Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer's Disease Neuroimaging Initiative cohort.

Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10-8 and 4.3 × 10-7). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.

Using Data-Dependent and -Independent Hybrid Acquisitions for Fast Liquid Chromatography-Based Untargeted Lipidomics.

Untargeted lipidomics using liquid chromatography (LC) coupled with tandem mass spectrometry (MS) is essential for large cohort studies. Using a fast LC gradient of less than 10 min for the rapid screening of lipids decreases the annotation rate, because of the lower coverage of the MS/MS spectra caused by the narrow peak width. A systematic procedure is proposed in this study to achieve a high annotation rate in fast LC-based untargeted lipidomics by integrating data-dependent acquisition (DDA) and sequential window acquisition of all-theoretical mass spectrometry data-independent acquisition (SWATH-DIA) techniques using the updated MS-DIAL program. This strategy uses variable SWATH-DIA methods for quality control (QC) samples, which are a mixture of biological samples that were analyzed multiple times to correct the MS signal drift. In contrast, biological samples are analyzed using DDA to facilitate the structural elucidation of lipids using the pure spectrum to the maximum extent. The workflow is demonstrated using an 8.6 min LC gradient, where the QC samples are analyzed using five different SWATH-DIA methods. The use of both DDA and SWATH-DIA achieves a 1.7-fold annotation coverage from publicly available benchmark data obtained using a fast LC-DDA-MS technique and offers 95.3% lipid coverage, as compared to the benchmark data set from a 25 min LC gradient. This study demonstrates that harmonized improvements in analytical conditions and informatics tools provide a comprehensive lipidome in fast LC-based untargeted lipidomics, not only for large-scale studies but also for small-scale experiments, contributing to both clinical applications and basic biology.

Safety, pharmacokinetics, and efficacy of belantamab mafodotin monotherapy in Japanese patients with relapsed or refractory multiple myeloma: DREAMM-11.

Belantamab mafodotin, a B-cell maturation antigen-targeting antibody-drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses.

Effects of Pawpaw (Asimina triloba) Seed Extract on the Differentiation and Fat Accumulation of 3T3-L1 Cells under Different Glucose Conditions.

Asimina triloba (pawpaw) contains various bioactive alkaloids and acetogenins. In the present study, the effects of pawpaw seed extract (PSE) on adipocyte differentiation and fat accumulation were investigated in 3T3-L1 cells under different glucose conditions. Treatment of undifferentiated cells with 10 ng/mL PSE increased lactic acid production, suggesting enhanced anaerobic glycolysis. PSE treatment also suppressed cell proliferation and decreased the nicotinamide adenine dinucleotide (NAD)+/NADH ratio in low-glucose medium; however, this effect was not observed in high-glucose medium. Additionally, PSE treatment under low-glucose conditions resulted in reduced accumulation of triglycerides and decreased expression of peroxisome proliferator-activated receptor (PPAR)-γ, CAAT/enhancer-binding protein (C/EBP)-α, and sterol regulatory element binding protein (SREBP)-1c in adipocyte-differentiated cells. PSE exerted greater effects on adipocyte differentiation and triglyceride content in 3T3-L1 cells under low-glucose conditions than under high-glucose conditions. These findings indicate that PSE enhances anaerobic glycolysis and inhibits adipocyte differentiation and fat accumulation in 3T3-L1 cells under glucose-restricted conditions.

Species-specific debromination of BDE99 in teleost fish: The relationship between debromination ability and bioaccumulation patterns of PBDEs.

