Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation

The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCRαβ and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαβ cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation

Experimental methods in phonosemantics: preliminary testing of the antonymic hypothesis as a way of mediating between the arbitrary nature of linguistic representation and aspects of iconism

The question of whether or not linguistic sounds might convey inherent meaning has never conclusively been resolved. This is an empirical study weighing evidence for and against the existence of phonosemantics, also known as sound symbolism or iconism. Contrary to well established principles such as the arbitrary nature of the sign and the double articulation, the phonosemantic hypothesis proposes that the sounds which compose a given word correlate with aspects of the meaning of that word by virtue of their articulatory features. 116 individuals of 19--73 years of age from both sexes were interviewed to determine their intuitions regarding potential meanings of linguistic sounds. The experiment consisted of three distinct parts. First, participants were asked to define nonsense words with their only cueing being the sound segments of the nonsense word. Second, for a given definition, participants were asked to create an appropriate-sounding nonsense word, uninfluenced by any real words. Finally, for a given image, participants were asked to create an appropriate-sounding nonsense word, uninfluenced by any real words. Participants' responses from the first part were analyzed for semantic patterns, while responses from the second and third parts were analyzed for phonic patterns. Data was interpreted according to the antonymic hypothesis, which states that iconism is most readily observable in articulations that can be set in antonymic contrast to other articulations. This includes points of articulation from the extremities of the vocal apparatus such as front, back, high, and low and manners of articulation such as stops and continuants. The data gathered presents little evidence in support of phonosemantics; hence, by default, the opposite case is made in support of arbitrary designative processes. However, it was determined that certain experimental procedures could be altered during future endeavors, perhaps leading to different results. This alteration primarily involves ways to better control extra-stimulus motivation (interference from real words) which was judged as the most crucial variable of the experimental process. (Published By University of Alabama Libraries

An Ig transmembrane domain motif improves the function of TCRs transduced in human T cells: Implications for immunotherapy

Adoptive transfer of T lymphocytes (ACT) engineered with T-cell receptors (TCRs) of known antitumor specificity is an effective therapeutic strategy. However, a major constraint of ACT is the unpredictable interference of the endogenous TCR α and β chains in pairing of the transduced TCR. This effect reduces the efficacy of the genetically modified primary T cells and carries the risk of generating novel TCR reactivities with unintended functional consequences. Here, we show a powerful approach to overcome these limitations. We engineered TCR α and β chains with mutations encompassing a conserved motif (FXXXFXXS) required to stabilize the pairing of immunoglobulin heavy chain transmembrane domains. Molecular modeling supported the preferential pairing of mutated TCR and impaired pairing between mutated and wild-type TCRs. Expression of the mutated TCR was similar to wild type and conferred the expected specificity. Fluorescence resonance energy transfer analysis in mouse splenocytes transduced with mutated or wild-type TCRs showed a higher proximity of the former over the latter. Importantly, we show that mutated TCRs effectively outcompete endogenous TCRs and improve in vitro antitumor cytotoxicity when expressed in ex vivo isolated human T cells. This approach should contribute to improving current protocols of anticancer immunetherapy protocols

The effects of authentic reading activities on the written production of novice college spanish students

Many scholars have researched reading-to-writing relations, some of which found reading to be an effective enhancer of writing (Al-Jarf, 2004; Asenciór, 2006; Lee, 1986a; Lee & Riley, 1990; Pérez-Sotelo & González-Bueno, 2003; Shang, 2007). Similar beginner college student samples were used previously by Asenciór (2006), Pérez-Sotelo and González-Bueno (2003), and Lee and Riley (1990). However, the current study was the first one to examine the effects of authentic readings on the written production of novice college Spanish students, especially on content/vocabulary and text organization. The present research included an experimental group and a control group. There were six written assignments over a 4-month period. The pretest and the posttest compared the overall writing abilities of the participating groups. During the treatment proper, the experimental group was asked to review four different authentic reading texts before writing, whereas the control group completed the assignments without any prior reading activity. The gains of the combined dependent variables content/vocabulary and text organization were analyzed. First, the results of the analysis of variance (ANOVA) gains in overall writing scores from pretest (Writing Assignment 1) to posttest (Writing Assignment 6) showed that authentic reading comprehension activities did not improve their writing abilities. Second, the results of the multivariate analysis of variance (MANOVA) performed on the gains from Writing Assignment 2 to Writing Assignment 5 in terms of content/vocabulary and text organization revealed that the experimental treatment did not have a statistically significant main effect on either one of the two dependent variables. However, group and gender had a statistically significant interactive effect on both dependent variables. Finally, the findings of the postexperimental survey administered to the participants in the experimental group revealed moderately positive attitudes toward the use of authentic readings prior to the writing assignments. The gender differences revealed by this investigation warrant further and more detailed research to determine possible underlying causes. (Published By University of Alabama Libraries

A unified analysis of the future as epistemic modality the view from Greek and Italian

International audienceWe offer an analysis of the Greek and Italian future morphemes as epistemic modal operators. The main empirical motivation comes from the fact that future morphemes have systematic purely epistemic readings-not only in Greek and Italian, but also in Dutch, German, and En-glish will. The existence of epistemic readings suggests that the future expressions quantify over epistemic, not metaphysical alternatives. We provide a unified analysis for epistemic and predic-tive readings as epistemic necessity, and the shift between the two is determined compositionally by the lower tense. Our account thus acknowledges a systematic interaction between modality and tense-but the future itself is a pure modal, not a mixed temporal/modal operator. We show that the modal base of the future is nonveridical, i.e. it includes p and ¬p worlds, parallel to epistemic modals such as must, and present arguments that future morphemes have much in common with epistemic modals and predicates of personal taste. We identify, finally, a subclass of epistemic futures which are ratificational, and argue that will is a member of this class