Association of prenatal vitamin E levels with child asthma and wheeze.

BACKGROUND: We investigated the individual and interaction effects of maternal plasma 𝛂- and ϒ-tocopherol levels (vitamin E isomers) on child asthma and wheeze at age 8-9. METHODS: Mother-child dyads were enrolled between 2006 and 2011 into the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) prenatal cohort. Maternal second-trimester samples were analyzed for tocopherol and lipid concentrations. We assessed child asthma/wheeze using the International Study of Asthma and Allergies in Childhood (ISAAC) and other self-reported Ent wheeze. In multivariable logistic regression analyses, we assessed associations between vitamin E isomers and child asthma/wheeze outcomes (n = 847 mother-child dyads) and tested for prespecified interaction terms. RESULTS: Median cholesterol-corrected tocopherol levels (interquartile range (IQR)) were 5.0 (4.3-5.7) and 0.8 (0.7-0.9) (umol/mmol) for 𝛂- and ϒ-tocopherol, respectively. Associations between 𝛂-tocopherol and asthma outcome variables were inverse but not statistically significant. In contrast, for ϒ-tocopherol, associations were in the positive direction, but also nonsignificant. Interactions analysis between tocopherols did not reach statistical significance for any outcome. Among children of women with a history of asthma, the likelihood of ever asthma in the child appears to be decreasing with increasing maternal 𝛂-tocopherol levels, whereas this trend was not observed among those without a history of asthma (p-interaction = .05). CONCLUSION: We observed no associations for prenatal 𝛂- or ϒ-tocopherol concentrations with child asthma/wheeze. We detected some evidence of effect modification by maternal asthma history in associations between 𝛂-tocopherol and child asthma.

Emulsions vs excipient emulsions as α-tocopherol delivery systems: Formulation optimization and behaviour under in vitro digestion.

Oil-in-water emulsions (EM) have been extensively used for the encapsulation of lipophilic bioactive compounds and posterior incorporation into food matrices to obtain functional foods. Conversely, novel excipient oil-in-water emulsions (EXC) present identical composition and structure as EM, albeit are not bioactive by themselves since no bioactive compound is encapsulated. Instead, EXC aims at improving the bioavailability of foods' natural bioactive compounds upon co-ingestion with nutrient-rich foods. In this work, EM and EXC were produced and their stability and functionality as delivery systems for α-tocopherol compared. Emulsions were formulated with corn oil and lecithin, and their composition was optimized using experimental designs. Formulations produced with 3 % lecithin and 5 % oil attained smallest particles sizes with the lowest polydispersity index of all tested formulations and remained stable up to 60 days. Encapsulation of α-tocopherol did not have a significative impact on the structural properties of the particles produced with the same composition. α-tocopherol stability during in vitro digestion was superior in EM regardless the processing methodology (EM stability < 50 %, EXC stability < 29 %), indicating that EM offered greater protection against the digestive environment. α-tocopherol's bioaccessibility was significantly increased when encapsulated or when digested with added excipient emulsions (82-92 % and 87-90 % for EM and EXC, respectively). In conclusion, EM were more efficient vehicles for the selected bioactive compound, however, the good results obtained with EXC imply that excipient emulsions have a great potential for applications on foods to improve their natural bioactive compounds' bioavailability without the need of further processing.

Genetic Factors Contributing to Interindividual Variability of α-Tocopherol Levels in Subcutaneous Adipose Tissue among Healthy Adult Males.

