Every Minor-Closed Property of Sparse Graphs is Testable

Suppose $G$ is a graph with degrees bounded by $d$, and one needs to remove more than $\epsilon n$ of its edges in order to make it planar. We show that in this case the statistics of local neighborhoods around vertices of $G$ is far from the statistics of local neighborhoods around vertices of any planar graph $G'$ with the same degree bound. In fact, a similar result is proved for any minor-closed property of bounded degree graphs. As an immediate corollary of the above result we infer that many well studied graph properties, like being planar, outer-planar, series-parallel, bounded genus, bounded tree-width and several others, are testable with a constant number of queries, where the constant may depend on $\epsilon$ and $d$, but not on the graph size. None of these properties was previously known to be testable even with $o(n)$ queries

Generative Social Choice

Traditionally, social choice theory has only been applicable to choices among a few predetermined alternatives but not to more complex decisions such as collectively selecting a textual statement. We introduce generative social choice, a framework that combines the mathematical rigor of social choice theory with large language models' capability to generate text and extrapolate preferences. This framework divides the design of AI-augmented democratic processes into two components: first, proving that the process satisfies rigorous representation guarantees when given access to oracle queries; second, empirically validating that these queries can be approximately implemented using a large language model. We illustrate this framework by applying it to the problem of generating a slate of statements that is representative of opinions expressed as free-form text, for instance in an online deliberative process

Safety and efficacy of an intra-oral electrostimulator for the relief of dry mouth in patients with chronic graft versus host disease: case Series

Objectives: Patients with chronic graft-versus-host disease (cGVHD) often suffer from dry mouth and oral mu - cosal lesions. The primary objective of this study was to investigate the safety of an intra-oral electrostimulator (GenNarino) in symptomatic cGVHD patients. The secondary objective was to study the impact on the salivary gland involvement of cGVHD patients. Study Design: This paper presents a case series. The study included patients treated for 4 weeks, randomly as - signed to the active device and then crossed-over to a sham-device or vice versa. The patients and clinicians were blind to the treatment delivered. Data regarding oral mucosal and salivary gland involvement were collected. Results: Six patients were included in this series. Most of the intraoral areas with manifestations of cGVHD were not in contact with the GenNarino device. Two patients developed mild mucosal lesions in areas in contact with the GenNarino during the study. However, only one of them had a change in the National Institutes of Health (NIH) score for oral cGVHD. The unstimulated and stimulated salivary flow rate increased in 4 out of the 5 pa - tients included in this analysis. Symptoms of dry mouth and general oral comfort improved. Conclusion: This study suggests that GenNarino is safe in cGVHD patients with respect to oral tissues. Furthermore the use of GenNarino resulted in subjective and objective improvements in dry mouth symptoms. A large scale study is needed to confirm the impact and safety of GenNarino on systemic cGVHD

Removal of Hepatitis C Virus-Infected Cells by a Zymogenized Bacterial Toxin

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and has become a global health threat. No HCV vaccine is currently available and treatment with antiviral therapy is associated with adverse side effects. Moreover, there is no preventive therapy for recurrent hepatitis C post liver transplantation. The NS3 serine protease is necessary for HCV replication and represents a prime target for developing anti HCV therapies. Recently we described a therapeutic approach for eradication of HCV infected cells that is based on protein delivery of two NS3 protease-activatable recombinant toxins we named “zymoxins”. These toxins were inactivated by fusion to rationally designed inhibitory peptides via NS3-cleavable linkers. Once delivered to cells where NS3 protease is present, the inhibitory peptide is removed resulting in re-activation of cytotoxic activity. The zymoxins we described suffered from two limitations: they required high levels of protease for activation and had basal activities in the un-activated form that resulted in a narrow potential therapeutic window. Here, we present a solution that overcame the major limitations of the “first generation zymoxins” by converting MazF ribonuclease, the toxic component of the E. coli chromosomal MazEF toxin-antitoxin system, into an NS3-activated zymoxin that is introduced to cells by means of gene delivery. We constructed an expression cassette that encodes for a single polypeptide that incorporates both the toxin and a fragment of its potent natural antidote, MazE, linked via an NS3-cleavable linker. While covalently paired to its inhibitor, the ribonuclease is well tolerated when expressed in naïve, healthy cells. In contrast, activating proteolysis that is induced by even low levels of NS3, results in an eradication of NS3 expressing model cells and HCV infected cells. Zymoxins may thus become a valuable tool in eradicating cells infected by intracellular pathogens that express intracellular proteases

