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Placenta accreta spectrum (PAS) disorder, an abnormal adherence of the placenta to the uterine wall, with variable degrees of invasion, is a major cause of maternal morbidity and mortality associated with severe postpartum hemorrhage. PAS is diagnosed using ultrasonography or with magnetic resonance imaging; in many centers there is a lack of PAS diagnostic expertise in diagnosing. Hence, we investigated the performance of selected maternal plasma protein biomarkers, antithrombin-III (AT-3), plasminogen activator inhibitor-I (PAI-I), soluble vascular endothelial growth factor receptor-II (sVEGFR-2), and soluble Tie-II (sT-2) for prenatal screening in pregnancies at a high risk of PAS. This prospective study, conducted in a tertiary hospital from September 2021 to May 2022, included pregnant women with placenta previa suspicious of PAS between 28 and 42 weeks of gestation. Four serum samples were collected from each woman to evaluate serum concentrations and compared between placenta previa (control) and PAS groups. The screening performances of the biomarkers were analyzed, and the best screening model for PAS was created. Twenty-two women with PAS and 18 with placenta previa alone were included (n = 40). The median concentrations of PAI-I, AT-3, sVEGFR-2, and sT-2 among the PAS group were 21.2, 6154.6, 7.5, and 12.8 ng/mL, respectively. The best screening model for PAS combined all four biomarkers with a history of cesarean delivery (77 % sensitivity, 89 % specificity, and an AUC of 0.87). A combination of the four maternal serum biomarkers in women with a history of cesarean delivery presented the most promising model for prenatal screening of PAS. A combination of the four maternal serum biomarkers with a history of cesarean delivery presented the most promising model for prenatal screening of PAS. • PAS disorder is a major cause of maternal morbidity and mortality. • PAI-I, AT-3, sVEGFR-2, sT-2 are useful for early diagnosis and prediction of PAS. • Single serum biomarkers had modest screening performances for PAS. • Combining all biomarkers with a history of c-section increased screening efficacy. [ABSTRACT FROM AUTHOR]

Seaweed is multicellular marine macroalgae that enhances the immunity of aquatic organisms. The study was designed to assess the ethanolic extract (EtOH) extracted from red seaweed (Gracilariopsis lemaneiformis) on Nile tilapia (Oreochromis niloticus) to evaluate growth, immunity and haematological parameters. The EtOH was applied with fish feed in four treatments such as T1‐control (0% EtOH), T2 (5% w/v EtOH), T3 (10% w/v EtOH) and T4 (15% w/v EtOH) each with three replicates. The initial average weight of the fish was 17.53 ± 2.1 g. Results showed that the growth increased gradually with the percentage of red seaweed extract, whereas the mean weight gain was found significantly higher in T4 (51.5 ± 4.2) than in the control. The specific growth rate (%) and survival rate (%) were found higher in T4 at the lowest FCR compared to other treatments (p < 0.05). The blood haemoglobin level of Nile tilapia was higher in T4 (11.5 g/dL) and lowest recorded in T1 (7.5 g/dL). However, the level of blood glucose interacted inversely with blood haemoglobin. The plasma protein level was also varied among the treatments (p > 0.05). The blood parameters, refractive index (RI) and spleen somatic index (SSI) were significantly different among the treatments. The RI of blood plasma and SSI were found to be better in T4 treatment. The research indicated that red seaweed extracts significantly enhanced the growth and boosted the immunity level of Nile tilapia. [ABSTRACT FROM AUTHOR]

Abstract Purposes Gastric cancer (GC) is one of the most common malignant tumors threatening human beings and has a poor prognosis. Therefore, exploring unveiled biomarkers or therapeutic targets for the diagnosis and treatment of GC is crucial. Methods A total of 5772 protein quantitative trait loci (pQTL) were aggregated from four latest large-scale proteomics cohorts. Two-sample Mendelian randomization (two-sample MR) was utilized to identify the causal effect of blood plasma proteins on GC. Heterogeneity, pleiotropy, and directionality analyses were employed to evaluate proteins identified via two-sample MR. The robustness of results was further validated via colocalization. The drug targets of proteins were evaluated to reveal the compounds that can interfere with these proteins. Results Ten proteins with potential causations in relation to GC were identified: LY6D, SLURP1, MLN, PSCA, THSD1, CFTR, PPM1B, KDM3A, TSC1, and HCG22. Among these proteins, LY6D, SLURP1, and THSD1 were considered as the most reliable biomarkers of GC due to their significant H4 posterior probabilities in colocalization analysis and absence of pleiotropy. Compound 35, nitrosamide, and 0175029-0000 were potential drugs or small molecules targeting LY6D, SLURP1, and THSD1, respectively. Conclusion This study identified several plasma proteins as potential biomarkers of GC and provided data support and new insights into the early diagnosis, intervention, and therapeutic targets of GC.

Purposes: Gastric cancer (GC) is one of the most common malignant tumors threatening human beings and has a poor prognosis. Therefore, exploring unveiled biomarkers or therapeutic targets for the diagnosis and treatment of GC is crucial. Methods: A total of 5772 protein quantitative trait loci (pQTL) were aggregated from four latest large-scale proteomics cohorts. Two-sample Mendelian randomization (two-sample MR) was utilized to identify the causal effect of blood plasma proteins on GC. Heterogeneity, pleiotropy, and directionality analyses were employed to evaluate proteins identified via two-sample MR. The robustness of results was further validated via colocalization. The drug targets of proteins were evaluated to reveal the compounds that can interfere with these proteins. Results: Ten proteins with potential causations in relation to GC were identified: LY6D, SLURP1, MLN, PSCA, THSD1, CFTR, PPM1B, KDM3A, TSC1, and HCG22. Among these proteins, LY6D, SLURP1, and THSD1 were considered as the most reliable biomarkers of GC due to their significant H4 posterior probabilities in colocalization analysis and absence of pleiotropy. Compound 35, nitrosamide, and 0175029-0000 were potential drugs or small molecules targeting LY6D, SLURP1, and THSD1, respectively. Conclusion: This study identified several plasma proteins as potential biomarkers of GC and provided data support and new insights into the early diagnosis, intervention, and therapeutic targets of GC. [ABSTRACT FROM AUTHOR]

Background: Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death. Methods: Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank. Results: After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant. Conclusions: The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field. [ABSTRACT FROM AUTHOR]

It remains challenging to translate the findings from genome-wide association studies (GWAS) of autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action rather than disease-specific. We performed a comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary statistics of AIDs under a cutting-edge systematic analytic framework. Specifically, we initially screened out the protein-AID associations using proteome-wide association study (PWAS), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we performed both Mendelian randomization (MR) and colocalization analyses to further identify protein-AID pairs with putatively causal relationships. We finally prioritized the potential drug targets for AIDs. A total of 174 protein-AID associations were identified by PWAS. AIDs-associated plasma proteins were significantly enriched in immune-related biological process and pathways, such as inflammatory response (P = 3.96 × 10–10). MR analysis further identified 97 protein-AID pairs with potential causal relationships, among which 21 pairs were highly supported by colocalization analysis (PP.H4 > 0.75), 10 of 21 were the newly discovered pairs and not reported in previous GWAS analyses. Further explorations showed that four proteins (TLR3, FCGR2A, IL23R, TCN1) have corresponding drugs, and 17 proteins have druggability. These findings will help us to further understand the biological mechanism of AIDs and highlight the potential of these proteins to develop as therapeutic targets for AIDs. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies. Methods: To identify potential therapeutic targets for PN, we employed twosample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genomewide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify proteinPN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on druggene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN. Results: Through MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN. Conclusion: Mendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN. [ABSTRACT FROM AUTHOR]