In humans, α-tocopherol (α-TOC) is mainly stored in adipose tissue, where it participates in preventing damages induced by inflammation and reactive oxygen species. Factors, including genetic ones, that explain adipose tissue α-TOC concentration remain poorly understood. This study, therefore, aimed to characterize the interindividual variability of adipose tissue α-TOC concentration in healthy individuals and to identify single nucleotide polymorphisms (SNPs) associated with it. The study used a randomized cross-over design with 42 healthy adult males. α-TOC concentration was measured in fasting plasma and periumbilical adipose tissue samples, both at fast and 8 h after consumption of three standard meals. Partial least squares (PLS) regression was performed to identify SNPs associated with the interindividual variability of adipose tissue α-TOC concentration. Adipose tissue α-TOC concentration was not associated with fasting plasma concentration (Pearson's r = 0.24, 95% CI: [-0.08, 0.51]). There was a high interindividual variability of adipose tissue α-TOC concentration (CV = 61%). A PLS regression model comprising 10 SNPs in five genes (PPARG, ABCA1, BUD13, CD36, and MGLL) explained 60% (adjusted R2) of the variability of this concentration. The interindividual variability of adipose tissue α-TOC concentration in humans is due, at least partly, to SNPs in genes involved in α-TOC and triglyceride metabolism.

Cis-Trans Isomerization of Unsaturated Fatty Acid Methyl Ester by Natural Sulfur Compounds in Model Systems.

Growing evidence indicates that the intake of trans fatty acids (TFAs) increases the risk of numerous diseases, such as cardiovascular diseases. Recently, our group found that certain natural sulfur compounds (allyl isothiocyanate [AITC] and diallyl disulfide [DADS]) promote cis to trans isomerization of fatty acid esters during heat treatment. However, little information is available on the fatty acid isomerization with them. In this study, we investigated the effects of oxygen and α-tocopherol (antioxidant) on isomerization of oleic acid (18:1) methyl ester (OA-ME) in the presence of AITC and DADS. Furthermore, the effect of the simultaneous use of AITC and DADS was evaluated. Our results indicate that oxygen enhances the AITC-induced trans isomerization, and DADS was found to promote trans isomerization but inhibit AITC-induced trans isomerization during heating. Both AITC- and DADS-induced trans isomerization were inhibited by α-tocopherol. These results indicate that the trans isomerization of fatty acids induced by sulfur compounds can be controlled by devising a cooking process and the food ingredients used together.

Chondroitin sulfate-tocopherol succinate modified exosomes for targeted drug delivery to CD44-positive cancer cells.

Exosomes (Exos), natural nanovesicles released by various cell types, show potential as an effective drug delivery platform due to their intrinsic role as transporters of biomolecules between different cells. However, Exos functionalization with targeting ligands is a critical step to enhance their targeting capability, which could be challenging. In this study, Exos were modified to specifically bind to CD44-positive cells by anchoring chondroitin sulfate (CS) to their surface. Exo modification was facilitated with CS conjugation with alpha-tocopherol succinate (TOS) as an anchorage. The modified Exos were utilized for delivering curcumin (Cur) to pancreatic cancer (PC) cells. In vitro Cur release studies revealed that Exos play a crucial role in maintaining Cur within themselves, demonstrating their potential as effective carriers for drug delivery to targeted locations. Notably, Cur loaded into the modified Exos exhibited enhanced cytotoxicity compared to unmodified Exo-Cur. Meanwhile, Exo-Cur-TOS-CS induced apoptosis more effectively in AsPC-1 cells than unmodified Exos (70.2 % versus 56.9 %). It is worth mentioning that with CD44-mediated cancer-specific targeting, Exo-CS enabled increased intracellular accumulation in AsPC-1 cells, showing promise as a targeted platform for cancer therapy. These results confirm that Exo modification has a positive impact on enhancing the therapeutic efficacy and cytotoxicity of drugs.

Effect of VP, MAP and combined packaging systems on the physicochemical properties and microbiological status of veal from unweaned calves.

The packaging system is one of the factors influencing the preservation of the nutritional value, microbiological safety, and sensory attributes of meat. The study investigated changes in physicochemical and microbiological properties taking place during 15-day refrigerated storage of two calf muscles, the longissimus lumborum (LL) and semitendinosus (ST), packaged in three systems, respectively, vacuum packing (VP), modified atmosphere packaging (MAP, 80% O2 + 20% CO2), and a combined system (VP + MAP, 8 d in VP followed by 7 d in MAP). LL and ST stored in VP had significantly lower levels of lipid oxidation, higher α-tocopherol content, and higher instrumentally measured tenderness in comparison with the samples stored in MAP. On the other hand, the MAP samples had lower purge loss at 5 and 15 days, a higher proportion of oxymyoglobin up to 10 days of storage, and a better microbiological status. Calf muscle samples stored in the VP + MAP system had intermediate values for TBARS and α-tocopherol content and at the same time were the most tender and had the lowest counts of Pseudomonas and Enterobacteriaceae bacteria at 15 days. All packaging systems ensured relatively good quality of veal characteristics up to the last day of storage. However, for MAP at 15 days of storage, unfavourable changes in colour (a high level of metmyoglobin and a decrease in oxymyoglobin, redness and R630/580 ratio) and in the lipid fraction (a high TBARS value and a significant decrease in α-tocopherol content) were observed.

