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Objective: To examine whether putatively atypical neuronal activity during internal attention in ADHD yields insights into processes underlying emotion dysregulation. Methods: We used a word processing paradigm to assess neural activations in adults with ADHD ( N = 46) compared to controls ( N = 43). We measured effects of valence, applied partial-least squares correlation analysis to assess multivariate brainbehavior relationships and ran subgroup analyses to isolate results driven by pure ADHD ( N = 18). Results: During internal attention, ADHD, compared to controls, have (1) increased activation in the right angular gyrus (rAG), which appears driven by pure, not comorbid, ADHD and (2) diminished activation in the insula and fronto-striatal circuitry. Diminished activations were driven by negatively-valenced internal attention and negatively correlated with increased affective lability within the ADHD group. Conclusion: Internal attention in ADHD is associated with increased rAG activation, possibly reflecting difficulty converging external and internal information, and diminished activation within emotion regulation circuitry.

The widespread application of modern machine learning has increased the need for robust statistical algorithms. This work studies one such fundamental statistical measure known as the Tukey depth. We study the problem in the continuum (population) limit. In particular, we derive the associated necessary conditions, which take the form of a first-order partial differential equation. We discuss the classical interpretation of this necessary condition as the viscosity solution of a Hamilton-Jacobi equation, but with a non-classical Hamiltonian with discontinuous dependence on the gradient at zero. We prove that this equation possesses a unique viscosity solution and that this solution always bounds the Tukey depth from below. In certain cases, we prove that the Tukey depth is equal to the viscosity solution, and we give some illustrations of standard numerical methods from the optimal control community which deal directly with the partial differential equation. We conclude by outlining several promising research directions both in terms of new numerical algorithms and theoretical challenges.

In this work we study statistical properties of graph-based clustering algorithms that rely on the optimization of balanced graph cuts, the main example being the optimization of Cheeger cuts. We consider proximity graphs built from data sampled from an underlying distribution supported on a generic smooth compact manifold $${\mathcal {M}}$$ M . In this setting, we obtain high probability convergence rates for both the Cheeger constant and the associated Cheeger cuts towards their continuum counterparts. The key technical tools are careful estimates of interpolation operators which lift empirical Cheeger cuts to the continuum, as well as continuum stability estimates for isoperimetric problems. To the best of our knowledge the quantitative estimates obtained here are the first of their kind.

Based on an affective neuroscience approach to appraisal theories of emotion, the present study tested the hypothesis that the amygdala is involved in the processing of concern-relevance. Thirty-five students with varying intrinsic academic intrinsic motivation performed three target detection tasks (i.e. targets vs. nontargets) using affectively neutral letter stimuli as targets. In one task, participants were given a cover story that their task-performance was indicative of future academic success. This intrinsic motivation task was controlled with two other tasks: an extrinsic motivation task allowing participants to earn money for themselves based on their task-performance, and a baseline task where participants were simply requested to perform the task while we were calibrating the scanner. Results illustrated an interaction effect both at the whole-brain and region-of-interest levels. When accounting for all three conditions, only during the intrinsic motivation condition did bilateral amygdala activation significantly increase with increasing academic intrinsic motivation scores when responding to targets (versus nontargets). Findings suggest inter-individual intrinsic motivations modulate amygdala response to otherwise neutral stimuli, consistently with the proposal that the amygdala is sensitive to the degree to which stimuli are relevant to the individual’s concerns. This stresses the need for more personalized analyses of brain responses to stimuli and tasks that are typically considered as “neutral” and hold important implications for psychiatric populations suffering from deficiencies in affective processing, particularly anxiety disorders.

