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Background: Increased amino acid availability stimulates muscle protein synthesis (MPS), which is critical for maintaining or increasing muscle mass when combined with training. Previous research suggests that whey protein is superior to soy protein in regard to stimulating MPS and muscle mass. Nevertheless, with respect to a future lack of dietary protein and an increasing need for using eco-friendly protein sources it is of great interest to investigate the quality of alternative protein sources, like insect protein. Objective: Our aim was to compare the postprandial amino acid (AA) availability and AA profile in the blood after ingestion of protein isolate from the lesser mealworm, whey isolate, and soy isolate. Design: Six healthy young men participated in a randomized cross-over study and received three different protein supplementations (25 g of crude protein from whey, soy, insect or placebo (water)) on four separate days. Blood samples were collected at pre, 0 min, 20 min, 40 min, 60 min, 90 min, and 120 min. Physical activity and dietary intake were standardized before each trial, and participants were instructed to be fasting from the night before. AA concentrations in blood samples were determined using 1H NMR spectroscopy. Results: A significant rise in blood concentration of essential amino acids (EAA), branched-chain amino acids (BCAA) and leucine was detected over the 120 min period for all protein supplements. Nevertheless, the change in AA profile was significantly greater after ingestion of whey than soy and insect protein (p < 0.05). Area under the curve (AUC) analysis and AA profile revealed comparable AA concentrations for soy and insect protein, whereas whey promoted a ~97% and ~140% greater AUC value than soy and insect protein, respectively. A tendency towards higher AA concentrations beyond the 120 min period was observed for insect protein. Conclusion: We report that ingestion of whey, soy, and insect protein isolate increases blood concentrations of EAA, BCAA, and leucine over a 120 min period (whey > insect = soy). Insect protein induced blood AA concentrations similar to soy protein. However, a tendency towards higher blood AA concentrations at the end of the 120 min period post ingestion was observed for insect protein, which indicates that it can be considered a “slow” digestible protein source.

Protein quality is important for patients needing medical nutrition, especially those dependent on tube feeding. A blend of dairy and vegetable proteins (35% whey, 25% casein, 20% soy, 20% pea; P4) developed to obtain a more balanced amino acid profile with higher chemical scores, was compared to its constituent single proteins. Fourteen healthy elderly subjects received P4, whey, casein, soy, and pea (18 g/360 mL bolus) on five separate visits. Blood samples were collected at baseline until 240 min after intake. Amino acid availability was calculated using incremental maximal concentration (iCmax) and area under the curve (iAUC). Availability for P4 as a sum of all amino acids was similar to casein (iCmax and iAUC) and whey (iCmax) and higher vs. soy (iCmax and iAUC) and pea (iCmax). Individual amino acid availability (iCmax and iAUC) showed different profiles reflecting the composition of the protein sources: availability of leucine and methionine was higher for P4 vs. soy and pea; availability of arginine was higher for P4 vs. casein and whey. Conclusions: The P4 amino acid profile was reflected in post-prandial plasma levels and may be regarded as more balanced compared to the constituent single proteins.

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits. Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.

ObjectivesWe explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.MethodsIndividuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.ResultsEighty-one individuals received treatment and were followed up for a mean of 29.0 (0–54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.ConclusionsA single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

ObjectivesThe efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).Methods431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.ResultsCompared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.ConclusionsSifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.Trial registration numberNCT01283139; Results.

Traumatic Brain Injury (TBI) is a significant risk factor for Alzheimer's Disease (AD). However, the mechanisms connecting TBI to AD pathology remain unclear. Identifying blood-based biomarkers of neuronal and astrocytic injury is crucial for advancing precision diagnostics and intervention by predicting neurodegeneration. This study evaluates serum biomarkers using the ultra-sensitive Single Molecule Array (SIMOA) platform to explore their association with TBI severity, sex-specific responses and potential relevance to AD. We conducted a subanalysis of 123 patients enrolled in the phase III NCT01048138 clinical trial at HCFMUSP. Participants with acute TBI were randomized to receive either biperiden or placebo. Serum samples were collected and analyzed at multiple time points for biomarkers including Tau, NfL, GFAP, and UCHL1 using SIMOA. Biomarker profiles were compared across treatment groups, TBI severity, sex, age and time post-injury. Additional analyses explored their relevance to AD-related neurodegenerative process. GFAP and NfL emerged as the most reliable biomarkers, strongly correlating with age, sex, TBI severity and temporal progression post-injury. Intriguingly, elevated levels of these biomarkers in the acute phase post-TBI were associated with astrocytic and axonal injury, which are critical in AD pathology. UCHL1 levels are also associated with trauma severity, sex, and time post-injury, but less significantly than NfL and GFAP. Women exhibited higher levels of levels Tau, GFAP and UCHL1 but lower NfL levels compared to men, suggesting a potential sex-specific response. Age-stratified analyses revealed increased NfL and GFAP levels in older patients, emphasizing the impact of age on astrocytic activation. While biperiden treatment did not significantly alter biomarker levels across the overall cohort, exploratory analyses also revealed possible sex-specific trends in treatment response. Our findings underscore the feasibility of serum biomarkers such as GFAP and NfL to bridge the understanding of the molecular link between TBI and AD. The SIMOA technology enables precise quantification of biomarkers, providing valuable knowledge into the time window from the moment of TBI to the development of AD, allowing for the analysis of long-term neurodegeneration. These results reinforces the importance of personalized approaches to diagnosis and therapeutic monitoring.

