Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Supportive people evoke positive affect, but do not reduce negative affect, while supportive groups result from favorable dyadic, not group effects.

BACKGROUND AND OBJECTIVES: We addressed understudied questions in social support. Do providers, who recipients agree are more supportive than others (i.e., consensually supportive), evoke more favorable affect in recipients? Do groups differ in their supportiveness and do supportive groups evoke favorable affect in their members? Can any group differences be explained by dyadic relationships within groups? METHODS: We analyzed data from seven samples of well-acquainted groups and groups of strangers in which participants rated each other on supportiveness, and affect experienced when with each group member. RESULTS: Social Relations Model analyses indicated that consensually supportive providers evoked higher positive affect in recipients but not lower negative affect. Uniquely supportive relationships evoked higher positive and lower negative affect. Groups differed in their supportiveness and more supportive groups evoked higher positive and lower negative affect. Correlations between support and affect at the level of groups primarily reflected dyadic relationships within groups, rather than the groups themselves. Groups of strangers showed the same effects as well-acquainted groups. CONCLUSIONS: The findings for consensually supportive providers and low negative affect is inconsistent with most social support theory. Supportive groups' links to affect could be explained by dyadic relationships within groups, rather than the groups themselves.

N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release.

Hydrogen sulfide (H2S) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable H2S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H2S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H2S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.

When Forecasting Mutually Supportive Matches Will Be Practically Impossible.

Forecasting which dyads will develop mutually supportive relationships is an important applied and basic research question. Applying psychometric theory to the design of forecasting studies shows that agreement between dyad members about their relationship (relational reciprocity) sets an upper limit for forecasting accuracy by determining the reliability of measurement. To test this, we estimated relational reciprocity in Study 1. Participants in seven samples (six student and one military; N = 504; Ndyads = 766) rated each other on support-related constructs in round-robin designs. Relational reciprocity was very low, undermining reliability. Formulas from psychometric theory predicted that forecasting supportive dyads would be practically impossible. To test this, we had participants in Study 2 complete a measure for matching dyads derived from recent theory. As predicted, supportive matches could not be forecast with acceptable precision. Theoretically, this falsifies some predictions of recent social-support theory. Practically, it remains unclear how to translate basic social-support research into effective interventions.

Release of electrolytes from W/O/W double emulsions stabilized by a soluble complex of modified pectin and whey protein isolate.

W/O/W double emulsions (DEs) stabilized by charged soluble complexes of whey protein isolate (WPI) and modified pectins were investigated in relation to their stability and the release of two types of electrolytes, NaCl and sodium ascorbate. WPI alone cannot properly stabilize the DEs. The droplet size is relatively large (100 microm) and increases with time. However, addition of modified pectin to form a soluble complex with WPI significantly improved the stability. DEs prepared with two types of oils (medium chain triglycerides (MCT) and R(+)-limonene) were studied by measuring droplet size, creaming, viscosity, and electrolyte release. Irrespective of their very different oil phase nature, both emulsions were stable against coalescence, but R(+)-limonene formed smaller droplets (25 microm) than MCT (35 microm). The electrolyte release rate was significantly higher from the R(+)-limonene that formed DEs with much lower viscosity. R(+)-limonene-DE released 75% of the NaCl after 28 days, while MCT-DE released only 50%. NaCl was released more slowly than sodium ascorbate. Apparently, the release mechanism from R(+)-limonene-DE was found to be "thinning the outer interface and release of the entire inner droplets" while it seems that the release from MCT-DE was slower and "diffusion controlled". DEs stabilized by WPI/C63 released 12% of the sodium ascorbate after 1 day in milk and remained stable for at least 8 days. However, DEs stabilized with only WPI released about 50% of the sodium ascorbate after 1 day, and phase separated after 8 days.

Double emulsions stabilized by a charged complex of modified pectin and whey protein isolate.

