Derandomized Parallel Repetition via Structured PCPs

A PCP is a proof system for NP in which the proof can be checked by a probabilistic verifier. The verifier is only allowed to read a very small portion of the proof, and in return is allowed to err with some bounded probability. The probability that the verifier accepts a false proof is called the soundness error, and is an important parameter of a PCP system that one seeks to minimize. Constructing PCPs with sub-constant soundness error and, at the same time, a minimal number of queries into the proof (namely two) is especially important due to applications for inapproximability. In this work we construct such PCP verifiers, i.e., PCPs that make only two queries and have sub-constant soundness error. Our construction can be viewed as a combinatorial alternative to the "manifold vs. point" construction, which is the only construction in the literature for this parameter range. The "manifold vs. point" PCP is based on a low degree test, while our construction is based on a direct product test. We also extend our construction to yield a decodable PCP (dPCP) with the same parameters. By plugging in this dPCP into the scheme of Dinur and Harsha (FOCS 2009) one gets an alternative construction of the result of Moshkovitz and Raz (FOCS 2008), namely: a construction of two-query PCPs with small soundness error and small alphabet size. Our construction of a PCP is based on extending the derandomized direct product test of Impagliazzo, Kabanets and Wigderson (STOC 09) to a derandomized parallel repetition theorem. More accurately, our PCP construction is obtained in two steps. We first prove a derandomized parallel repetition theorem for specially structured PCPs. Then, we show that any PCP can be transformed into one that has the required structure, by embedding it on a de-Bruijn graph

Toward the KRW Composition Conjecture: Cubic Formula Lower Bounds via Communication Complexity

One of the major challenges of the research in circuit complexity is proving super-polynomial lower bounds for de-Morgan formulas. Karchmer, Raz, and Wigderson suggested to approach this problem by proving that formula complexity behaves "as expected" with respect to the composition of functions f * g. They showed that this conjecture, if proved, would imply super-polynomial formula lower bounds. The first step toward proving the KRW conjecture was made by Edmonds et al., who proved an analogue of the conjecture for the composition of "universal relations". In this work, we extend the argument of Edmonds et al. further to f * g where f is an arbitrary function and g is the parity function. While this special case of the KRW conjecture was already proved implicitly in Hastad\u27s work on random restrictions, our proof seems more likely to be generalizable to other cases of the conjecture. In particular, our proof uses an entirely different approach, based on communication complexity technique of Karchmer and Wigderson. In addition, our proof gives a new structural result, which roughly says that the naive way for computing f * g is the only optimal way. Along the way, we obtain a new proof of the state-of-the-art formula lower bound of n^{3-o(1)} due to Hastad

Metaphor in Sign Languages

Metaphor abounds in both sign and spoken languages. However, in sign languages, languages in the visual-manual modality, metaphors work a bit differently than they do in spoken languages. In this paper we explore some of the ways in which metaphors in sign languages differ from metaphors in spoken languages. We address three differences: (a) Some metaphors are very common in spoken languages yet are infelicitous in sign languages; (b) Body-part terms are possible in very specific types of metaphors in sign languages, but are not so restricted in spoken languages; (c) Similes in some sign languages are dispreferred in predicative positions in which metaphors are fine, in contrast to spoken languages where both can appear in these environments. We argue that these differences can be explained by two seemingly unrelated principles: the Double Mapping Constraint (Meir, 2010), which accounts for the interaction between metaphor and iconicity in languages, and Croft’s (2003) constraint regarding the autonomy and dependency of elements in metaphorical constructions. We further argue that the study of metaphor in the signed modality offers novel insights concerning the nature of metaphor in general, and the role of figurative speech in language