Polybrominated diphenyl ethers (PBDEs) are known to be broken down by debromination reactions in the natural environment, such as by photolysis, microbial and metabolic processes. Although species-specific debromination of PBDEs by fish has also been reported, it has only rarely been studied from the phylogenetic perspective. The objective of this study is to reveal the factors affecting species-specific debromination through validation between the bioaccumulation of PBDEs in muscle tissue and the ability to debrominate BDE99. As environmental observations, PBDE concentrations in muscle tissues were analyzed in 25 wild fish (Cyprinidae, Gobiidae and others). As in vitro experiments, debromination experiments were conducted using the hepatic microsomes of 21 fish species. Significant amounts of BDE99 were detected in almost none of the Cyprinidae. A relatively higher debromination ability was confirmed in the Cyprinidae in in vitro experiments. The Cyprinidae thus appears to be a family with high debromination ability. BDE99 has been detected in some goby species but not others. This pattern was also seen in in vitro experiments, suggesting that debromination ability is not consistent within the Gobiidae. In further quantitative comparisons, kinetic parameters such as Km and vmax were determined for selected fish species. The common carp (Cyprinus carpio) and the Japanese crucian carp (Carassius cuvieri), both Cyprinidae, showed higher vmax values, whereas vmax values among three Gobiidae diverged widely. A comparison of field observations and in vitro experiments, revealed the bioaccumulation ratio of BDE99 to be affected by the BDE99 debromination ability of each fish species. This is the first report on classification of BDE99 accumulation ratio by debromination ability and a phylogenetic species comparison based on kinetic parameters for debromination reactions of PBDEs by fish.

Stochastic modelling of the effects of human-mobility restriction and viral infection characteristics on the spread of COVID-19.

After several months of "lockdown" as the sole answer to the COVID-19 pandemic, balancing the re-opening of society against the implementation of non-pharmaceutical measures needed for minimizing interpersonal contacts has become important. Here, we present a stochastic model that examines this problem. In our model, people are allowed to move between discrete positions on a one-dimensional grid with viral infection possible when two people are collocated at the same site. Our model features three sets of adjustable parameters, which characterize (i) viral transmission, (ii) viral detection, and (iii) degree of personal mobility, and as such, it is able to provide a qualitative assessment of the potential for second-wave infection outbreaks based on the timing, extent, and pattern of the lockdown relaxation strategies. Our results suggest that a full lockdown will yield the lowest number of infections (as anticipated) but we also found that when personal mobility exceeded a critical level, infections increased, quickly reaching a plateau that depended solely on the population density. Confinement was not effective if not accompanied by a detection/quarantine capacity surpassing 40% of the symptomatic patients. Finally, taking action to ensure a viral transmission probability of less than 0.4, which, in real life, may mean actions such as social distancing or mask-wearing, could be as effective as a soft lockdown.

Food Lipidomics for 155 Agricultural Plant Products.

Lipids exhibit functional bioactivities based on their polar and acyl chain properties; humans obtain lipids from dietary plant product intake. Therefore, the identification of different molecular species facilitates the evaluation of biological functions and nutrition levels and new phenotype-modulating lipid structures. As a rapid screening strategy, we performed untargeted lipidomics for 155 agricultural products in 58 species from 23 plant families, wherein product-specific lipid diversities were shown using computational mass spectrometry. We characterized 716 lipid species, for which the profiles revealed the National Center for Biotechnology Information-established organismal classification and unique plant tissue metabotypes. Moreover, we annotated unreported subclasses in plant lipidology; e.g., triacylglycerol estolide (TG-EST) was detected in rice seeds (Oryza sativa) and several plant species. TG-EST is known as the precursor molecule producing the fatty acid ester of hydroxy fatty acid, which lowers ambient glycemia and improves glucose tolerance. Hence, our method can identify agricultural plant products containing valuable lipid ingredients.

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants.

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [Cmax ] and area under the concentration-time curve [AUC0-t ]) increased in an approximately dose-proportional manner. The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in Cmax and AUC0-t , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms.

Design of Hollow Protein Nanoparticles with Modifiable Interior and Exterior Surfaces.

Protein-based nanoparticles hold promise for a broad range of applications. Here, we report the production of a uniform anionic hollow protein nanoparticle, designated TIP60, which spontaneously assembles from a designed fusion protein subunit based on the geometric features of polyhedra. We show that TIP60 tolerates mutation and both its interior and exterior surfaces can be chemically modified. Moreover, TIP60 forms larger structures upon the addition of a cationic protein. Therefore, TIP60 can be used as a modifiable nano-building block for further molecular assembly.