Habitual behavior has been identified as a key process involved in a variety of mental health disorders. Previous research has shown that habit is not a unitary construct. The present study examined how different components of habitual behavior relate to problematic reward-seeking behaviors and compulsive behaviors. Four hundred and one participants completed a French version of the Creature of Habit Scale, which measures two components of habitual behavior: routine and automaticity. Participants also completed questionnaires assessing compulsivity, impulsivity, stress, and a variety of problematic reward-seeking behaviors, from which five transdiagnostic factors were extracted using an exploratory factor analysis. A dynamic network analysis indicated that the two habitual behavior components were differentially related to these transdiagnostic factors: routine was associated to compulsivity, while automaticity was associated to problematic media consumption. These findings suggest that taking the non-unitary architecture of habit into account may help to better understand the role of habit in mental health.

Recent numerical simulations have shown the existence of multiple self-similar solutions to the Cauchy problem for the 2-dimensional incompressible Euler equation, with initial vorticity in L l o c p ( R 2 ) , 1 ≤ p + ∞ . Toward a rigorous validation of these computations, in this paper we analytically construct self-similar solutions (i) on an outer domain of the form { | x | > R } , and (ii) in a neighborhood of the points where the solution exhibits a spiraling vortex singularity. The outer solution is obtained as the fixed point of a contractive transformation, based on the Biot-Savart formula and integration along characteristics. The inner solution is constructed using a system of adapted coordinates, following the approach of V. Elling (2016) [17] .

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.

Secondary restless legs syndrome is now considered one of the most common disorders you have never heard of. With a prevalence of around 5 to 15%, this disorder affects a significant portion of the population and therefore requires attention. The objective of this review was to look at all of the possible secondary causes of restless legs syndrome and whether there is strong enough evidence to support these associations. It is now widely accepted that the first depiction of possible RLS was outlined in 1672 by the well-known English Physician Sir Thomas Willis. Restless legs syndrome diagnoses has to meet the criteria set out by the international restless legs syndrome study group (IRLSSG). Restless legs syndrome can present in many various forms and can occur at any time throughout life. Patients who suffer from restless legs syndrome will often experience motor and sensory symptoms, or one of the two components. There are also other associated features such as sleep disturbances and fatigue, that can often negatively affect the quality of life of the sufferer. Restless legs syndrome can be treated with various nonpharmacological and pharmacological options. In this review we found a strong association between restless legs syndrome and iron deficiency, renal disease and pregnancy. Parkinson’s disease, essential tremor, some neuropathies and familial ataxias also showed some strong evidence towards an increase in the prevalence of restless legs syndrome in these disorders, however more long-term studies need to be done. We looked at many other possible associations, such as multiple sclerosis, myelinopathy, fibromyalgia and stroke. These, however, lack concrete findings to their associations, with possible alternative factors contributing to these associations with restless legs syndrome. It is important that restless legs syndrome sufferers be identified. Patients with mild symptoms, might simply need reassurance, while more moderate to severe symptoms might need pharmacological treatment. It is imperative that these secondary causes be screened when making the diagnosis of restless legs syndrome, as by treating them the symptoms of restless legs syndrome may be resolved and therefore not require other treatment modalities specific to restless legs syndrome., Pacijenti koji pate od sindroma nemirnih nogu često će imati motoričke i senzorne simptome, ili jednu od dvije komponente. Postoje i druge povezane značajke poput poremećaja spavanja i umora, koje često mogu negativno utjecati na kvalitetu života oboljelog. Sindrom nemirnih nogu može se liječiti raznim nefarmakološkim i farmakološkim mogućnostima. U ovom smo pregledu pronašli snažnu povezanost između sindroma nemirnih nogu i nedostatka željeza, bolesti bubrega i trudnoće. Parkinsonova bolest, esencijalni tremor, neke neuropatije i obiteljske ataksije također su pokazali neke snažne dokaze o Sekundarni sindrom nemirnih nogu sada se smatra jednim od najčešćih poremećaja za koji nikada niste čuli. S prevalencijom od oko 5 do 15%, ovaj poremećaj pogađa značajan dio populacije i zato zahtijeva pažnju. Cilj ovog pregleda bio je sagledati sve moguće sekundarne uzroke sindroma nemirnih nogu i postoje li dovoljno snažni dokazi koji podupiru ove asocijacije. Sada je široko prihvaćeno da je prvi prikaz mogućeg RLS-a izložio 1672. godine poznati engleski liječnik Sir Thomas Willis. Dijagnoze sindroma nemirnih nogu moraju udovoljavati kriterijima koje je postavila međunarodna istraživačka skupina za sindrom nemirnih nogu (IRLSSG). Sindrom nemirnih nogu može se pojaviti na mnogo različitih načina i može se javiti povećanju prevalencije sindroma nemirnih nogu kod ovih poremećaja, međutim potrebno je napraviti dugoročnija ispitivanja. Pregledali smo mnoge druge moguće povezanosti, poput multiple skleroze, mijelinopatije, fibromialgije i moždanog udara. Njima, međutim, nedostaju konkretni nalazi o njihovim udrugama, a mogući alternativni čimbenici doprinose tim udruženjima sa sindromom nemirnih nogu. Važno je identificirati oboljele od sindroma nemirnih nogu. Pacijentima s blagim simptomima možda će jednostavno trebati osiguranje, dok umjerenim do težim simptomima može biti potrebno farmakološko liječenje. Ove sekundarne uzroke morat će se pregledati prilikom postavljanja dijagnoze sindroma nemirnih nogu, jer se njihovim liječenjem simptomi sindroma nemirnih nogu mogu riješiti i stoga ne zahtijevaju druge modalitete liječenja specifične za sindrom nemirnih nogu.

