Approaches to estimate bidirectional causal effects using Mendelian randomization with application to body mass index and fasting glucose.

Mendelian randomization (MR) is an epidemiological framework using genetic variants as instrumental variables (IVs) to examine the causal effect of exposures on outcomes. Statistical methods based on unidirectional MR (UMR) are widely used to estimate the causal effects of exposures on outcomes in observational studies. To estimate the bidirectional causal effects between two phenotypes, investigators have naively applied UMR methods separately in each direction. However, bidirectional causal effects between two phenotypes create a feedback loop that biases the estimation when UMR methods are naively applied. To overcome this limitation, we proposed two novel approaches to estimate bidirectional causal effects using MR: BiRatio and BiLIML, which are extensions of the standard ratio, and limited information maximum likelihood (LIML) methods, respectively. We compared the performance of the two proposed methods with the naive application of UMR methods through extensive simulations of several scenarios involving varying numbers of strong and weak IVs. Our simulation results showed that when multiple strong IVs are used, the proposed methods provided accurate bidirectional causal effect estimation in terms of median absolute bias and relative median absolute bias. Furthermore, compared to the BiRatio method, the BiLIML method provided a more accurate estimation of causal effects when weak IVs were used. Therefore, based on our simulations, we concluded that the BiLIML should be used for bidirectional causal effect estimation. We applied the proposed methods to investigate the potential bidirectional relationship between obesity and diabetes using the data from the Multi-Ethnic Study of Atherosclerosis cohort. We used body mass index (BMI) and fasting glucose (FG) as measures of obesity and type 2 diabetes, respectively. Our results from the BiLIML method revealed the bidirectional causal relationship between BMI and FG in across all racial populations. Specifically, in the White/Caucasian population, a 1 kg/m2 increase in BMI increased FG by 0.70 mg/dL (95% confidence interval [CI]: 0.3517-1.0489; p = 8.43×10-5), and 1 mg/dL increase in FG increased BMI by 0.10 kg/m2 (95% CI: 0.0441-0.1640; p = 6.79×10-4). Our study provides novel findings and quantifies the effect sizes of the bidirectional causal relationship between BMI and FG. However, further studies are needed to understand the biological and functional mechanisms underlying the bidirectional pathway.

Outcomes of patients with pre-existing disability managed by mobile stroke units: A sub-analysis of the BEST-MSU study.

BACKGROUND: Few data exist on acute stroke treatment in patients with pre-existing disability (PD) since they are usually excluded from clinical trials. A recent trial of mobile stroke units (MSUs) demonstrated faster treatment and improved outcomes, and included PD patients. AIM: To determine outcomes with tissue plasminogen activator (tPA), and benefit of MSU versus management by emergency medical services (EMS), for PD patients. METHODS: Primary outcomes were utility-weighted modified Rankin Scale (uw-mRS). Linear and logistic regression models compared outcomes in patients with versus without PD, and PD patients treated by MSU versus standard management by EMS. Time metrics, safety, quality of life, and health-care utilization were compared. RESULTS: Of the 1047 tPA-eligible ischemic stroke patients, 254 were with PD (baseline mRS 2-5) and 793 were without PD (baseline mRS 0-1). Although PD patients had worse 90-day uw-mRS, higher mortality, more health-care utilization, and worse quality of life than non-disabled patients, 53% returned to at least their baseline mRS, those treated faster had better outcome, and there was no increased bleeding risk. Comparing PD patients treated by MSU versus EMS, 90-day uw-mRS was 0.42 versus 0.36 (p = 0.07) and 57% versus 46% returned to at least their baseline mRS. There was no interaction between disability status and MSU versus EMS group assignment (p = 0.67) for 90-day uw-mRS. CONCLUSION: PD did not prevent the benefit of faster treatment with tPA in the BEST-MSU study. Our data support inclusion of PD patients in the MSU management paradigm.

Enhancement of water barrier and antimicrobial properties of chitosan/gelatin films by hydrophobic deep eutectic solvent.

