure in complex genomes. In this study, a high-throughput method was developed to identify spontaneous loss-of-function alleles for the resistance gene N and the transgenic avirulence gene P50 in allotetraploid tobacco. A total of 2134 loss-of-function alleles of the N gene were identified after screening 14 million F1 hybrids. Analysis of these mutants revealed striking evolutionary patterns for genes in polyploids. Only 14 of the loss-of-function mutations were caused by spontaneous point mutations or indels, while the others were caused by homeologous recombination (with a frequency of ∼1/12 000) or chromosome loss (∼1/15 000). Loss of the chromosome with the P50 insertion occurred at a similar frequency (∼1/13 000), and the frequency of spontaneous segmental deletion in this chromosome was ∼1/16 000. Both homeologous recombination and chromosome loss considerably decreased the viability of the mutants. Our data suggest that the high mutation rate in polyploids is probably due to the occurrence of homeologous recombination and the tolerance of large mutations such as chromosome loss in polyploid genomes. Frequent mutations tend to drive polyploids to extinction unless a novel mutation helps the polyploid to effectively compete with diploids or find a new ecological niche.