Highlights d Developed high-throughput assays for SpCas9 and performed a small-molecule screen d Identified reversible and cell-permeable inhibitors that disrupt SpCas9-DNA binding d Inhibitors allow dose and temporal control of (non)-nucleasebased SpCas9 systems d Identified a pharmacophore for SpCas9 inhibition using structure-activity studies

Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p < 0.001); frequent formations of tertiary lymphoid structures (p < 0.001); higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001); and higher expression of double-stranded RNA-activated protein kinase, which can be induced by interferons (p = 0.008). Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001). Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients’ responses to immunotherapy.

This study examined the Argument Structure Complexity Hypothesis (ASCH, [J. Neuroling. 16 (2003) 151]), by investigating agrammatic aphasic comprehension and elicited production of two types of intransitive verbs (i.e. unergatives and unaccusatives) in sentence contexts. The ASCH attributes production difficulty frequently observed in agrammatic aphasia to the argument structure entries of verbs, stating that verbs with a more complex argument structure (in terms of the number and type of arguments) are more difficult for agrammatic aphasic patients to produce than those with a less complex argument structure. Results showed that eight agrammatic aphasic subjects had production difficulty with unaccusative verb sentences, as compared to unergatives, in the face of near-normal comprehension of both sentence types. These findings support the ASCH that predicts production difficulty with sentences involving unaccusatives with more complex argument structures. Error patterns observed also indicated successful lemma access in that the full array of verb argument structures were produced during sentence attempts, suggesting that complex argument structures hinder appropriate processing after the lemma level.

A variety of studies have reported that learners of English as a second language find subject relative clauses easier to produce and comprehend than direct object relatives, but it is unclear whether this preference should be attributed to structural factors or to a linear distance effect. This paper seeks to resolve this issue and to extend our understanding of SLA in general by investigating the interpretation of subject and direct object relative clauses by English-speaking learners of Korean, a left-branching language in which subject gaps in relative clauses are more distant from the head than are object gaps. The results of a comprehension task conducted with 53 beginning and intermediate learners point toward a strong preference for subject relative clauses, favoring the structural account.