Amount definites

Our project in the paper is twofold. First, we present an analysis of weak definites in general. Second, we present an analysis of the Semitic state inflection and its role in determining strong and weak definiteness, and introduce a novel type of weak definites which we call amount definites. Adopting the choice-function analysis of (in)definiteness, we analyse weak definiteness as the application of a type-shifted definite determiner to a relational noun. This application results in the reinterpretation of the relational noun as functional. When this function is in turn applied to the possessor, the definiteness of the result depends on the definiteness of the possessor. In Hebrew, weak definites often take the form of noun phrases headed by a noun marked with construct-state inflection; the paper discusses the interpretation of all construct-state nouns as relational. In colloquial Hebrew, the type-shifted definite determiner used in the formation of weak definites may take the form of a numeral (or other amount nouns) marked with emphatic-state inflection. We name weak definites headed by emphatic-state amount nouns amount definites, and compare the properties of amount definites to those of definite noun phrases where the amount noun is marked with construct-state inflection, which are strong definites.Cet article a un double but. Il présente d’une part une analyse générale des définis faibles et d’autre part une analyse de la flexion en sémitique et de son rôle dans la détermination de la définitude faible ou forte. Nous introduisons un nouveau type de définis faibles que nous appelons les définis de quantité (‘amount definites’). En nous appuyant sur une caractérisation de la définitude et de l’indéfinitude en termes de fonction de choix, nous analysons les définis faibles comme résultant de l’application d’un déterminant défini monté en type à un nom relationnel. Cette application fait suite à la réinterprétation du nom relationnel en nom fonctionnel. Quand cette fonction s’applique à un possesseur, la définitude du résultat est fonction de la définitude du possesseur. En hébreu, les définis faibles prennent souvent la forme de syntagmes nominaux avec pour tête un nom à l’état construit ; l’article discute l’interprétation de tous les noms à l’état construit comme des noms relationnels. En hébreu parlé, le défini monté en type utilisé dans la formation des définis faibles peut prendre la forme d’un numéral (ou d’un autre nom de quantité) marqué par une flexion à l’état emphatique. Nous appelons définis de quantité (‘amount definites’) les définis faibles dont la tête est un nom de quantité marqué par une flexion à l’état emphatique et nous comparons les propriétés des définis de quantité aux propriétés des syntagmes nominaux dont la tête est un nom de quantité à l’état construit, ces derniers étant des définis forts

Enhancing Theory-of-Mind Discourse among Deaf Parents of Children with Hearing Loss

Children with hearing loss often have difficulties in the socio-emotional domain that can be attributed to a significant delay in the development of theory of mind (ToM). The current article describes a workshop aimed at enhancing deaf parents' awareness of the importance of ToM development and enriching parent-child conversations with developmentally appropriate mental state contents. Eight deaf mothers from mid- low SES background participated in six sessions and were guided to enrich their mental discourse while naturally interacting with their deaf children. The mothers' use of mental terms was assessed at the beginning and end of the program. Following their participation in the workshop, mothers used more mental terms when interacting with their children, explained more elaborately mental motives underlying people's behavior and described their children's personality by referring more frequently to their social likes and dislikes. We conclude that parental guidance that addresses parents' interests and needs can assist in enriching their mental discourse and mediation when interacting with their children. As parents are major agents in enhancing development of theory of mind, the reported change may have long-lasting effects on their children

A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson\u27s disease.A Novel Super-Resolution Microscopy Platform for Cutaneous Alpha-Synuclein Detection in Parkinson’s Disease

Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.This study was supported by Janssen Research & Development, LLC.Peer reviewe

Ectopic PDX-1 Expression Directly Reprograms Human Keratinocytes along Pancreatic Insulin-Producing Cells Fate

BACKGROUND: Cellular differentiation and lineage commitment have previously been considered irreversible processes. However, recent studies have indicated that differentiated adult cells can be reprogrammed to pluripotency and, in some cases, directly into alternate committed lineages. However, although pluripotent cells can be induced in numerous somatic cell sources, it was thought that inducing alternate committed lineages is primarily only possible in cells of developmentally related tissues. Here, we challenge this view and analyze whether direct adult cell reprogramming to alternate committed lineages can cross the boundaries of distinct developmental germ layers. METHODOLOGY/PRINCIPAL FINDINGS: We ectopically expressed non-integrating pancreatic differentiation factors in ectoderm-derived human keratinocytes to determine whether these factors could directly induce endoderm-derived pancreatic lineage and β-cell-like function. We found that PDX-1 and to a lesser extent other pancreatic transcription factors, could rapidly and specifically activate pancreatic lineage and β-cell-like functional characteristics in ectoderm-derived human keratinocytes. Human keratinocytes transdifferentiated along the β cell lineage produced processed and secreted insulin in response to elevated glucose concentrations. Using irreversible lineage tracing for KRT-5 promoter activity, we present supporting evidence that insulin-positive cells induced by ectopic PDX-1 expression are generated in ectoderm derived keratinocytes. CONCLUSIONS/SIGNIFICANCE: These findings constitute the first demonstration of human ectoderm cells to endoderm derived pancreatic cells transdifferentiation. The study represents a proof of concept which suggests that transcription factors induced reprogramming is wider and more general developmental process than initially considered. These results expanded the arsenal of adult cells that can be used as a cell source for generating functional endocrine pancreatic cells. Directly reprogramming somatic cells into alternate desired tissues has important implications in developing patient-specific, regenerative medicine approaches

A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson’s disease

Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status