The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability 1 – 3 . Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins 4 , 5 . Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery. Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.

Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) was an NIH-funded RCT that randomized 173 participants with Alzheimer's Disease (AD) and agitation to escitalopram or placebo for 12 weeks assessing efficacy for clinically significant agitation. There was no significant advantage for escitalopram in treating agitation. This might be attributed to including participants at various stages of AD brain pathology that would be reflected in levels of blood biomarkers. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow up regarding: (1) agitation severity (NPI-C-A+A); (2) cognitive status, (MMSE); and (3) escitalopram treatment. Abeta42, Abeta40, GFAP, NfL were measured using SIMOA N4PE assays, and pTau217 using the Alzpath-pTau217 SIMOA on Quanterix HD-X. Abeta40, Abeta42, pTau217, GFAP, and NfL were available for 82 participants. pTau217>0.42 pg/ml and Abeta42/40<0.04 pg/ml indicated significant amyloid pathology. Of 82 participants with pTau217 data, 77 (94%) scored above threshold supporting the clinical diagnosis of AD. In contrast, only 47 were below threshold for Abeta42/40. There was 61% agreement between biomarker cut-offs for pTau217 and Abeta42/40. No baseline associations between biomarkers and NPI-C-A+A scores were significant (p >0.05). Baseline higher pTau217 predicted higher NPI-C-A+A scores at week 6 (beta=3.26, p <0.001) and week 12 (beta=2.86, p = 0.01) after randomization. Baseline associations between Abeta40, Abeta42, NfL and MMSE scores were not significant (p >0.05). However, baseline higher levels of GFAP (beta=-0.02, p = 0.0002) and pTau217 (beta=-2.68, p = 0.003) were associated with lower baseline MMSE scores. Baseline Abeta40, GFAP and NfL were not associated with treatment outcomes. After adjusting for treatment, higher baseline pTau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (OR=2.79, p = 0.02) and 12 (OR=2.55, p = 0.02) compared to baseline. Baseline blood levels of pTau217 confirmed the presence of significant AD brain amyloid pathology in 94% of participants. Independent of treatment assignment, higher baseline blood levels of pTau217 predicted lower baseline MMSE scores and higher agitation severity at weeks 6 and 12 after randomization.

Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.

Elevated levels of blood-based biomarkers such as neurofilament light chain (NfL) and neuron-specific enolase (NSE) are associated with poor neurological outcome after out-of-hospital cardiac arrest (OHCA). This study investigates the relationship between regional grey matter volume reduction and levels of glial fibrillary acidic protein (GFAP), NfL, NSE, and total-tau (t-tau) protein. This substudy of the Xe-Hypotheca trial included 110 patients randomized to receive either inhaled xenon with target temperature management (TTM) at 33 °C for 24 h ( n  = 55) or TTM alone ( n  = 55). Voxel-based morphometry was used to assess grey matter volume changes in MRI scans acquired 36–52 h and 10 days after OHCA in 45 survivors. Blood biomarkers were measured upon intensive care unit arrival and at 24, 48 and 72 h post-OHCA. NfL levels positively correlated with grey matter volume reduction in the thalamus and cingulate cortex at 24 h post-OHCA. T-tau showed more extensive pattern of significant correlations, increasing in both magnitude and spatial extent from baseline to 48 h post-OHCA. No significant biomarker–volume associations were observed for GFAP or NSE, and no treatment group differences were detected. Elevated NfL and t-tau levels were associated with region-specific grey matter volume reduction within the first 10 days after OHCA. Among the four biomarkers studied, t-tau demonstrated the strongest and most widespread associations, suggesting its potential as a marker for early ischemic grey matter volume reduction after OHCA. ClinicalTrials.gov NCT00879892, 13/04/2009.