Biodegradable chitosan/gelatin (CS/GEL) films have attracted attention as food packaging, but the poor water sensitivity and functional limitations of these films should be addressed. In this study, the hydrophobic deep eutectic solvent (DES, 0-15 %) consisting of thymol and octanoic acid was used to improve the water resistance and antibacterial performance of the CS/GEL composite films. FTIR and SEM analyses revealed a strong interaction between the CS/GEL matrix and DES. The films blended with DES showed increased water contact angle values and thermal stability. Furthermore, the addition of DES resulted in a significant increase in the elasticity and decrease water vapor transmission rate (WVTR). The CS/GEL films blended with 9% DES showed a 38.5% decrease in WVTR compared to those without DES. Additionally, the DES-containing film displayed good antibacterial activity against Staphylococcus aureus and Escherichia coli. Overall, the CS/GEL-DES composite films are expected to contribute an improvement to food packaging.

Influence of Gelatin-Chitosan-Glycerol Edible Coating Incorporated with Chlorogenic Acid, Gallic Acid, and Resveratrol on the Preservation of Fresh Beef.

Chlorogenic acid (CA), gallic acid (GA), and resveratrol (RES) were added to a gelatin (GEL)-chitosan (CHI)-glycerol (GLY) edible coating, and their effects on the coating of fresh beef preservation were investigated. The results revealed that CA had the most significant improvement effect on fresh beef preservation. The combination of GEL-CHI-GLY-CA preserved the color of the beef better and delayed the increase of the total volatile base nitrogen, even though its total phenolic content decreased at a faster rate during beef preservation. GA also improved the preservation effect as on the 12th day of storage, the beef samples treated with GEL-CHI-GLY-GA had the lowest thiobarbituric acid reactive substances (0.76 mg Malondialdehyde (MDA)/kg) and total viable count (6.0 log cfu/g). On the whole, though RES showed an improvement on beef preservation, the improvement was not as good as the other two polyphenols. After 12 days of storage, the beef samples treated with GEL-CHI-GLY-RES had a higher pH value (6.25) than the other two polyphenol treatmed groups. Overall, the three polyphenol-added combinations increased the shelf life of beef by approximately 3-6 days compared to the control group (treated GEL-CHI-GLY with distilled water).

Structure and Processing Properties of Nine Yam (Dioscorea opposita Thunb) Starches from South China: A Comparison Study.

In order to explore the processing and application potential of Chinese yam starch, nine kinds of Chinese yam starch (GY11, GY5, GY2, GXPY, LCY, SFY, MPY, SYPY, ASY) from South China were collected and characterized. The chemical composition, rheological properties, thermal properties, and in vitro starch digestion were compared, and the correlation between the structure and processing properties of these yam starches was analyzed using Pearson correlation. The results show that GY2 had the highest amylose content of 28.70%. All the yam starches were similarly elliptical, and all the yam starch gels showed pseudoplastic behavior. Yam starches showed similar pasting temperatures and resistant starch content, but SYPY showed the largest particle size (28.4 µm), SFY showed the highest setback (2712.33 cp), and LCY showed the highest peak viscosity (6145.67 cp) and breakdown (2672.33 cp). In addition, these yam starches also showed different crystal types (A-type, B-type, C-type), relative crystallinity (26.54-31.48%), the ratios of 1045/1022 cm-1 (0.836-1.213), pasting properties, and rheological properties, so the yam starches have different application potentials. The rheological and pasting properties were related to the structural properties of starch, such as DI, Mw, and particle size, and were also closely related to the thermodynamic properties. The appropriate processing methods and purposes of the processed products of these yam starches can be selected according to their characteristics.

Influence of Adding Chinese Yam (Dioscorea opposita Thunb.) Flour on Dough Rheology, Gluten Structure, Baking Performance, and Antioxidant Properties of Bread.