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected

Toxin-Based Therapeutic Approaches

Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin

The Israeli Idea of Intelligence: Anatomy of the Israeli National Intelligence Culture

The academic field of intelligence studies has acknowledged that different nations perceive and practice intelligence differently: i.e., that they have distinct national intelligence cultures drawing on distinct ideas of intelligence. However, while research into intelligence cultures is developing, it remains heavily focused on the US and UK. Meanwhile, although Israeli intelligence has received extensive attention through historical and practical perspectives, with studies focusing on analytical failures, counterterrorism, and covert operations, hitherto there has been no comprehensive study of it through a cultural lens. The thesis addresses this gap and offers a conceptualization (anatomy) of the Israeli national intelligence culture, by applying a strategic cultures framework and adopting a social constructivist research approach. It is based on 34 elite interviews with former and acting Israeli practitioners. The thesis finds that Israeli intelligence culture is distinctive in the way in which it rejects formal management of the intelligence system on the national level, preferring informal cooperation between agencies and pluralism of intelligence assessments. Intelligence in Israel is action-inclined and integrated in decision-making. It is also practice-inclined and has been averse to intelligence theories and scientific methods, preferring adaptation through bottom-up innovations. These characteristics reflect several sources: an Israeli strategic culture of exceptionalism arising from a sense of living under existential threats; a political culture of securitization; the historical origins of military intelligence dominance; and typical Israeli ‘chutzpah’. They also reflect lessons learned from two major traumas of Israeli intelligence: the Yom Kippur War in 1973, and the Second Lebanon War in 2006. The thesis argues that Israeli intelligence culture is not unitary in essence nor fixed in time. However, moral courage, contrarian thinking, individual responsibility, and a sense of national mission have persisted as its foundational professional values. They highlight the enduring status of intelligence as a core pillar of Israeli national security.</p

Learning Decision-Making Functions Given Cardinal and Ordinal Consensus Data

Decision-making and reaching consensus are an integral part of everyday life, and studying how individuals reach these decisions is an important problem in psychology, economics, and social choice theory. Our work develops methods and theory for learning the nature of decisions reached upon by individual decision makers or groups of individuals using data. We consider two tasks, where we have access to data on: 1) Cardinal utilities for d individuals with cardinal consensus values that the group or decision maker arrives at, 2) Cardinal utilities for d individuals for pairs of actions, with ordinal information about the consensus, i.e., which action is better according to the consensus. Under some axioms of social choice theory, the set of possible decision functions reduces to the set of weighted power means, M(u, w, p) = (∑ᵢ₌₁ᵈ wᵢ uᵢᵖ)¹ᐟᵖ, where uᵢ indicate the d utilities, w ∈ ∆_{d - 1} denotes the weights assigned to the d individuals, and p ∈ ℝ (Cousins 2023). For instance, p = 1 corresponds to a weighted utilitiarian function, and p = -∞ is the egalitarian welfare function. Our goal is to learn w ∈ ∆_{d - 1} and p ∈ ℝ for the two tasks given data. The first task is analogous to regression, and we show that owing to the monotonicity in w and p (Qi 2000}, learning these parameters given cardinal utilities and social welfare values is a PAC-learnable task. For the second task, we wish to learn w, p such that, given pairs of actions u, v ∈ ℝ₊ᵈ, the preference is given as C((u, v), w, p) = sign(ln(M(u, w, p)) - ln(M(v, w, p))). This is analogous to classification; however, convexity of the loss function in w and p is not guaranteed. We analyze two related cases - one in which the weights w are known, and another in which the weights are unknown. We prove that both cases are PAC-learnable given positive u, v by giving an O(log d) bound on the VC dimension for the known weights case, and an O(d log d) bound for the unknown weights case. We also establish PAC-learnability for noisy data under IID (Natarajan 2013) and logistic noise models for this task. Finally, we demonstrate how simple algorithms can be useful to learn w and p up to moderately high d through experiments on simulated data