Every Quantifier Isn\u27t the Same: Informativity Matters for Ambiguity Resolution in Quantifier-Negation Sentences

Empirical work on quantifier-not sentences has focused primarily on universal quantifiers, exploring the ambiguity that arises when logical operators interact (e.g., Everyone didn’t go could mean No one went or Not all went). In their Rational Speech Act model of this ambiguity resolution, Savinelli et al.(2017) demonstrate that pragmatic factors (such as model priors over the likely world states) stand to explain divergent behavior between children and adults. We extend this work to a broader empirical base, exploring the model\u27s predictions for sentences with a wider range of quantifiers (some, no); we then test those predictions against behavioral data collected in a series of experiments. We find that a straightforward extension of the Savinelli et al. model captures the range of quantifier-not behavior we gather, thereby providing strong support for this cognitive model of probabilistic ambiguity resolution. In particular, the model explains interpretation preferences on the basis of informativity and prior beliefs over world states, such that interpretations that are more informative are preferred

Corpus evidence for the role of world knowledge in ambiguity reduction: Using high positive expectations to inform quantifier scope

Every-negation utterances (e.g., Every vote doesn’t count) are ambiguous between a surface scope interpretation (e.g., No vote counts) and an inverse scope interpretation (e.g., Not all votes count). Investigations into the interpretation of these utterances have found variation: child and adult interpretations diverge (e.g., Musolino 1999) and adult interpretations of specific constructions show considerable disagreement (Carden 1973, Heringer 1970, Attali et al. 2021). Can we concretely identify factors to explain some of this variation and predict tendencies in individual interpretations? Here we show that a type of expectation about the world (which we call a high positive expectation), which can surface in the linguistic contexts of every-negation utterances, predicts experimental preferences for the inverse scope interpretation of different every-negation utterances. These findings suggest that (1) world knowledge, as set up in a linguistic context, helps to effectively reduce the ambiguity of potentiallyambiguous utterances for listeners, and (2) given that high positive expectations are a kind of affirmative context, negation use is felicitous in affirmative contexts (e.g., Wason 1961)

Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products

Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia

ObjectivesDespite advances in endovascular therapies, critical limb ischemia (CLI) continues to be associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. We sought to explore the feasibility of conducting a definitive trial of a bone marrow-derived cellular therapy for CLI in this “no option” population.MethodsA pilot, multicenter, prospective, randomized, double-blind, placebo-controlled trial for “no option” CLI patients was performed. The therapy consisted of bone marrow aspirate concentrate (BMAC), prepared using a point of service centrifugation technique and injected percutaneously in 40 injections to the affected limb. Patients were randomized to BMAC or sham injections (dilute blood). We are reporting the 12-week data.ResultsForty-eight patients were enrolled. The mean age was 69.5 years (range, 42-93 years). Males predominated (68%). Diabetes was present in 50%. Tissue loss (Rutherford 5) was present in 30 patients (62.5%), and 18 (37.5%) had rest pain without tissue loss (Rutherford 4). Patients were deemed unsuitable for conventional revascularization based on multiple prior failed revascularization efforts (24 [50%]), poor distal targets (43 [89.6%]), and medical risk (six [12.5%]). Thirty-four patients were treated with BMAC and 14 with sham injections. There were no adverse events attributed to the injections. Renal function was not affected. Effective blinding was confirmed; blinding index of 61% to 85%. Subjective and objective outcome measures were effectively obtained with the exception of treadmill walking times, which could only be obtained at baseline and follow-up in 15 of 48 subjects. This pilot study was not powered to demonstrate statistical significance but did demonstrate favorable trends for BMAC versus control in major amputations (17.6% vs 28.6%), improved pain (44% vs 25%), improved ankle brachial index (ABI; 32.4% vs 7.1%), improved Rutherford classification (35.3% vs 14.3%), and quality-of-life scoring better for BMAC in six of eight domains.ConclusionsIn this multicenter, randomized, double-blind, placebo-controlled trial of autologous bone marrow cell therapy for CLI, the therapy was well tolerated without significant adverse events. The BMAC group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls. This pilot allowed us to identify several areas for improvement for future trials and CLI studies. These recommendations include elimination of treadmill testing, stratification by Rutherford class, and more liberal inclusion of patients with renal insufficiency. Our strongest recommendation is that CLI studies that include Rutherford 4 patients should incorporate a composite endpoint reflecting pain and quality of life

The Grizzly, September 15, 2011

New CAB Events Coming This Fall • UC Commemorates 9/11 • CAB Hosts Activities Fair in Zack\u27s • GSA Welcomes New Board • Tips to Assist with Time Management • New Math Professor Brings Biostatistics Expertise • Peer Docent Program Returns to Berman • Senior Reminisces on Semester Spent Abroad • Opinions: Updated Sexual Assault Policy Needs Awareness; Libya Should Look to Spain When Rebuilding Government • Fast Start has Volleyball on Track for the Playoffs • Cross Country Eyes Continued Improvement in 2011 • Men\u27s Basketball Team Goes Abroadhttps://digitalcommons.ursinus.edu/grizzlynews/1839/thumbnail.jp

Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products