Despite the high prevalence and economic burden of chronic kidney disease (CKD) in the United States, federal funding for kidney-related research, prevention, and education activities under the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) remains substantially lower compared to other chronic diseases. More federal support is needed to promote critical research that will expand knowledge of kidney health and disease, develop new and effective therapies, and reduce health disparities. In 2021, the National Kidney Foundation (NKF) convened 2 Research Roundtables (preclinical and clinical research), comprising nephrology leaders from prominent US academic institutions and the pharmaceutical industry, key bodies with expertise in research, and including individuals with CKD and their caregivers and kidney donors. The goal of these roundtables was to identify priorities for preclinical and clinical kidney-related research. The research priorities identified by the Research Roundtables and presented in this position statement outline attainable opportunities for groundbreaking and critically needed innovations that will benefit patients with kidney disease in the next 5-10 years. Research priorities fall within 4 preclinical science themes (expand data science capability, define kidney disease mechanisms and utilize genetic tools to identify new therapeutic targets, develop better models of human disease, and test cell-specific drug delivery systems and utilize gene editing) and 3 clinical science themes (expand number and inclusivity of clinical trials, develop and test interventions to reduce health disparities, and support implementation science). These priorities in kidney-related research, if supported by additional funding by federal agencies, will increase our understanding of the development and progression of kidney disease among diverse populations, attract additional industry investment, and lead to new and more personalized treatments.

This paper completely resolves the asymptotic development of order 2 2 by Γ \Gamma -convergence of the mass-constrained Cahn–Hilliard functional. Important new results on the slow motion of interfaces for the mass preserving Allen–Cahn equation and the Cahn–Hilliard equations in higher dimension are obtained as an application.

Kidney disease is an important US public health problem because it affects over 37 million Americans, and Medicare expenditures for patients with chronic kidney disease now alone exceed $130 billion annually. Kidney disease is characterized by strong racial, ethnic, and socioeconomic disparities, and reducing kidney disease incidence will positively impact US health disparities. Due to the aging of the US population and an unabated obesity epidemic, the number of patients receiving treatment for kidney failure is anticipated to increase, which will escalate kidney disease health expenditures. The historical and current investment in kidney-related research via the National Institute of Diabetes and Digestive and Kidney Diseases has severely lagged behind ongoing expenditures for kidney disease care. Increasing research investment will identify, develop, and increase implementation of interventions to slow kidney disease progression, reduce incidence of kidney failure, enhance survival, and improve quality of life. This perspective states the urgent reasons why increasing investment in kidney-related research is important for US public health. The National Kidney Foundation and the American Society of Nephrology are working together to advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases. The long-term goal is to reduce the burden of kidney disease in the US population and improve the quality of life of patients living with kidney disease.