AbstractPolyphenolic compounds have received much attention due to their major function as antioxidants. Sinapic acid (SA) is an orally bioavailable phytochemical with excellent free radical scavenging property transported in the blood by human serum albumin (HSA) which is the chief carrier protein found abundantly in human plasma. SA contains a single phenolic group. This study investigates the binding and interaction mechanism between SA and HSA by multiple spectroscopic and calorimetric techniques, such as UV/visible absorption spectroscopy, intrinsic fluorescence studies, Fourier transform infrared (FTIR) spectroscopy and isothermal titration calorimetry (ITC). UV/visible absorption spectroscopy showed hyperchromicity in the absorption spectra, suggestive of structural change due to complex formation between HSA and SA. Intrinsic fluorescence measurements, performed at three different temperatures, showed quenching of the fluorescence spectra and the mechanism of quenching was static in nature which occurred due to ground state complex formation. The FTIR results demonstrated a 16% decrease in α-helical content of the secondary structure of HSA in the presence of SA. Hydrogen bonds and hydrophobic forces were the main forces of interaction, according to the thermodynamic characteristics found through ITC. Moreover, the data obtained through ITC indicated strong binding affinity between HSA and SA and supported the exothermic and spontaneous nature of the interaction. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and sacroiliac joints. Recent genetic studies suggest certain plasma proteins may play a causal role in AS development. This study aims to identify and characterize these proteins using Mendelian randomization (MR) and colocalization analyses. Methods: Plasma protein data were obtained from recent publications in Nature Genetics, integrating data from five previous GWAS datasets, including 738 cispQTLs for 734 plasma proteins. GWAS summary data for AS were sourced from IGAS and other European cohorts. MR analyses were conducted using "TwoSampleMR" to assess causal links between plasma protein levels and AS. Colocalization analysis was performed with the coloc R package to identify shared genetic variants. Sensitivity analyses and protein-protein interaction (PPI) network analyses were conducted to validate findings and explore therapeutic targets. We performed Phenome-wide association study (PheWAS) to examine the potential side effects of drug protein on AS treatment. Results: After FDR correction, eight significant proteins were identified: IL7R, TYMP, IL12B, CCL8, TNFAIP6, IL18R1, IL23R, and ERAP1. Elevated levels of IL7R, IL12B, CCL8, IL18R1, IL23R, and ERAP1 increased AS risk, whereas elevated TYMP and TNFAIP6 levels decreased AS risk. Colocalization analysis indicated that IL23R, IL7R, and TYMP likely share causal variants with AS. PPI network analysis identified IL23R and IL7R as potential new therapeutic targets. Conclusions: This study identified eight plasma proteins with significant associations with AS risk, suggesting IL23R, IL7R, and TYMP as promising therapeutic targets. Further research is needed to explore underlying mechanisms and potential for drug repurposing. [ABSTRACT FROM AUTHOR]

The objective of this paper is to evaluate the effect of periodic exposure to formaldehyde in the anatomy laboratory on some plasma protein levels in male Wistar rats using appropriate standard procedures. Data obtained showed that formaldehyde air level were 0.06±0.00 ppm (parts per million) at the control site, 0.47±0.02 ppm in the dissection hall on non-dissection days, and 1.95±0.02 ppm in the dissection hall on dissection days. Plasma levels of albumin, globulin and fibrinogen were 4.76±0.13 g/l, 3.12±0.07 g/l and 1.04±0.16 g/l respectively on non-dissection days and 5.06±0.07 g/l, 3.24±0.06 g/l and 1.18±0.18 g/l respectively on dissection days. Results revealed significant increase in the atmospheric levels of formaldehyde in the dissection hall but the plasma protein levels showed no significant difference. In conclusion, exposure to formaldehyde in the Anatomy laboratory may not affect plasma protein levels in Wistar rats.

This study aimed to investigate the effect of ultrasound combined with plasma protein (UPP) treatment on the structure, physicochemical and rheological properties of myofibrillar protein (MP). The results indicated that the UPP group caused changes in the secondary structure, increased fluorescence intensity and enhanced surface hydrophobicity of MP. Then, UPP significantly decreased the content of free and total sulfhydryl group, and high molecular weight protein contents were observed in MP. These findings implied moderate cross-linking and aggregation between plasma protein and MP in this ultrasound treatment. Furthermore, the physical characteristics, stability and rheological properties of MP were improved in UPP, as evidenced by increased storage modulus and decreased loss angle tangent. Therefore, this study suggested that the combined treatment not only had the potential to enhance the product quality in the process of ground meat, but also improved the utilization rate and added value of plasma proteins.

ABSTRACT Seaweed is multicellular marine macroalgae that enhances the immunity of aquatic organisms. The study was designed to assess the ethanolic extract (EtOH) extracted from red seaweed (Gracilariopsis lemaneiformis) on Nile tilapia (Oreochromis niloticus) to evaluate growth, immunity and haematological parameters. The EtOH was applied with fish feed in four treatments such as T1‐control (0% EtOH), T2 (5% w/v EtOH), T3 (10% w/v EtOH) and T4 (15% w/v EtOH) each with three replicates. The initial average weight of the fish was 17.53 ± 2.1 g. Results showed that the growth increased gradually with the percentage of red seaweed extract, whereas the mean weight gain was found significantly higher in T4 (51.5 ± 4.2) than in the control. The specific growth rate (%) and survival rate (%) were found higher in T4 at the lowest FCR compared to other treatments (p 0.05). The blood parameters, refractive index (RI) and spleen somatic index (SSI) were significantly different among the treatments. The RI of blood plasma and SSI were found to be better in T4 treatment. The research indicated that red seaweed extracts significantly enhanced the growth and boosted the immunity level of Nile tilapia.

Background: There is no evidence of peptides-probiotics symbiosis as supplements in aquafeeds. Aim: To evaluate the effect of peptides and probiotics supplementation via diet on blood parameters and growth performance of juvenile P. brachypomus, an Amazonian fish, during the growth-out phase. Methods: 120 juvenile P. brachypomus (242.77 g) were placed into twelve 200-L tanks (10 fish/tank), housed in an indoor open system with constant water renovation (flow rate:1.50 L/min). The experiment used a completely randomized design with a 4×5 factorial arrangement [4 doses of supplementation (CD: commercial diet; PepD: CD+1.50% of peptides per CD weight; ProD: CD+40.00 mL of activated probiotics per kg of diet (Lactobacillus spp., Rhodopseudomonas spp., Saccharomycetes spp.); PepProD: CD+Pep+Pro); 5 sampling times (0, 2nd, 4th, 6th, 8th week); n=3]. Fish were fed twice a day at a feeding rate of 1% of body weight. At each sampling time, blood was collected and fish were measured for growth performance analysis. Data was analyzed by using two-way ANOVA and Tukey's test (p0.05). Plasma glucose decreased for all fish in the 2nd week (59.56 mg/dL); then, that level increased in fish fed with the CD (89.00 mg/dL), while fish fed with PepD, ProD and PepProD showed constant values (57.22 mg/dL). The plasma protein levels were constant in fish fed with the PepD and PepProD, (p>0.05), while fish fed with the CD and ProD showed non-constant and higher values. At the end of the trial, fish fed with the PepProD showed the highest weight gain and the lowest feed conversion rate (39.66 g; 0.97). Conclusion: It is possible to maintain the stability of plasma glucose and plasma protein by supplementing diets with peptides, but the peptides-probiotics symbiosis administrated via diet contributes to maintain the stability of plasma glucose and plasma protein and to improve the growth performance of juvenile P. brachypomus during the growth-out phase. [Open Vet J 2024; 14(6.000): 1384-1393]

Abstract According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR)

Abstract Background While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. Methods Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. Results Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). 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. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. Conclusion Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.