Tocopherol-human serum albumin nanoparticles enhance lapatinib delivery and overcome doxorubicin resistance in breast cancer.

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 µg/ml on MCF7 (S) and 8.02 µg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

[Box: see text].

Comparative Study of Camellia oleifera Seed Oil on Chemical Constituents, Antioxidant Activities and Physicochemical Characteristics from Southern China.

Eleven kinds of Camellia oleifera seed oils (CSOs) were evaluated in terms of chemical constituents, antioxidant activities, acid value (AV) as well as peroxide value (POV). These CSOs contained abundant ß-sitosterol, squalene, α-tocopherol and phenolics, in which the squalene was the distinct constituent with the content between 45.8±0.8 and 184.1±5.5 mg/kg. The ß-sitosterol ranging from 143.7±4.8 to 1704.6±72.0 mg/kg contributed a considerable content to total accompaniments. Palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid were present in these CSOs, in which the dominant fatty acid was oleic acid with the content between 59.66±0.72 and 82.89±2.16 g/100 g. The AV ranged from 0.1±0.0 to 1.3±0.0 mg KOH/g, and the POV was between 0.1±0.0 and 1.0±0.0 g/100 g. These CSOs showed antioxidant activity based on DPPH and ABTS radical scavenging assay. Both α-tocopherol and ß-sitosterol contents showed a positive correlation with DPPH and ABTS values, respectively, while the α-tocopherol content showed a negative correlation with AV. These results suggested that CSO can be categorized into high oleic acid vegetable oil with abundant active constituents, of which the quality presented variation among different origins. These accompaniments may contribute to the delay of its quality deterioration.

Calculation of reference intervals for the concentrations of α-tocopherol and retinol in serum using indirect data-mining procedures.

BACKGROUND: Establishing adequate reference intervals (RIs) for vitamins A and E is essential for diagnosing and preventing deficiencies. Due to the current boom in data mining and its easy applicability, more laboratories are establishing RIs using indirect methods. Our study aims to obtain RIs using four indirect data-mining procedures (Bhattacharya, Hoffmann, Kosmic, and RefineR) for vitamins A and E. MATERIAL AND METHODS: 8943 individuals were collected to establish the RIs. After using different data cleaning steps and checking whether these data should be divided according to age and gender based on multiple linear regression and variance component analyses, indirect RIs were calculated using specific Excel spreadsheets or R-packages software. RESULTS: A total of 2004 records were eligible. For vitamin A, the RIs obtained were (1.11 - 2.68) µmol/L, (1.13 - 2.70) µmol/L, (1.13 - 2.71) µmol/L, and (1.17 - 2.66) µmol/L using the Bhattacharya, Hoffmann, Kosmic and RefineR approaches, respectively. For vitamin E, these intervals were (17.3 - 49.9) µmol/L (Bhattacharya), (17.3 - 48.9) µmol/L (Hoffmann), (19.6 - 50.3) µmol/L (Kosmic), and (19.4 - 50.9) µmol/L (RefineR). In all cases, the RIs were comparable. CONCLUSIONS: Suitable RIs for vitamins A and E were calculated using four indirect methods that are suitable and adapted to our population's demographic characteristics.

Elucidating causal relationships of diet-derived circulating antioxidants and the risk of non-scarring alopecia: A Mendelian randomization study.