We establish an equivalence between a family of adversarial training problems for non-parametric binary classification and a family of regularized risk minimization problems where the regularizer is a nonlocal perimeter functional. The resulting regularized risk minimization problems admit exact convex relaxations of the type $L^1+\text{(nonlocal)}\operatorname{TV}$, a form frequently studied in image analysis and graph-based learning. A rich geometric structure is revealed by this reformulation which in turn allows us to establish a series of properties of optimal solutions of the original problem, including the existence of minimal and maximal solutions (interpreted in a suitable sense) and the existence of regular solutions (also interpreted in a suitable sense). In addition, we highlight how the connection between adversarial training and perimeter minimization problems provides a novel, directly interpretable, statistical motivation for a family of regularized risk minimization problems involving perimeter/total variation. The majority of our theoretical results are independent of the distance used to define adversarial attacks.

The paper considers distributed gradient flow (DGF) for multi-agent nonconvex optimization. DGF is a continuous-time approximation of distributed gradient descent that is often easier to study than its discrete-time counterpart. The paper has two main contributions. First, the paper considers optimization of nonsmooth, nonconvex objective functions. It is shown that DGF converges to critical points in this setting. The paper then considers the problem of avoiding saddle points. It is shown that if agents' objective functions are assumed to be smooth and nonconvex, then DGF can only converge to a saddle point from a zero-measure set of initial conditions. To establish this result, the paper proves a stable manifold theorem for DGF, which is a fundamental contribution of independent interest. In a companion paper, analogous results are derived for discrete-time algorithms.

BackgroundT-cell lymphomas and leukemias are a class of diseases lacking durable effective therapies, where median survival for patients suffering from relapsed/refractory disease is often measured in months. Translation of B-cell targeting CAR-T therapeutic success to T-cell malignancies comes with significant challenges. Notably, the shared expression of target antigens on malignant T-cells and in the T-cell product itself results in CAR-T activation and fratricide during manufacturing. To overcome the challenges associated with creating CD5-targeting CAR-Ts, we developed a process to simultaneously base edit five target genes, including CD5 and PD1, to produce potency-enhanced allogeneic anti-CD5 CAR T-cells for use as an off-the-shelf treatment for T-cell malignancies.MethodsAnti-CD5 CAR-Ts were produced in a GMP-compatible process using T-cells isolated from healthy human donors. T-cells were modified using base editing technology to simultaneously knock-out five target genes in a single electroporation step. Edited T-cells were transduced with a lentivirus encoding a second-generation anti-CD5 CAR. Knockout frequencies were evaluated by flow cytometry and next-generation sequencing. Anti-CD5 CAR-Ts were then characterized for their specificity in vitro and potency in in vivo xenograft tumor models.ResultsSimultaneous base editing at five genomic loci resulted in anti-CD5 CAR-Ts edited with 94–98% efficiency at each target gene, greatly diminishing the likelihood of GvHD, CAR-T rejection, fratricide, and checkpoint inhibitor activation. In addition, CD5 has an established role as a negative regulator of TCR signaling, and T cells lacking CD5 have enhanced proliferative capacity.1 Anti-CD5 CAR T-cells with or without CD5 KO demonstrated equally potent cytotoxicity and cytokine production in vitro against CD5 expressing tumor lines. However, CD5 KO greatly improved in vivo efficacy of anti-CD5 CAR-Ts in a murine model of T-ALL against established tumor xenografts. Mice previously cleared of tumor underwent a second tumor challenge to assess the persistence of anti-CD5 CAR-T cells and were cleared of tumor a second time, indicating extended persistence of functional anti-CD5 CAR-T cells in vivo.ConclusionsOur approach addresses current technological limitations in developing and applying CAR-Ts that target T-cell malignancies and demonstrates that simultaneous multiplex base editing of up to five targets can create universally compatible, fratricide-resistant, therapeutically active anti-CD5 CAR-Ts. We further demonstrate that CD5 knockout produces CAR-T cells with enhanced potency capable of clearing multiple tumor challenges in vivo. We are progressing this CD5-targeting CAR-T cell product towards potential clinical development for the treatment of T cell malignancies and other CD5+ hematological tumors.ReferenceGuillaume V, Peredo G, Romain R. CD5, an Undercover Regulator of TCR Signaling. Frontiers in Immunology 2018;9:2900.Ethics ApprovalAll animal studies were performed according to the guidelines and approval of the Institutional Animal Care and Use Committee.

