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Making a judgment of learning (JOL) during study can improve later test performance, a phenomenon called JOL reactivity. In paired-associates learning, JOLs improve memory for strongly (not weakly) related word pairs. JOLs appear to strengthen cue-target associations, enhancing future performance on tests sensitive to those associations. We investigated whether JOL reactivity would emerge in feedback-based category learning, wherein participants learn novel stimulus-response associations. We investigated whether this effect would be present for novel test items and if it would depend upon stimulus-category relatedness. Participants completed a category learning task; some performed JOLs throughout learning. At test, participants categorized novel and previously studied stimuli of varying degrees of stimulus-category relatedness. We found JOL reactivity for both novel and previously studied stimuli, and no effect of relatedness. Our experiment provides preliminary evidence that JOL reactivity can be produced in feedback-based category learning. COVIS theory provides an excellent framework for future investigations.

Technetium-99, a prevalent by-product of the nuclear fuel cycle, is a transition metal with 9 accessible oxidation states and a half-life of 2.1 × 105 years. 99TcVII has been found in the environment surrounding National Lab sites and fuel reprocessing centers, and its separation and long-term storage is complicated by its extensive redox chemistry. In our prior work we have reported the synthesis and reduction of TcVO to TcIVO in α1- and α2-Wells–Dawson P2W17O6110– polyoxometalates and reported on the polyoxometalate features that promote reduction and stabilization. In this work we report on the oxidation state stabilization of TcVO, TcVIO and TcVIN within the α-Keggin PW11O397– polyoxometalate. Both Density Functional Theory and experimental results show that Tc in TBA4[TcVIN-PW11O39] can be reduced to TcV, but any subsequent electrons reduce the tungsten framework of the polyoxometalate. TBA4[TcVO-PW11O39] however, can be theoretically reduced down to TcI before reduction of the polyoxometalate occurs.

We move forward the important topic of water entry by documenting splash dynamics arising from the impact of hydrophilic spheres with buoyant millimetric microplastics, mimicked in our study by polystyrene beads. Collision with small, buoyant beads is yet another means to manipulate splash dynamics. In this experimental study, we investigate the fluid–structure interactions between beads and hydrophilic spheres for Froude numbers in the range of 20 − 100. Generally, hydrophilic spheres entering a liquid bath below the critical velocity of 8 m/s produce minimal fluid displacement and no cavity formation. The presence of proximally adjacent beads atop the fluid with respect to impacting spheres promote flow separation and compound cavities for sufficiently large Froude numbers, while suppressing the growth of splash crowns. Compound cavities consist of a shallow, quasi-static first cavity that seals near the water line, and a second, deeper cavity produced in the wake of descending spheres. A vertically protruding Worthington jet follows cavity collapse. The resulting splash metrics differ from those of hydrophobic spheres with respect to the properties of impacted beads. We find impactors traversing a deep liquid pool layered with beads experience drag reduction when compared to entry into a clean pool due to the drag-reducing benefits of flow separation while not offering a high inertial penalty. Our study unravels the physics behind the widely encountered interaction of solid projectiles impacting passively floating particles, and our results translate to the entry dynamics of water-diving creatures and projectiles into water bodies polluted by floating millimetric microplastics. [ABSTRACT FROM AUTHOR]

We have developed SSTMap, a software package for mapping structural and thermodynamic water properties in molecular dynamics trajectories. The package introduces automated analysis and mapping of local measures of frustration and enhancement of water structure. The thermodynamic calculations are based on Inhomogeneous Fluid Solvation Theory (IST), which is implemented using both site-based and grid-based approaches. The package also extends the applicability of solvation analysis calculations to multiple molecular dynamics (MD) simulation programs by using existing cross-platform tools for parsing MD parameter and trajectory files. SSTMap is implemented in Python and contains both command-line tools and a Python module to facilitate flexibility in setting up calculations and for automated generation of large data sets involving analysis of multiple solutes. Output is generated in formats compatible with popular Python data science packages. This tool will be used by the molecular modeling community for computational analysis of water in problems of biophysical interest such as ligand binding and protein function.

Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies., Introduction Adoptive cell transfer (ACT) using genetically engineered T cells has entered the standard of care for patients with refractory B cell malignancies, including pediatric acute lymphoblastic leukemia (ALL) (1) [...]

[Display omitted] Pathogenic variants of phospholipase C gamma 2 (PLCG2) cause 2 related forms of autosomal-dominant immune dysregulation (ID), PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Since describing these conditions, many PLCG2 variants of uncertain significance have been identified by clinical sequencing of patients with diverse features of ID. We sought to functionally classify PLCG2 variants and explore known and novel genotype-function-phenotype relationships. Clinical data from patients with PLCG2 variants were obtained via standardized questionnaire. PLCG2 variants were generated by mutagenesis of enhanced green fluorescent protein (EGFP) -PLCG2 plasmid, which was overexpressed in Plcg2- deficient DT-40 B cells. B-cell receptor–induced calcium flux and extracellular signal-regulated kinase phosphorylation were assayed by flow cytometry. In some cases, stimulation-induced calcium flux was also measured in primary patient cells. Three-fourths of PLCG2 variants produced functional alteration of B-cell activation, in vitro. Thirteen variants led to gain of function (GOF); however, most functional variants defined a new class of PLCG2 mutation, monoallelic loss of function (LOF). Susceptibility to infection and autoinflammation were common with both GOF and LOF variants, whereas a new phenotypic cluster consisting of humoral immune deficiency, autoinflammation, susceptibility to herpesvirus infection, and natural killer cell dysfunction was observed in association with multiple heterozygous LOF variants detected in both familial and sporadic cases. In some cases, PLCG2 variants produced greater effects in natural killer cells than in B cells. This work expands the genotypic and phenotypic associations with functional variation in PLCG2, including a novel form of ID in carriers of heterozygous loss of PLCG2 function. It also demonstrates the need for more diverse assays for assessing the impact of PLCG2 variants on human disease. [ABSTRACT FROM AUTHOR]

UBQLN1 functions in autophagy and proteasome-mediated protein degradation. It contains an N-terminal ubiquitin-like domain (UBL), a C-terminal ubiquitin-associated domain (UBA), and a flexible central region which functions as a chaperone to prevent protein aggregation. Here, we report the 1H, 15N, and 13C resonance assignments for the backbone (NH, N, C', Cα, and Hα) and sidechain Cβ atoms of the UBQLN1 UBA and an N-terminally adjacent segment called the UBA-adjacent domain (UBAA). We find a subset of the resonances corresponding to the UBAA to have concentration-dependent chemical shifts, likely due to self-association. We also find the backbone amide nitrogen of T572 to be shifted upfield relative to the average value for a threonine amide nitrogen, a phenomenon likely caused by T572 Hγ1 engagement in a hydrogen bond with adjacent backbone carbonyl atoms. The assignments described in this manuscript can be used to study the protein dynamics of the UBQLN1 UBA and UBAA as well as the interaction of these domains with other proteins. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less- differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen- experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less- differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt- driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies., Introduction Adoptive cell transfer (ACT), the ex vivo expansion and reinfusion of antigen-specific (Ag-specific) T cells, represents a potentially curative treatment for patients with advanced cancer (1-4) and viral-reactivation syndromes [...]