Double emulsions based on naturally occurring stabilizers for food applications were studied. Two charged biopolymers, whey protein isolate (WPI) and enzymatic modified pectins, interacted in aqueous solution to form a charge-charge complex that was utilized as a hydrophilic polymeric steric stabilizer improving the double emulsion stability. The main factors that influence the interaction between protein and pectin were investigated in relation to double emulsion stability: creaming, coalescence, and water transport between aqueous phases. The pH determined the size of the complex formed. Thus at pH 6, where a soluble complex was obtained between some molecular positively charged patches on the protein and negatively charged fractions of the hydrocolloids, the double emulsion was the most stable. With the smallest droplet size (ca. 15 microm), the lowest creaming, highest yield, and minimized water transport were obtained. The best concentration and ratio to form the soluble complex are 4 wt% WPI and 0.5 wt% pectin (for 30 wt% of the W/O inner phase). The influence of the charge distribution (degree of order of the carboxylic groups) of the pectin on the associated complex was also investigated, and it was found that the more "ordered" pectin (U63) formed the most stable double emulsion against water transport.

On the confocal images and the rheology of whey protein isolated and modified pectins associated complex.

The conditions necessary to form an associated complex between whey protein isolate (WPI) and enzymatically modified pectin in water, at pH values above the isoelectric point of the protein, have been documented. The existence of the complex is not easily verified and its characterization in solution is even more complicated, since the structure is an intermediate entity between the non-interacting, incompatible aqueous soluble mixture of the biopolymers, and a strongly interacting coacervated precipitating complex. Evidence for the formation of this associated complex is provided from confocal laser scanning microscope images and rheological behavior of the aqueous mixtures. The associated complex is characterized by small fluorescent "patches" interpreted as small aggregates. The viscosity of this solution is greater than that of its individual biopolymer constituents, indicating a synergy of attractive interactions that occurs in the solution. While individually, the pectin and the WPI solutions at the studied range of concentrations exhibit moderately non-Newtonian behavior, at specific weight ratios, mixtures of the two behave either as highly entangled polymeric structures or as weak gels. The values of the storage modulus G' are equal to or greater than those of the loss modulus G''. We conclude that the associated complexes are formed at pH 6, and at 4 wt% WPI with a pectin concentration ranging from 0.1 to 0.75 wt%. The influence of the charge distribution (degree of order of the carboxylic groups) of pectin on the associated complex was also investigated, and it was found that the more "ordered" pectin (U63) favors the formation of the associated soluble complex.

Nano-sized self-assemblies of nonionic surfactants as solubilization reservoirs and microreactors for food systems.

In recent studies we have found unique mixtures of food-grade oils, two or more food-grade nonionic hydrophilic emulsifiers, cosolvent (polyol), and coemulsifiers that self-assemble to form mixed reverse micelles ("the concentrate") and can be diluted with an aqueous phase, progressively and continuously, without phase separation, and are transformed into bicontinuous structures and finally, upon further dilution, can be inverted into oil-in-water nanodroplets. The "concentrate" is capable of solubilizing nutraceuticals, drugs, antioxidants, and other compounds that are poorly soluble in water or in the oil phase, with 10-20 times more solubility capacity than that of any food-grade oils or water phase. For example, phytosterols were solubilized up to 12 times more than the dissolution capacity of the oil (-(+)-limonene) for the same compounds. Similarly, the solubilization of lycopene in the concentrate was found to be ten times more than in the corresponding oil. The effects of the guest molecule and microemulsions ingredients on the microstructure transitions and their interfacial reactivity were studied, and the correlation between the surface activity of the guest molecule and its effect on the phase transitions was determined. The advantages of these systems in protecting the solubilizates from environmental reactivity (oxidation), was demonstrated. Lycopene did not oxidize-even after 75 days in an open vessel-if solubilized in the microemulsion medium, while if left unformulated, it was totally oxidized. The systems are unique since they demonstrate significant interfacial reactivity. Maillard reactions between sugars and amino acids, carried out at the O/W interface, can be kinetically controlled better than reactions carried out in the aqueous phase; the products are more regioselective and can form Maillard compounds that are not found in aqueous phase processes. Advanced analytical techniques such as SAXS, PGSE-NMR, and viscosity measurements have been used to evaluate the microstructures of the reverse and direct swollen micelles in both the absence and presence of the guest molecules.