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34

The paper studies a distributed gradient descent (DGD) process and considers the problem of showing that in nonconvex optimization problems, DGD typically converges to local minima rather than saddle points. The paper considers unconstrained minimization of a smooth objective function. In centralized settings, the problem of demonstrating nonconvergence to saddle points of gradient descent (and variants) is typically handled by way of the stable-manifold theorem from classical dynamical systems theory. However, the classical stable-manifold theorem is not applicable in distributed settings. The paper develops an appropriate stable-manifold theorem for DGD showing that convergence to saddle points may only occur from a low-dimensional stable manifold. Under appropriate assumptions (e.g., coercivity), this result implies that DGD typically converges to local minima and not to saddle points.

This paper investigates the use of methods from partial differential equations and the Calculus of variations to study learning problems that are regularized using graph Laplacians. Graph Laplacians are a powerful, flexible method for capturing local and global geometry in many classes of learning problems, and the techniques developed in this paper help to broaden the methodology of studying such problems. In particular, we develop the use of maximum principle arguments to establish asymptotic consistency guarantees within the context of noise corrupted, non-parametric regression with samples living on an unknown manifold embedded in $\mathbb{R}^d$. The maximum principle arguments provide a new technical tool which informs parameter selection by giving concrete error estimates in terms of various regularization parameters. A review of learning algorithms which utilize graph Laplacians, as well as previous developments in the use of differential equation and variational techniques to study those algorithms, is given. In addition, new connections are drawn between Laplacian methods and other machine learning techniques, such as kernel regression and k-nearest neighbor methods.

Environmental variation can play an important role in ecological competition by influencing the relative advantage between competing species. Here, we consider such effects by extending a classical, competitive Moran model to incorporate an environment that fluctuates periodically in time. We adapt methods from work on these classical models to investigate the effects of the magnitude and frequency of environmental fluctuations on two important population statistics: the probability of fixation and the mean time to fixation. In particular, we find that for small frequencies, the system behaves similar to a system with a constant fitness difference between the two species, and for large frequencies, the system behaves similar to a neutrally competitive model. Most interestingly, the system exhibits nontrivial behavior for intermediate frequencies. We conclude by showing that our results agree quite well with recent theoretical work on competitive models with a stochastically changing environment, and discuss how the methods we develop ease the mathematical analysis required to study such models.

This work provides a rigorous framework for studying continuous-time control problems in uncertain environments. The framework models uncertainty in state dynamics as a probability measure on the space of functions. Such a probability measure is permitted to change over time as agents learn about their environment. This model can be seen as a variant of either Bayesian reinforcement learning (RL) or adaptive optimal control. We study conditions for locally optimal trajectories within this model, in particular deriving an appropriate dynamic programming principle and Hamilton–Jacobi equations. Some discussion of variants of the model are also provided, including one potential framework for studying the tradeoff between exploration and exploitation in RL.

The goal of this paper is to solve a long standing open problem, namely, the asymptotic development of order $2$ by $\Gamma$-convergence of the mass-constrained Cahn-Hilliard functional. This is achieved by introducing a novel rearrangement technique, which works without Dirichlet boundary conditions.