Previous observational studies revealed controversy about the effect of circulating antioxidants on risk of alopecia. In the present study, we investigated the causal relationships between diet-derived circulating antioxidants and 2 non-scarring alopecia using Mendelian randomization (MR). Instrumental variables for antioxidants (lycopene, retinol, ascorbate, ß-carotene, α-tocopherol, and γ-tocopherol) were selected from published studies. Data for alopecia areata (AA) and androgenetic alopecia (AGA) was obtained from the FinnGen study project (R9 released in 2023), including 195 cases and 201,019 controls for AGA and 682 cases and 361,140 controls for AA. We used the inverse variance weighted method as the primary MR method. Three additional methods were used as sensitivity analysis to validate the robustness of the results. We found a causal relationship between absolute ß-carotene levels and AGA risk (P = .039), but not with AA (P = .283). The results of Wald ratio showed a protective effect of absolute ß-carotene levels against AGA, with per 0.1 ln-transformed ß-carotene being associated with a 76% lower risk of AGA (OR: 0.24, 95% CI: 0.06-0.93). Based on the fixed effects inverse variance weighting results, we found that α-tocopherol was protective against both AGA (P = .026) and AA (P = .018). For each unit increase in α-tocopherol, the effects of change in AGA and AA were 0.02 (95% CI: 0.00-0.61) and 0.10 (95% CI: 0.01-0.67), respectively. The results did not reveal any other causal relationships. Our study identified 3 causal associations of antioxidants with the risk of non-scarring alopecia. These results provide new insights into the prevention of non-scarring alopecia through diet.

Gelatin/dextran active films incorporated with cinnamaldehyde and α-tocopherol for scallop (Patinopecten yessoensis) adductor muscle preservation.

Scallops are rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid but perishable due to their microbial growth and lipid oxidation. In this study, gelatin/dextran films containing cinnamaldehyde and α-tocopherol (0% + 0%, 0.3% + 0.3%, 0.6% + 0.6%, 0.9% + 0.9%, and 1.2% + 1.2%, w/w) as active fillers were developed by solution casting method, and their preservation effects on scallop adductor muscle refrigerated at 4°C for 0, 3, 6, 9, and 12 days were evaluated. Inclusion of the two active fillers did not influence the thermal stability of the films but created heterogenous and discontinuous film microstructure and increased the film hydrophobicity. Increase in the concentrations of active fillers lowered the mechanical properties and water vapor permeability of the films but increased their crystallinity, thickness, water contact angle, opacity, antibacterial property, and antioxidant property. The longest release times for both cinnamaldehyde and α-tocopherol were found in 95% (v/v) ethanol solution. The gelatin/dextran films containing 1.2% (w/w) of active fillers (Gelatin [Ge]/Dextran [Dx]/1.2 film) improved the chemical stability of refrigerated scallop adductor muscle. The total viable count (TVC) of the unpackaged scallop adductor muscle exceeded the recommended limit of 7 lg CFU/g on day 6 (7.07 ± 0.50 lg CFU/g), whereas the TVC of the Ge/Dx/1.2 film-packaged scallop adductor muscle was still below the limit on day 9 (5.60 ± 0.50 lg CFU/g). Thus, the Ge/Dx/1.2 film can extend the shelf life of refrigerated scallop adductor muscle by at least 3 days. Overall, the developed gelatin/dextran active packaging films are promising for the preservation of aquatic food products.

Vitamin E nomenclature. Is RRR-α-tocopherol the only vitamin E?

It has generally been accepted that vitamin E refers to a group of tocochromanols, α-, ß-, γ-, and δ-tocopherols and the corresponding four tocotrienols. Recently, Azzi and colleagues proposed to restrict the term vitamin E only to RRR-α-tocopherol, not to other tocopherols and tocotrienols (Azzi A et al. Free Radic Biol Med. 2023; 207:178-180. doi: 10.1016/j.freeradbiomed.2023.06.029). The aim of this paper is to express our opinion on the nomenclature of vitamin E based on available scientific data. In our opinion, it would be inappropriate to exclude all the tocochromanols other than RRR-α-tocopherol from the vitamin E group at this stage when the molecular mechanisms showing how vitamin E deficiency causes diseases such as ataxia and how vitamin E prevents/reverses such diseases are not elucidated. Understanding of whole functions of tocochromanols including underlying mechanisms and dynamics is essential before revision of currently accepted definition of vitamin E. The potential roles of γ-tocopherol and tocotrienols are discussed despite whether they are vitamin function should be clarified in the future studies.