Background: Previous epidemiological studies have identified a correlation between serum protein levels and Psoriatic Arthritis (PsA). However, the precise nature of this relationship remains uncertain. Therefore, our objective was to assess whether circulating levels of 2,923 plasma proteins are associated with the risk of PsA, utilizing the Mendelian randomization (MR) approach. Methods: Two-sample MR analysis was performed to assess the causal impact of proteins on PsA risk. Exposure data for plasma proteins were sourced from a genome-wide association study (GWAS) conducted within the UK Biobank Pharma Proteomics Project, which encompassed 2,923 unique plasma proteins. The outcome data for PsA were sourced from the FinnGen study, a large-scale genomics initiative, comprising 3,537 cases and 262,844 controls. Additionally, colocalization analysis, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. Results: We thoroughly assessed the association between 1,837 plasma proteins and PsA risk, identifying seven proteins associated with PsA risk. An inverse association of Interleukin-10 (IL-10) with PsA risk was observed [odds ratio (OR)=0.45, 95% confidence interval (CI), 0.28 to 0.70, PFDR=0.072]. Additionally, Apolipoprotein F (APOF) has a positive effect on PsA risk (OR=2.08, 95% CI, 1.51 to 2.86, PFDR=0.005). Subsequently, we found strong evidence indicating that IL-10 and APOF were colocalized with PsA associations (PP.H4 = 0.834 for IL-10 and PP.H4 = 0.900 for APOF). Phenome-wide association analysis suggested that these two proteins may have dual effects on other clinical traits (PFDR<0.1). Conclusion: This study identified 7 plasma proteins associated with PsA risk, particularly IL-10 and APOF, which offer new insights into its etiology. Further studies are needed to assess the utility and effectiveness of these candidate proteins. [ABSTRACT FROM AUTHOR]

Background: Hospital transfusion services order blood products to satisfy orders and maintain inventory levels during unexpected periods of increased blood demand. Surplus inventory may outdate before being allocated to a recipient. Blood product outdating is the largest contributor to blood wastage. Study Design: A province‐wide redistribution program was designed and implemented to redistribute near‐outdate plasma protein and related blood products from low‐usage to high‐usage hospitals. Program operations and details are described in this paper. Two transport container configurations were designed and validated for transport of all blood products. A cost‐analysis was performed to determine the effectiveness of this redistribution program. Results: A total of 130 hospital transfusion services contributed at least one near‐outdate blood product for redistribution between January 2012 and March 2020. These services redistributed 15,499 products through 3412 shipments, preventing the outdating of $17,570,700 CAD worth of product. Program costs were $14,900 for shipping and $30,000 for staffing. Failed time limits or non‐compliance with packing configurations resulted in $388,200 worth of blood products (97 shipments containing 816 products) being discarded. Courier transport delays was the most common reason (42/97; 43%) for transport failure. Conclusion: Redistributing near‐outdate blood products between hospitals is a feasible solution to minimize outdating. Despite heterogeneity of Canadian blood product inventory, all products (each with unique storage and transport requirements) were successfully redistributed in one of two validated and simple containers. Total operation costs of this program were small in comparison to the $17.6 million in savings associated with preventing the discard of outdated products. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) initially emerged as oral antidiabetic medication but were subsequently discovered to exhibit pleiotropic actions. Insomnia is a prevalent and debilitating sleep disorder. To date, the causality between SGLT2 inhibitors and insomnia remains unclear. This study aims to evaluate the causality between SGLT2 inhibitors and insomnia and identify potential plasma protein mediators. Using a two-sample Mendelian Randomization (MR) analysis, we estimated the causality of SGLT2 inhibition on insomnia and sleep duration. Additionally, employing a two-step and proteome-wide MR analysis, we evaluated the causal link of SGLT2 inhibition on 4907 circulating proteins and the causality of SGLT2 inhibition-driven plasma proteins on insomnia. We applied a false discovery rate (FDR) correction for multiple comparisons. Furthermore, mediation analyses were used to identify plasma proteins that mediate the effects of SGLT2 inhibition on insomnia. SGLT2 inhibition was negatively correlated with insomnia (odds ratio [OR] = 0.791, 95 % confidence interval [CI] [0.715, 0.876], P = 5.579*10^-6) and positively correlated with sleep duration (β = 0.186, 95 % CI [0.059, 0.314], P = 0.004). Among the 4907 circulating proteins, diadenosine tetraphosphatase (Ap4A) was identified as being linked to both SGLT2 inhibition and insomnia. Mediation analysis indicated that the effect of SGLT2 inhibition on insomnia partially operates through Ap4A (β = −0.018, 95 % CI [−0.036, −0.005], P = 0.023), with a mediation proportion of 7.7 %. The study indicated a causality between SGLT2 inhibition and insomnia, with plasma Ap4A potentially serving as a mediator. • Few previous studies have explored the relationship between SGLT2 inhibition and insomnia. • Mendelian randomization made us able to evaluate the causality of SGLT2 inhibition on insomnia. • Genetically-predicted SGLT2 inhibition negatively correlated to insomnia. • Plasma AP4A level mediates the inhibitory effect of SGLT2 inhibition on insomnia. [ABSTRACT FROM AUTHOR]