Any vaginal product that alters the mucosal environment and impairs the immune barrier increases the risk of sexually transmitted infections, especially HIV infection, which thrives on mucosal damage and inflammation. The FDA-recommended rabbit vaginal irritation (RVI) model serves as a first line selection tool for vaginal products; however, for decades it has been limited to histopathology scoring, insufficient to select safe anti-HIV microbicides. In this study we incorporate to the RVI model a novel quantitative nuclease protection assay (qNPA) to quantify mRNA levels of 25 genes representing leukocyte differentiation markers, toll-like receptors (TLR), cytokines, chemokines, epithelial repair, microbicidal and vascular markers, by designing two multiplex arrays. Tissue sections were obtained from 36 rabbits (6 per treatment arm) after 14 daily applications of a placebo gel, saline, 4% nonoxynol-9 (N-9), and three combinations of the anti-HIV microbicides tenofovir (TFV) and UC781 in escalating concentrations (highest: 10% TFV+2.5%UC781). Results showed that increased expression levels of toll-like receptor (TLR)-4, interleukin (IL)-1β, CXCL8, epithelial membrane protein (EMP)-1 (P

The paper studies the convergence properties of (continuous) best-response dynamics from game theory. Despite their fundamental role in game theory, best-response dynamics are poorly understood in many games of interest due to the discontinuous, set-valued nature of the best-response map. The paper focuses on elucidating several important properties of best-response dynamics in the class of multi-agent games known as potential games---a class of games with fundamental importance in multi-agent systems and distributed control. It is shown that in almost every potential game and for almost every initial condition, the best-response dynamics (i) have a unique solution, (ii) converge to pure-strategy Nash equilibria, and (iii) converge at an exponential rate.

The note considers normalized gradient descent (NGD), a natural modification of classical gradient descent (GD) in optimization problems. A serious shortcoming of GD in non-convex problems is that GD may take arbitrarily long to escape from the neighborhood of a saddle point. This issue can make the convergence of GD arbitrarily slow, particularly in high-dimensional non-convex problems where the relative number of saddle points is often large. The paper focuses on continuous-time descent. It is shown that, contrary to standard GD, NGD escapes saddle points `quickly.' In particular, it is shown that (i) NGD `almost never' converges to saddle points and (ii) the time required for NGD to escape from a ball of radius $r$ about a saddle point $x^*$ is at most $5\sqrt{\kappa}r$, where $\kappa$ is the condition number of the Hessian of $f$ at $x^*$. As an application of this result, a global convergence-time bound is established for NGD under mild assumptions.

A fundamental problem with the Nash equilibrium concept is the existence of certain “structurally deficient” equilibria that (i) lack fundamental robustness properties, and (ii) are difficult to analyze. The notion of a “regular” Nash equilibrium was introduced by Harsanyi. Such equilibria are isolated, highly robust, and relatively simple to analyze. A game is said to be regular if all equilibria in the game are regular. In this paper it is shown that almost all potential games are regular. That is, except for a closed subset with Lebesgue measure zero, all potential games are regular. As an immediate consequence of this, the paper also proves an oddness result for potential games: In almost all potential games, the number of Nash equilibrium strategies is finite and odd. Specialized results are given for weighted potential games, exact potential games, and games with identical payoffs. Applications of the results to game-theoretic learning are discussed.