Deciphering the enigma of the function of alpha-tocopherol as a vitamin.

α-Tocopherol (α-T) is a vitamin, but the reasons for the α-T requirement are controversial. Given that α-T deficiency was first identified in embryos, we studied to the premier model of vertebrate embryo development, the zebrafish embryo. We developed an α-T-deficient diet for zebrafish and used fish consuming this diet to produce α-T deficient (E-) embryos. We showed that α-T deficiency causes increased lipid peroxidation, leading to metabolic dysregulation that impacts both biochemical and morphological changes at very early stages in development. These changes occur at an early developmental window, which takes place prior to an analogous time to when a human knows she is pregnant. We found that α-T limits the chain reaction of lipid peroxidation and protects metabolic pathways and integrated gene expression networks that control embryonic development. Importantly, not only is α-T critical during early development, but the neurodevelopmental process is highly dependent on α-T trafficking by the α-T transfer protein (TTPa). Data from both gene expression and evaluation of the metabolome in E- embryos suggest that the activity of the mechanistic Target of Rapamycin (mTOR) signaling pathway is dysregulated-mTOR is a master regulatory mechanism, which controls both metabolism and neurodevelopment. Our findings suggest that TTPa is needed not only for regulation of plasma α-T in adults but is a key regulator during embryogenesis.

Metabolism of 11'-α- and 11'-γ-Tocomonoenols in HepG2 Cells Favors the γ-Congener and Results Predominantly in Carboxymethylbutyl-Hydroxychromans.

SCOPE: Tocomonoenols (T1) are little-known vitamin E derivatives naturally occurring in foods. Limited knowledge exists regarding the cellular uptake and metabolism of α-tocomonoenol (αT1) and none about that of γ-tocomonoenol (γT1). METHODS AND RESULTS: The study investigates the cytotoxicity, uptake, and metabolism of αT1 and γT1 in HepG2 cells compared to the α- and γ-tocopherols (T) and -tocotrienols (T3). None of the studied tocochromanols are cytotoxic up to 100 µmol L-1. The uptake of the γ-congeners is significantly higher than that of the corresponding α-forms, whereas no significant differences are observed based on the degree of saturation of the sidechain. Carboxymethylbutyl-hydroxychromans (CMBHC) are the predominant short-chain metabolites of all tocochromanols and conversion is higher for γT1 than αT1 as well as for the γ-congeners of T and T3. The rate of metabolism increases with the number of double bonds in the sidechain. The rate of metabolic conversion of the T1 is more similar to tocopherols than to that of the tocotrienols. CONCLUSION: This is the first evidence that both αT1 and γT1 follow the same sidechain degradation pathway and exert similar rates of metabolism than tocopherols. Therefore, investigation into the biological activities of tocomonoenols is warranted.

Formation of Epoxy Fatty Acids in Triacylglycerol Standards during Heating.

Epoxy fatty acid formation during heating was estimated using triolein (OOO) and trilinolein (LLL). Epoxy octadecanoic acids were found in heated OOO, while epoxy octadecenoic acids were found in heated LLL. The content of epoxy fatty acids increased with heating time, and trans-epoxy fatty acids were formed significantly more than cis-epoxy fatty acids. A comparison between OOO and LLL indicated that epoxy fatty acid formation was higher in the OOO than that in the LLL. Heating tests in the presence of α- tocopherol suggested that the formation of epoxy fatty acids could be suppressed by antioxidants.

Alpha-tocopherol inhibits ferroptosis and promotes neural function recovery in rats with spinal cord injury via downregulating Alox15.