Background: Proteome‐wide Mendelian randomization studies have been increasingly utilized to identify potential drug targets for diseases. We aimed to identify potential therapeutic targets for migraine and its subtypes through the application of Mendelian randomization and co‐localization analysis methods. Methods: We utilized cis‐protein quantitative trait loci data for 1378 plasma proteins available from two studies with 7213 individuals and 35,559 individuals, respectively. Summary data for migraine and its subtypes were obtained from a genetic study involving up to 1,339,303 individuals. Proteins that passed both the discovery and validation Mendelian randomization analysis, sensitivity analysis, heterogeneity test, and pleiotropy test, were associated with ≥2 outcomes, and received strong support from co‐localization analysis (PP.H4.abf ≥0.80) and were classified as tier 1 proteins. Results: We identified three tier 1 proteins (LRP11, ITIH1, and ADGRF5), whose genes have not been previously identified as causal genes for migraine in genetic studies. LRP11 was significantly associated with the risk of any migraine (OR [odds ratio] = 0.968, 95% CI [confidence interval] = 0.955–0.981, p = 1.27 × 10−6) and significantly/suggestively associated with three migraine subtypes. ITIH1 was significantly associated with the risk of any migraine (OR = 1.044, 95% CI = 1.024–1.065, p = 1.08 × 10−5) and migraine with visual disturbances. ADGRF5 was significantly associated with the risk of any migraine (OR = 0.964, 95% CI = 0.946–0.982, p = 8.74 × 10−5) and suggestively associated with migraine with aura. The effects of LRP11 and ADGRF5 were further replicated using cerebrospinal fluid protein data. Apart from ADGRF5, there was no evidence of potential adverse consequences when modulating the plasma levels. We also identified another four proteins (PLCG1, ARHGAP25, CHGA, and MANBA) with no potential adverse consequences when modulating the plasma levels, and their genes were not reported by previous genetic studies. Conclusions: We found compelling evidence for two proteins and suggestive evidence for four proteins that could be promising targets for migraine treatment without significant adverse consequences. The corresponding genes were not reported in previous genetic studies. Future studies are needed to confirm the causal role of these proteins and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. Methods: Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. Results: Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). 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. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. Conclusion: Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval. [ABSTRACT FROM AUTHOR]

Background: The currently available medications for treating membranous nephropathy (MN) still have unsatisfactory efficacy in inhibiting disease recurrence, slowing down its progression, and even halting the development of end-stage renal disease. There is still a need to develop novel drugs targeting MN. Methods: We utilized summary statistics of MN from the Kiryluk Lab and obtained plasma protein data from Zheng et al. We performed a Bidirectional Mendelian randomization analysis, HEIDI test, mediation analysis, Bayesian colocalization, phenotype scanning, drug bank analysis, and protein-protein interaction network. Results: The Mendelian randomization analysis uncovered 8 distinct proteins associated with MN after multiple false discovery rate corrections. Proteins related to an increased risk of MN in plasma include ABO [(Histo-Blood Group Abo System Transferase) (WR OR = 1.12, 95%CI:1.05-1.19, FDR=0.09, PPH4 = 0.79)], VWF [(Von Willebrand Factor) (WR OR = 1.41, 95%CI:1.16-1.72, FDR=0.02, PPH4 = 0.81)] and CD209 [(Cd209 Antigen) (WR OR = 1.19, 95%CI:1.07-1.31, FDR=0.09, PPH4 = 0.78)], and proteins that have a protective effect on MN: HRG [(Histidine-Rich Glycoprotein) (WR OR = 0.84, 95%CI:0.76-0.93, FDR=0.02, PPH4 = 0.80)], CD27 [(Cd27 Antigen) (WR OR = 0.78, 95%CI:0.68-0.90, FDR=0.02, PPH4 = 0.80)], LRPPRC [(Leucine-Rich Ppr Motif-Containing Protein, Mitochondrial) (WR OR = 0.79, 95%CI:0.69-0.91, FDR=0.09, PPH4 = 0.80)], TIMP4 [(Metalloproteinase Inhibitor 4) (WR OR = 0.67, 95%CI:0.53-0.84, FDR=0.09, PPH4 = 0.79)] and MAP2K4 [(Dual Specificity Mitogen-Activated Protein Kinase Kinase 4) (WR OR = 0.82, 95%CI:0.72-0.92, FDR=0.09, PPH4 = 0.80)]. ABO, HRG, and TIMP4 successfully passed the HEIDI test. None of these proteins exhibited a reverse causal relationship. Bayesian colocalization analysis provided evidence that all of them share variants with MN. We identified type 1 diabetes, trunk fat, and asthma as having intermediate effects in these pathways. Conclusions: Our comprehensive analysis indicates a causal effect of ABO, CD27, VWF, HRG, CD209, LRPPRC, MAP2K4, and TIMP4 at the genetically determined circulating levels on the risk of MN. These proteins can potentially be a promising therapeutic target for the treatment of MN. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are emerging as a serious public health hazard, influencing an increasing number of individuals worldwide. However, the effect of modifiable lifestyle factors on psychiatric disorders remains unclear. Genome-wide association studies (GWAS) summary statistics were obtained mainly from Psychiatric Genomics Consortium and UK Biobank, with sample sizes varying between 10,000 and 1,200,000. The two-sample Mendelian randomization (MR) method was applied to investigate the causal associations between 45 lifestyle factors and 13 psychiatric disorders, and screen potential mediator proteins from 2992 candidate plasma proteins. We implemented a four-step framework with step-by-step screening incorporating two-step, univariable, and multivariable MR. We found causal effects of strenuous sports or other exercise on Tourette's syndrome (OR [95%CI]: 0.0047 [5.24E-04–0.042]); lifelong smoking index on attention-deficit hyperactivity disorder (10.53 [6.96–15.93]), anxiety disorders (3.44 [1.95–6.05]), bipolar disorder (BD) (2.25 [1.64–3.09]), BD II (2.89 [1.81–4.62]), and major depressive disorder (MDD) (2.47 [1.90–3.20]); and educational years on anorexia nervosa (AN) (1.47 [1.22–1.76]), and MDD (0.74 [0.66–0.83]). Five proteins were found to have causal associations with psychiatric disorders, namely ADH1B, GHDC, STOM, CD226, and TP63. STOM, a membrane protein deficient in the erythrocytes of hereditary stomatocytosis patients, may mediate the effect of educational attainment on AN. The mechanisms underlying the effects of lifestyle factors on psychiatric disorders require further investigation. These findings could help assess the risk of psychiatric disorders based on lifestyle factors and also support lifestyle interventions as a prevention strategy for mental illness. • Individuals who engaged in strenuous sports or other exercises causally associated with a lower risk of Tourette's syndrome. • Higher lifelong smoking index was causally linked to a higher risk of ADHD, ANX, BD, and MDD. • Longer educational attainment causally associated with a higher risk of AN and lower risk of MDD. • STOM may mediate the effect of educational attainment on anorexia nervosa. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to detect potential cytokines markers involved in the Graves' orbitopathy (GO). Materials and Methods: We measured 25 plasma cytokines using label-free quantitative proteomic analysis in the pilot cohort. In validation cohort, NORCH3, TBP, α-enolase (ENO1), GPX3, ORM1, extracellular matrix protein-1 (ECM1), SERPINE, IGF1, IGKV1, and SPARC were validated using ELISA kits. We used label-free liquid chromatography--mass spectrometry/MS (LC--MS/MS) quantitative proteomic to analyze plasma cytokines content of Graves' disease and GO patients. Results: The validation cohort showed that the concentrations of ECM1, ENO1, and GPX3, (244.4276 pg/ml, 4.361807 ng/ml, and 17.72794 pmol/ml, respectively) were significantly lower in GO patients samples than those in Graves' patients (257.3197 pg/ml, 4.601592 ng/ml, and 21.33118 pmol/ml, respectively). Both univariate and multivariate logistic analyses indicated that GPX3, ECM1, and ENO might be predictors of Graves' ophthalmopathy. A receiver-operating characteristic curve with an area under the curve of 0.938, a sensitivity of 84.4%, and a specificity of 90.5% underscored the applicability of this method. Conclusions: ECM1, ENO1, and GPX3 were associated with the presence of the GO group and may be good biomarkers that play an important role in the pathogenesis of GO. [ABSTRACT FROM AUTHOR]