Impacts of wheat flour substituted with various levels of Chinese yam (Dioscorea opposita Thunb.) flour (from 0% to 25%) on the dough rheological characteristics, gluten structure, baking performance, and antioxidant properties of bread were investigated. The water absorption increased significantly (p < 0.05), while development time and stability decreased remarkably (p < 0.05) as the proportion of yam flour increased. SEM results indicated that the addition of yam flour destroyed the gluten network structure in the dough. Fourier Transform Infrared Spectroscopy (FTIR) spectra showed that addition of yam flour decreased the content of α-helix and ß-sheet in gluten. With the increase in the proportion of yam flour, the specific volume and overall acceptability decreased (p < 0.05) whereas the total phenolics content (TPC), polysaccharides content, total flavonoids content (TFC), allantoin content, The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capability, fractal dimension, and hardness increased (p < 0.05). Overall, breads made of wheat flour replacement with no more than 15% Guihuai number 2 yam flour were of a high quality and had more antioxidant properties. These showed that Guihuai number 2 had broad application prospects in baked products.

DR-SIP: protocols for higher order structure modeling with distance restraints- and cyclic symmetry-imposed packing.

MOTIVATION: Quaternary structure determination for transmembrane/soluble proteins requires a reliable computational protocol that leverages observed distance restraints and/or cyclic symmetry (Cn symmetry) found in most homo-oligomeric transmembrane proteins. RESULTS: We survey 118 X-ray crystallographically solved structures of homo-oligomeric transmembrane proteins (HoTPs) and find that ∼97% are Cn symmetric. Given the prevalence of Cn symmetric HoTPs and the benefits of incorporating geometry restraints in aiding quaternary structure determination, we introduce two new filters, the distance-restraints (DR) and the Symmetry-Imposed Packing (SIP) filters. SIP relies on a new method that can rebuild the closest ideal Cn symmetric complex from docking poses containing a homo-dimer without prior knowledge of the number (n) of monomers. Using only the geometrical filter, SIP, near-native poses of 7 HoTPs in their monomeric states can be correctly identified in the top-10 for 71% of all cases, or 29% among 31 HoTP structures obtained through homology modeling, while ZDOCK alone returns 14 and 3%, respectively. When the n is given, the optional n-mer filter is applied with SIP and returns the near-native poses for 76% of the test set within the top-10, outperforming M-ZDOCK's 55% and Sam's 47%. While applying only SIP to three HoTPs that comes with distance restraints, we found the near-native poses were ranked 1st, 1st and 10th among 54 000 possible decoys. The results are further improved to 1st, 1st and 3rd when both DR and SIP filters are used. By applying only DR, a soluble system with distance restraints is recovered at the 1st-ranked pose. AVAILABILITY AND IMPLEMENTATION: https://github.com/capslockwizard/drsip. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes.

In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4+ T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IAg7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide grooves and for strong CD4+ T cell stimulation. Here, we present crystal structures showing how these mutations control CD4+ T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal stricking similarities between mouse and human CD4+ TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9-23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation of fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism limited to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.

S100B as an antagonist to block the interaction between S100A1 and the RAGE V domain.

Ca2+-binding human S100A1 protein is a type of S100 protein. S100A1 is a significant mediator during inflammation when Ca2+ binds to its EF-hand motifs. Receptors for advanced glycation end products (RAGE) correspond to 5 domains: the cytoplasmic, transmembrane, C2, C1, and V domains. The V domain of RAGE is one of the most important target proteins for S100A1. It binds to the hydrophobic surface and triggers signaling transduction cascades that induce cell growth, cell proliferation, and tumorigenesis. We used nuclear magnetic resonance (NMR) spectroscopy to characterize the interaction between S100A1 and the RAGE V domain. We found that S100B could interact with S100A1 via NMR 1H-15N HSQC titrations. We used the HADDOCK program to generate the following two binary complexes based on the NMR titration results: S100A1-RAGE V domain and S100A1-S100B. After overlapping these two complex structures, we found that S100B plays a crucial role in blocking the interaction site between RAGE V domain and S100A1. A cell proliferation assay WST-1 also supported our results. This report could potentially be useful for new protein development for cancer treatment.