Spinal cord injury (SCI) is a type of central nervous system (CNS) injury in which ferroptosis is becoming a promising target for treatment. Alpha-tocopherol (Vitamin E, Vit E) is a compound with anti-ferroptosis activity. The mechanism of alpha-tocopherol in regulating ferroptosis after SCI has not been deeply studied. In this study, rats with SCI were treated by Alpha-tocopherol based on bioinformatic analysis and molecular docking prediction. Behavioral tests and histological findings showed that Alpha-tocopherol promoted neural function recovery and tissue repairment in rats with SCI. Subsequently, regulatory effects of Alpha-tocopherol on Alox15 and ferroptosis were detected and then localized by immunofluorescence. In vitro, alpha-tocopherol improved the ROS accumulation, iron overload, lipid peroxidation and mitochondrial dysfunction. The effects of Alpha-tocopherol on the expression of Alox15, Ptgs2 and 4Hne were validated in vitro. Finally, the inhibitory effects of Alpha-tocopherol on Alox15 and ferroptosis were weakened by the mutation of 87th residue of Alox15. In summary, alpha-tocopherol could alleviate SCI-induced ferroptosis by downregulating Alox15 to promote neural function recovery in rats with SCI. Findings in this study could help further our understanding on SCI-induced ferroptosis and provide a novel insight for treating SCI.

No genetic causal association between circulating alpha-tocopherol levels and osteoarthritis, a two-sample Mendelian randomization analysis.

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E-8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR-Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.

Investigation of the effects of pentoxifylline and alpha tocopherol treatment on recovery in rats with Achilles tendon rupture.

Although the Achilles tendon is the largest and strongest tendon in the body, healing of the Achilles tendon is the most common injury, and this process is difficult due to poor tendon circulation; moreover, the underlying mechanism has not been fully elucidated. In our study, we aimed to investigate the effects of pentoxifylline and alpha-tocopherol administered separately or in combination on rats with Achilles tendon injury. Forty-eight male Wistar rats weighing 230 ± 30 g were used in the study. The rats were randomly divided into eight groups of six animals each. Tendons were evaluated histopathologically and biomechanically. According to the statistical analysis, the vascularity density in the pentoxifylline group on day 14 was significantly greater than that in the other groups (p < 0.05). The collagen arrangement in the pentoxifylline and alpha-tocopherol groups on day 14 was found to be firmer and smoother than that in the control group (p < 0.05). The collagen arrangement in the pentoxifylline group on day 28 was greater than that in the other groups (p < 0.05). The biomechanical results were significantly greater in all groups (p < 0.05). Pentoxifylline contributed to tendon healing both through neovascularization in the early period and by improving collagen orientation in the late period, while alpha-tocopherol had a positive effect on collagen orientation in the early period. No beneficial effects were observed when pentoxifylline and alpha-tocopherol were used together. We believe that further research is needed to understand the effects of this combination therapy on tendon healing.

AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans.

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4+ T cell and memory B cell responses. Antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

Both external and internal factors induce heterogeneity in senescing leaves of deciduous trees.

Autumn senescence is characterised by spatial and temporal heterogeneity. We show that senescing birch (Betula spp.) leaves had lower PSII activity (probed by the F V /F M chlorophyll a fluorescence parameter) in late autumn than in early autumn. We confirmed that PSII repair slows down with decreasing temperature, while rates of photodamage and recovery, measured under laboratory conditions at 20°C, were similar in these leaves. We propose that low temperatures during late autumn hinder repair and lead to accumulation of non-functional PSII units in senescing leaves. Fluorescence imaging of birch revealed that chlorophyll preferentially disappeared from inter-veinal leaf areas. These areas showed no recovery capacity and low non-photochemical quenching while green veinal areas of senescing leaves resembled green leaves. However, green and yellow leaf areas showed similar values of photochemical quenching. Analyses of thylakoids isolated from maple (Acer platanoides ) leaves showed that red, senescing leaves contained high amounts of carotenoids and α-tocopherol, and our calculations suggest that α-tocopherol was synthesised during autumn. Thylakoids isolated from red maple leaves produced little singlet oxygen, probably due to the high antioxidant content. However, the rate of PSII photodamage did not decrease. The data show that the heterogeneity of senescing leaves must be taken into account to fully understand autumn senescence.