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Alzheimer's disease (AD) is suggested to be a heterogeneous disorder, but limited studies explore the heterogeneity of the Mild Cognitive Impairment (MCI) stage. This study aimed to tackle such problems using the CIMLR (Cancer Integration via Multikernel Learning) algorithm to cluster brain structural features extracted from T1-weighted Magnetic Resonance Images of MCI patients from Alzheimer's Disease Neuroimaging Initiative. The demographic and cognitive results, characteristics of brain structural features, plasma biomarkers, and longitudinal cognitive trajectory were analyzed for each cluster. The CIMLR clustering analysis revealed four distinct clusters. Cluster 1 is the oldest group but has had mild atrophy and moderate progression with elevated Tumor Necrosis Factor Receptor 2 level; and low Brain-Derived Neurotrophic Factor and CD40 Ligand levels. Cluster 2 showed the highest risk for aggressive MCI progression, with abnormal Leptin, Adiponectin, and Creatine kinase-MB values. Cluster 3 exhibited a low level of Monokine Induced by Gamma Interferon and mild atrophy that shared similar patterns with Cluster 1. Cluster 4 represented the healthiest group during longitudinal tracking, with the mildest Parahippocampal atrophy, which was found to be positively correlated with cognitive impairment and amino acid levels. The longitudinal analyses showed the potential of Hepatocyte Growth Factor as a marker for slow cognitive impairment; Cortisol and Neurofilament Light Polypeptide as prognosis markers for aggressive MCI progression. These findings may lay out new suggestions for further research contributing to the accurate diagnosis and precision medicine for dementia and AD.

Abstract Background We aim to examine the association between ultra-processed foods (UPF) consumption and cardiovascular disease (CVD) risk and to identify plasma proteins associated with UPF. Methods This prospective cohort study included 26,369 participants from the Swedish Malmö Diet and Cancer Study, established in 1991–1996. Dietary intake was assessed using a modified diet history method, and UPF consumption was estimated using the NOVA classification system. A total of 88 selected CVD-related proteins were measured among 4475 subjects. Incident CVD (coronary heart disease and ischemic stroke) was defined as a hospital admission or death through registers. Cox proportional hazards regression models were performed to analyze the associations of UPF intake with risks of CVD. Linear regression models were used to identify the plasma proteins associated with UPF intake. Results During 24.6 years of median follow-up, 6236 participants developed CVD, of whom 3566 developed coronary heart disease and 3272 developed ischemic stroke. The adjusted hazard ratio (95% confidence interval) in the 4th versus 1st quartile of UPF was 1.18 (1.08, 1.29) for CVD, 1.20 (1.07, 1.35) for coronary heart disease, and 1.17 (1.03, 1.32) for ischemic stroke. Plasma proteins interleukin 18, tumor necrosis factor receptor 2, macrophage colony-stimulating factor 1, thrombomodulin, tumor necrosis factor receptor 1, hepatocyte growth factor, stem cell factor, resistin, C–C motif chemokine 3, and endothelial cell-specific molecule 1 were positively associated with UPF after correcting for multiple testing. Conclusions Our study showed that high UPF intake increased the risk of CVD and was associated with several protein biomarkers. Future studies are warranted to validate these findings and assess the potential pathways between UPF intake and CVD.

Background: We aim to examine the association between ultra-processed foods (UPF) consumption and cardiovascular disease (CVD) risk and to identify plasma proteins associated with UPF. Methods: This prospective cohort study included 26,369 participants from the Swedish Malmö Diet and Cancer Study, established in 1991–1996. Dietary intake was assessed using a modified diet history method, and UPF consumption was estimated using the NOVA classification system. A total of 88 selected CVD-related proteins were measured among 4475 subjects. Incident CVD (coronary heart disease and ischemic stroke) was defined as a hospital admission or death through registers. Cox proportional hazards regression models were performed to analyze the associations of UPF intake with risks of CVD. Linear regression models were used to identify the plasma proteins associated with UPF intake. Results: During 24.6 years of median follow-up, 6236 participants developed CVD, of whom 3566 developed coronary heart disease and 3272 developed ischemic stroke. The adjusted hazard ratio (95% confidence interval) in the 4th versus 1st quartile of UPF was 1.18 (1.08, 1.29) for CVD, 1.20 (1.07, 1.35) for coronary heart disease, and 1.17 (1.03, 1.32) for ischemic stroke. Plasma proteins interleukin 18, tumor necrosis factor receptor 2, macrophage colony-stimulating factor 1, thrombomodulin, tumor necrosis factor receptor 1, hepatocyte growth factor, stem cell factor, resistin, C–C motif chemokine 3, and endothelial cell-specific molecule 1 were positively associated with UPF after correcting for multiple testing. Conclusions: Our study showed that high UPF intake increased the risk of CVD and was associated with several protein biomarkers. Future studies are warranted to validate these findings and assess the potential pathways between UPF intake and CVD. [ABSTRACT FROM AUTHOR]

Chromolaena odorata is a potential feed source but is low in methionine, which might affect the rumen function. Therefore providing efficient nutrient/s might improve rumen function. The study aimed to assess the efficacy of a concentrate containing Chromolaena odorata meal, hydroxy methionine analog (HMA), and palm oil on blood metabolites of fattened cattle. Sixteen Bali cattle (Bos sondaicus) with an average body weight of 130.5kg ± 32.5 were allotted into four dietary treatments (and four replicates) using a Completely Randomized Block Design with 4 cattle in each Group. The treatments were concentrates with no addition of palm oil and/or HMA as the control diet (Group I), added with 3 g HMA (CMA) (Group II), added with 0.5% palm oil (Group III) and (CPO) added with a combination of 3 g HMA and 0.5% palm oil (CMO) Group IV). The concentrate was offered to the animals at a rate of 2% liveweight, whilst rice straws were provided ad libitum as the source of fiber. The concentrate contained 18% crude protein and 12 MJ ME/kg DM to target a live weight gain of at least 0.6 kg/day. Blood metabolites measured were total cholesterol levels, plasma glucose, plasma proteins, and plasma urea. Collected data were subjected to analysis of variance with the significance level set at an alpha value of ≤ 0.05. The results showed that providing concentratecontaining. C. odorata with or without HMA and/or palm oil (Group IV) only significantly affected blood plasma proteins, whereas other blood metabolites were unaffected. It might be concluded that there is no benefit of adding palm oil or methionine analog to chromolaena-based concentrate for fattened cattle since it will not affect the concentration of blood metabolites. [ABSTRACT FROM AUTHOR]

According to the free drug hypothesis (FDH), only free, unbound drug is available to interact with biological targets. This hypothesis is the fundamental principle that continues to explain the vast majority of all pharmacokinetic and pharmacodynamic processes. Under the FDH, the free drug concentration at the target site is considered the driver of pharmacodynamic activity and pharmacokinetic processes. However, deviations from the FDH are observed in hepatic uptake and clearance predictions, where observed unbound intrinsic hepatic clearance (CLint,u) is larger than expected. Such deviations are commonly observed when plasma proteins are present and form the basis of the so-called plasma protein-mediated uptake effect (PMUE). This review will discuss the basis of plasma protein binding as it pertains to hepatic clearance based on the FDH, as well as several hypotheses that may explain the underlying mechanisms of PMUE. Notably, some, but not all, potential mechanisms remained aligned with the FDH. Finally, we will outline possible experimental strategies to elucidate PMUE mechanisms. Understanding the mechanisms of PMUE and its potential contribution to clearance underprediction is vital to improving the drug development process. [ABSTRACT FROM AUTHOR]

Background: Interpretable machine learning (ML) for early detection of cancer has the potential to improve risk assessment and early intervention. Methods: Data from 261 proteins related to inflammation and/or tumor processes in 123 blood samples collected from healthy persons, but of whom a sub‐group later developed squamous cell carcinoma of the oral tongue (SCCOT), were analyzed. Samples from people who developed SCCOT within less than 5 years were classified as tumor‐to‐be and all other samples as tumor‐free. The optimal ML algorithm for feature selection was identified and feature importance computed by the SHapley Additive exPlanations (SHAP) method. Five popular ML algorithms (AdaBoost, Artificial neural networks [ANNs], Decision Tree [DT], eXtreme Gradient Boosting [XGBoost], and Support Vector Machine [SVM]) were applied to establish prediction models, and decisions of the optimal models were interpreted by SHAP. Results: Using the 22 selected features, the SVM prediction model showed the best performance (sensitivity = 0.867, specificity = 0.859, balanced accuracy = 0.863, area under the receiver operating characteristic curve [ROC‐AUC] = 0.924). SHAP analysis revealed that the 22 features rendered varying person‐specific impacts on model decision and the top three contributors to prediction were Interleukin 10 (IL10), TNF Receptor Associated Factor 2 (TRAF2), and Kallikrein Related Peptidase 12 (KLK12). Conclusion: Using multidimensional plasma protein analysis and interpretable ML, we outline a systematic approach for early detection of SCCOT before the appearance of clinical signs. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the effect of pectin supplemented feeds on the growth, gut morphology and immunology of Labeo rohita. Experimental feeds containing various concentrations of pectin including control (0%), T1 (0.5%), T2 (1.0%), T3 (2.0%), and T4 (4.0%) were administered to L. rohita twice per day at a rate of 3% body weight. There was a significant (P < 0.05) decrease in average final weight, weight gain%, net weight gain and specific growth rate observed in treatment groups in order of control > T1 > T2 > T3 > T4 while feed conversion ratio was significantly (P < 0.05) higher in T4 compared to the other groups T3 > T2 > T1 > control. Immunological parameters of peroxidase, protease and antiprotease (trypsin) showed significant (P T2 > T1 > control group. Total protein, protease and antiprotease activity were significantly (P < 0.05) higher in the control compared to treatment groups T1 > T2 > T3 > T4. An increased level of the non-starch polysaccharide pectin in feed caused acute effects on gut morphometry. Villus length, villus width, and an increase in mucosal folds were abnormal but no significant (P > 0.05) abnormality was observed in the control group. In the submucosal part of the intestine, hyperplasia was shown in loose connective tissues and in adipose tissue cells in the treated groups. In conclusion, dietary pectin supplementation from 0.5% to 4% had negative effects on the growth, immunological parameters and gut histomorphology of L. rohita.

Context α2-Macroglobulin (α2-M) is believed to be a potential anti-irradiation agent, but related mechanisms remains unclear.Objective We investigated the irradiation protective effect of α2-M.Materials and methods A total of 10 Gy dose of irradiation was used to damage human skin fibroblasts. The influence of α2-M (100 µg/mL) on the proliferation, migration, invasion and apoptosis of fibroblasts was observed using Cell Counting Kit-8 (CCK8), wound healing, transwell, and flow cytometry. Malondialdehyde, superoxide dismutase and catalase was measured using related ELISA kits. The levels of mitochondrial membrane potential and calcium were detected using flow cytometry. The expression of transient receptor potential melastatin 2 (TRPM2) was investigated through western blotting and immunofluorescence staining.Results High purity of α2-M was isolated from Cohn fraction IV. α2-M significantly increased cell proliferation, migration, invasion, but suppressed cell apoptosis after irradiation. The promotion of cell proliferation, migration and invasion by α2-M exceeded over 50% compared group irradiation. The increased cell ratio in the S phase and decreased cell ratio in the G2 phase induced by irradiation were remarkably reversed by α2-M. α2-M markedly suppressed the increased oxidative stress level caused by irradiation. The mitochondrial damage induced by irradiation was improved by α2-M through inhibiting mitochondrial membrane potential loss, calcium and TRPM2 expression.Discussion and conclusions α2-M significantly promoted the decreased fibroblast viability and improved the mitochondria dysfunction caused by irradiation. α2-M might present anti-radiation effect through alleviating mitochondrial dysfunction caused by irradiation. This study could provide a novel understanding about the improvement of α2-M on irradiation-induced injury.

With an aim to evaluate the culture potential of Indian white shrimp, Penaeus indicus grow-out farming trials were carried out under different salinity regimes and stocking densities across the coastal states of India (West Bengal, Odisha, Andhra Pradesh, Tamil Nadu, and Kerala). The growth performance and immunity status were assessed under two different stocking densities (low and high) at each salinity regime (S1: 3–7; S2: 8–15; S3:15–25; S4:25–35; and S5:40–60 ppt) for a period of 80–120 days. Significantly higher growth was observed in the salinity range of 15 to 35 ppt with average daily growth (ADG) up to 0.195 ± 0.032 compared to low ADG of 0.125 ± 0.021 in very low and very high salinity range (< 7 ppt and > 40 ppt). Similarly, the final mean harvest weight of P. indicus reared at 15–25 ppt salinity was significantly (p < 0.05) higher compared to other salinity ranges. The lower stocking density treatment ponds demonstrated higher mean harvest weight (18–30 g) with a production ranged from 2200.59 ± 331.09 kg/ha/crop to 3611.02 ± 218.23 kg/ha/crop compared to higher density ponds (12–20 g) which was ranged from 4338.67 ± 650.37 kg/ha/crop to 7817.31 ± 158.78 kg/ha/crop. The total productivity (kg/ha/crop) significantly (p < 0.05) increased with increase in stocking density by 20–30% while it was comparable between salinity ranges. The prophenoloxidase (PPO) activity gradually increased or decreased correspondingly to the salinity level with significantly lower PPO activity being observed at very low (5 ppt) and very high (60 ppt) than other salinity ranges. The serum protein and lysozyme also varied with the salinity range. Different densities did not affect immune parameters much, although lower stocking density was showing marginal increase. This study is based on large data from multi-location trials undertaken across different salinity ranges and stocking densities and provides a field-level assessment of growth potential of this native shrimp species in different geographic locations. [ABSTRACT FROM AUTHOR]

Simple Summary: The interactions between circulating tumor cells (CTCs) and plasma proteins are critical for hematogenous metastasis, and understanding the molecular mechanisms behind these interactions can improve liquid-biopsy-based diagnostics and cancer therapies. This review summarizes recent literature on the surface molecules of CTCs that interact with coagulation proteins and their biological and clinical relevance. It also discusses future research directions to expand our knowledge of the CTC interactome, which can lead to the discovery of new molecular markers for diagnostics and additional targets for cancer therapies. Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs sense their environment with surface-exposed receptors. The recognition of corresponding ligands, e.g., fibrinogen, by integrins can induce intracellular signaling processes driving CTCs' survival. Other receptors, such as tissue factor (TF), enable CTCs to induce coagulation. Cancer-associated thrombosis (CAT) is adversely connected to patients' outcome. However, cancer cells have also the ability to inhibit coagulation, e.g., through expressing thrombomodulin (TM) or heparan sulfate (HS), an activator of antithrombin (AT). To that extent, individual CTCs can interact with plasma proteins, and whether these interactions are connected to metastasis or clinical symptoms such as CAT is largely unknown. In the present review, we discuss the biological and clinical relevance of cancer-cell-expressed surface molecules and their interaction with plasma proteins. We aim to encourage future research to expand our knowledge of the CTC interactome, as this may not only yield new molecular markers improving liquid-biopsy-based diagnostics but also additional targets for better cancer therapies. [ABSTRACT FROM AUTHOR]

Genome‐wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high‐risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1142 circulating proteins with breast cancer risk in 133 384 cases and 113 789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500 kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS‐identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple‐negative breast cancer risk at FDR <0.05. Adjustment for the GWAS‐identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS‐identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling and NF‐κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk. [ABSTRACT FROM AUTHOR]

Background Finding effective and safe therapeutic drugs for atrial fibrillation (AF) is an important concern for clinicians. Proteome‐wide Mendelian randomization analysis provides new ideas for finding potential drug targets. Methods and Results Using a proteome‐wide Mendelian randomization approach, we assessed the genetic predictive causality between thousands of proteins and AF risk and found that genetically predicted plasma levels of phosphomevalonate kinase, tumor necrosis factor ligand superfamily member 12, sulfhydryl oxidase 2, interleukin‐6 receptor subunit alpha, and low‐affinity immunoglobulin gamma Fc region receptor II‐b might decrease AF risk, while genetically predicted plasma levels of beta‐mannosidase, collagen alpha‐1(XV) chain, ANXA4 (annexin A4), COF2 (cofilin‐2), and RAB1A (Ras‐related protein Rab‐1A) might increase AF risk (P

Freshwater turtles are sensitive to environmental changes and can serve as sentinel species for ecosystem health assessments. The Efroymson Restoration at Kankakee Sands in northwestern Indiana, USA has been restored in the past 25 yr from primarily agricultural land to a mosaic of prairie and wetland habitats. Health assessments of 40 free-ranging painted turtles (Chrysemys picta) at Kankakee Sands were performed in May 2021 to evaluate overall health status, screen for infectious diseases, and obtain baseline clinical pathology values in this population. Assessment of each turtle included a physical examination, complete blood count, plasma biochemistry panel, blood lactate level, venous blood gas analysis, serum trace mineral panel, serum vitamin D3 level, and plasma protein electrophoresis. Oral and cloacal swabs were tested for adenoviruses, herpesviruses, frog virus 3, and Mycoplasmopsis species by PCR in 39 painted turtles. Four turtles were positive for adenovirus, which shared 100% homology to Sulawesi tortoise adenovirus. Two turtles were herpesvirus-positive with 100% homology to emydid herpesvirus 1. No Mycoplasmopsis spp. or frog virus 3 was detected. Female turtles had significantly higher manganese, prealbumin, uric acid, triglycerides, and ionized calcium levels, while male turtles had significantly higher cholesterol, glutamate dehydrogenase, and CO2 levels. These baseline data can be used for future research into freshwater turtle health in restored wetland habitats. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the effect of pectin supplemented feeds on the growth, gut morphology and immunology of Labeo rohita. Experimental feeds containing various concentrations of pectin including control (0%), T1 (0.5%), T2 (1.0%), T3 (2.0%), and T4 (4.0%) were administered to L. rohita twice per day at a rate of 3% body weight. There was a significant (P < 0.05) decrease in average final weight, weight gain%, net weight gain and specific growth rate observed in treatment groups in order of control > T1 > T2 > T3 > T4 while feed conversion ratio was significantly (P < 0.05) higher in T4 compared to the other groups T3 > T2 > T1 > control. Immunological parameters of peroxidase, protease and antiprotease (trypsin) showed significant (P < 0.05) results between control and treated groups. Peroxidase activity was significantly (P < 0.05) higher in T4 group fish compared to T3 > T2 > T1 > control group. Total protein, protease and antiprotease activity were significantly (P < 0.05) higher in the control compared to treatment groups T1 > T2 > T3 > T4. An increased level of the nonstarch polysaccharide pectin in feed caused acute effects on gut morphometry. Villus length, villus width, and an increase in mucosal folds were abnormal but no significant (P > 0.05) abnormality was observed in the control group. In the submucosal part of the intestine, hyperplasia was shown in loose connective tissues and in adipose tissue cells in the treated groups. In conclusion, dietary pectin supplementation from 0.5% to 4% had negative effects on the growth, immunological parameters and gut histomorphology of L. rohita. [ABSTRACT FROM AUTHOR]

Context: Although several risk proteins for hypothyroidism have been reported in recent years, many more plasma proteins have not been tested. Objective: To determine potential mechanisms and novel causal plasma proteins for hypothyroidism using Mendelian randomization (MR). Methods: A large-scale plasma proteome MR analysis was conducted using protein quantitative trait loci (pQTLs) for 2297 plasma proteins. We classified pQTLs into 4 different groups. MR analyses were conducted within the 4 groups simultaneously. Significant proteins were discovered and validated in 2 different cohorts. Colocalization analysis and enrichment analysis were conducted using proteins found with MR. Results: Thirty-one proteins were identified in the discovery cohort. Among them, 13 were validated in the validation cohort. Nine of the 13 proteins are risk factors (ISG15, Fc receptor-like protein 2, tumor necrosis factor ligand superfamily member 14, Rab-2A, FcRL3, thrombomodulin, interferon [IFN]-lambda-1, platelet glycoprotein Ib alpha chain, IL-7RA) for hypothyroidism, whereas others are protective proteins (protein O-glucosyltransferase 1 [POGLUT1], tumor necrosis factor ligand superfamily, 3-hydroxyisobutyryl-CoA hydrolase, transferrin receptor protein 1). Among the significant proteins, POGLUT1 strongly colocalized with expression quantitative trait loci from whole blood (posterior probability of colocalization [PP4]=0.978) and the thyroid (PP4=0.978). Two different trans-pQTLs (rs2111485 PP4=0.998; rs35103715 PP4= 0.998) for IFN-lambda-1 strongly colocalized with hypothyroidism in different chromosomes. Conclusion: Thirteen various proteins were identified and validated to be associated with hypothyroidism using univariable MR. We reinforced and expanded the effect of IFN on hypothyroidism. Several proteins identified in this study could explain part of the association between the coagulation system and hypothyroidism. Our study broadens the causal proteins for hypothyroidism and provides the relationships between plasma proteins and hypothyroidism. The proteins identified in this study can be used as early screening biomarkers for hypothyroidism. [ABSTRACT FROM AUTHOR]

• The genetically predicted levels of 18 circulating plasma proteins were associated with ECG traits. • The impact of plasma proteins on the risk of ECG traits was partly mediated through anthropometric measurements. • New insights of cardiac conduction provide a valuable reference for the development of arrhythmia drugs. Cardiac conduction disorders predispose individuals to arrhythmias, currently but the exact mechanisms of cardiac conduction remain elusive. The study sought to identify the causal association between circulating plasma proteins and electrocardiogram (ECG) traits, offer valuable biological insights and clinical guidance into cardiac conduction. Proteome-wide Mendelian randomization (MR) analysis was firstly conducted to assess causal associations between plasma proteins and five ECG traits, including P wave duration (PWD), QRS duration, PR, QT and RR intervals. Multiple sensitivity analyses were implemented. The reverse MR analysis, colocalization analysis and replication analysis were used to consolidate the reliability of our results. Then, we conducted mediation analysis to explore potential mechanism between plasma proteins and ECG traits. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to clarify the biological functions of target proteins. Finally, phenome-wide MR (Phe-MR) and drug databases were searched. We identified 3 proteins (FAM151A, VEGF165, VEGF121) associated with PWD, 12 proteins (ABHD10, ADK, Cathepsin_S, DUSP13, Ephrin_A3, MAPRE2, OMG, PAM, PMM1, SH3BGRL3, TCP4, SYT11) linked to PR interval, 1 protein (PKC_A) related to QRS duration, and 2 proteins (MXRA7, SVEP1) associated with QT interval. A significant causal effects of ECG traits on them was not found in reverse MR. Colocalization and replication analyses strengthened our findings further. The impacts were partly mediated by anthropometric measures. Enrichment analysis of target proteins mainly enriched for multiple key pathways such as regulation of hydrolase activity and fibronectin binding. Through drug databases searching, 5 identified proteins (VEGFA, ADK, PAM, Cathepsin_S, PKC_A) were considered druggable. We discovered significant causal associations between genetically predicted levels of 18 plasma proteins and ECG traits. These results highlight the importance of circulating plasma proteins in cardiac conduction and open up the possibility of novel arrhythmia drug development. [ABSTRACT FROM AUTHOR]

Abstract Understanding material‐protein interactions is the basis for regulating material‐blood interactions, which is a common topic of interest for medical material developers. In recent years, researchers have conducted extensive studies on (1) the structural characteristics of the plasma protein adsorption layer on the material surface, including the evolution of the protein adsorption layer and its typical binary structure. (2) Influence factors of the protein adsorption layer formation include protein factors (e.g., isoelectric point, structural stability), material factors (e.g., wettability, surface charge, morphology, size), and environmental factors. (3) Effects of some common plasma proteins in the protein adsorption layer on material‐blood interactions. Here, we review the important research results in this field, hoping to provide a reference for future development of advanced blood contact materials.

Aims The aim of this study was to explore the genetic correlation and causal relationship between blood plasma proteins and rheumatoid arthritis (RA). Methods Based on the genome-wide association studies (GWAS) summary statistics of RA from European descent and the GWAS summary datasets of 3,622 plasma proteins, we explored the relationship between RA and plasma proteins from three aspects. First, linkage disequilibrium score regression (LD score regression) was applied to detect the genetic correlation between RA and plasma proteins. Mendelian randomization (MR) analysis was then used to evaluate the causal association between RA and plasma proteins. Finally, GEO2R was used to screen the differentially expressed genes (DEGs) between patients with RA and healthy controls. Results We found that seven kinds of plasma proteins had genetic correlations with RA, such as Soluble Receptor for Advanced Glycation End Products (sRAGE) (correlation coefficient = 0.2582, p = 0.049), vesicle transport protein USE1 (correlation coefficient = 0.1337, p = 0.018), and spermatogenesis-associated protein 20 (correlation coefficient = 0.3706, p = 0.018). There was a significant causal relationship between sRAGE and RA. By comparing the genes encoding seven plasma proteins, we found that only USE1 was a DEG associated with RA. Conclusion Our study identified a set of candidate plasma proteins that showed signals correlated with RA. Since the results of this study need further experimental verification, they should be interpreted with caution. However, we hope that this paper will provide new insights for the discovery of pathogenic genes and RA pathogenesis in the future. Cite this article: Bone Joint Res 2022;11(2):134–142.

Background and aimsPrimary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR).MethodsA total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted.ResultsThree plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10-5), CD40 (OR=0.814 [0.741-0.895], p=1.96×10-5) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10-6) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC.ConclusionsWe expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.

Context: a2-Macroglobulin (a2-M) is believed to be a potential anti-irradiation agent, but related mechanisms remains unclear. Objective: We investigated the irradiation protective effect of a2-M. Objective: We investigated the irradiation protective effect of a2-M. Materials and methods: A total of 10 Gy dose of irradiation was used to damage human skin fibroblasts. The influence of a2-M (100 mg/mL) on the proliferation, migration, invasion and apoptosis of fibroblasts was observed using Cell Counting Kit-8 (CCK8), wound healing, transwell, and flow cytometry. Malondialdehyde, superoxide dismutase and catalase was measured using related ELISA kits. The levels of mitochondrial membrane potential and calcium were detected using flow cytometry. The expression of transient receptor potential melastatin 2 (TRPM2) was investigated through western blotting and immunofluorescence staining. Results: High purity of a2-M was isolated from Cohn fraction IV. a2-M significantly increased cell proliferation, migration, invasion, but suppressed cell apoptosis after irradiation. The promotion of cell proliferation, migration and invasion by a2-M exceeded over 50% compared group irradiation. The increased cell ratio in the S phase and decreased cell ratio in the G2 phase induced by irradiation were remarkably reversed by a2-M. a2-M markedly suppressed the increased oxidative stress level caused by irradiation. The mitochondrial damage induced by irradiation was improved by a2-M through inhibiting mitochondrial membrane potential loss, calcium and TRPM2 expression. Discussion and conclusions: a2-M significantly promoted the decreased fibroblast viability and improved the mitochondria dysfunction caused by irradiation. a2-M might present anti-radiation effect through alleviating mitochondrial dysfunction caused by irradiation. This study could provide a novel understanding about the improvement of a2-M on irradiation-induced injury. [ABSTRACT FROM AUTHOR]

Background: Intracranial aneurysms are the main cause of subarachnoid hemorrhage (SAH), a severe stroke with devastating effects. However, there are no existing medications for intracranial aneurysms (IAs) and novel therapeutic targets are required., Methods: We performed a summary data-based Mendelian Randomization (MR) analysis to explore the causal association between circulating plasma proteins and the risk of IAs and SAH. Colocalization analysis was conducted to identify shared causal variants between circulating plasma proteins and IAs, as well as SAH. Finally, mediation MR analyses were conducted to clarify the role of potential plasma proteins in aneurysm formation., Results: Proteome-wide MR analysis showed that FGF5 (fibroblast growth factor 5) had a causal effect on IA and SAH risk (Pfdr < 0.05). Moreover, genetic variants affecting FGF5 expression levels showed strong evidence of colocalization with IA risk (PPH4 = 0.993) and SAH risk (PPH = 0.988), suggesting that this protein represents a potential direct target for IA intervention. Mediation analysis using two-step MR showed that systolic blood pressure and diastolic blood pressure mediate the effects of FGF5 on IA and SAH., Conclusion: Our investigation identified a causal connection between FGF5 and IAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)