Autologous CAR-T therapies have demonstrated remarkable efficacy in treating some hematologic cancers. While these therapies can have substantial clinical benefit for patients, generating bespoke cell therapies creates manufacturing challenges, resulting in inconsistent products and delays in treatment that are often incompatible with effective clinical management of patients. Strategies to create universally-compatible CAR-T therapies, generated from single donors for the treatment of many patients, have been developed as a solution to these challenges, thereby reducing cost of goods, lot-to-lot variability and enabling timely treatment. Mitigating the risks of graft-versus-host-disease (GvHD) and host rejection of CAR-Ts are important components of any strategy to generate these universal therapies. Most first generation approaches utilize DNA double strand break (DSB)-inducing nucleases to ablate the expression of relevant genes in donor T cells to overcome these barriers. However, simultaneous induction of multiple DSBs results in a cell population containing genomic rearrangements, and can lead to significantly reduced cell proliferation. Approaches to develop CAR-T therapies for T cell malignancies, such as T-ALL, encounter additional challenges, including extensive fratricide caused by targeting T cell surface markers such as CD3 and CD7, which are present on both the malignant and the CAR-T cells. Resolving this issue requires additional gene editing, leading to, in the case of nuclease-based strategies, an increased number of DSBs, further genomic rearrangements, and decreased cell expansion. Base editors (BEs) are a novel class of gene editing reagents that enable programmable, single-base changes in genomic DNA without creating DSBs. Work in the Qasim lab has demonstrated proof of concept for an alternative means of producing universal, fratricide-resistant CAR-T cells for treating T cell malignancies by using cytosine base editor (CBE) technology. Here, we demonstrate a previously-unpublished CBE that produces greatly diminished off-target effects while preserving on-target activity. Using multiplex base editing, we demonstrate simultaneous knockout of four genes (TRAC, CD7, CD52, and PDCD1) with between 80-95% efficiency, producing engineered CAR-T cells with greatly diminished risk of GvHD, graft cell rejection, fratricide, and exhaustion. We show that, in contrast to nuclease editing, concurrent modification of four genetic loci using our reduced off-target CBE produces highly efficient gene knockouts with no detectable genomic rearrangements and no observable change in cell expansion compared to control conditions. T-ALL is a heterogeneous disease with variable expression of CD3 and CD7 across tumor cells in the same patient. To reduce the risk of antigen escape by tumor cells during the course of treatment with base edited CAR-Ts, we envisioned creating two independent CAR-T populations targeting CD3 (3CAR-Ts) or CD7 (7CAR-Ts). Alone or in combination, base edited 3CAR-Ts and 7CAR-Ts demonstrate robust cytokine release, potent in vitro cytotoxicity, and in vivo tumor control with antigen-positive tumor cells, and display minimal antigen-independent activity. Taken together, our approach addresses existing limitations in CAR-T cell manufacturing and demonstrates that simultaneous base editing using an improved specificity CBE at four target genes is a feasible strategy for generating universal, fratricide-resistant CAR-T cells for the potential treatment of T cell malignancies such as T-ALL. More generally, this program demonstrates the potential for base editing to create highly-engineered cell therapies featuring at least four simultaneous edits, which can confer a wide range of desirable therapeutic attributes. Disclosures Qasim: CellMedica: Research Funding; Bellicum: Research Funding; Servier: Research Funding; Orchard Therapeutics: Equity Ownership; UCLB: Other: revenue share eligibility; Autolus: Equity Ownership.

The goal of this paper is to study the slow motion of solutions of the nonlocal Allen–Cahn equation in a bounded domain \(\Omega \subset \mathbb {R}^n\), for \(n > 1\). The initial data is assumed to be close to a configuration whose interface separating the states minimizes the surface area (or perimeter); both local and global perimeter minimizers are taken into account. The evolution of interfaces on a time scale \(\varepsilon ^{-1}\) is deduced, where \(\varepsilon \) is the interaction length parameter. The key tool is a second-order \(\Gamma \)-convergence analysis of the energy functional, which provides sharp energy estimates. New regularity results are derived for the isoperimetric function of a domain. Slow motion of solutions for the Cahn–Hilliard equation starting close to global perimeter minimizers is proved as well.

Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

This work considers the problem of binary classification: given training data x1, . . ., xn from a certain population, together with associated labels y1,. . ., yn ∈ {0,1}, determine the best label for an element x not among the training data. More specifically, this work considers a variant of the regularized empirical risk functional which is defined intrinsically to the observed data and does not depend on the underlying population. Tools from modern analysis are used to obtain a concise proof of asymptotic consistency as regularization parameters are taken to zero at rates related to the size of the sample. These analytical tools give a new framework for understanding overfitting and underfitting, and rigorously connect the notion of overfitting with a loss of compactness.

Two types of solute-solute interactions are investigated in this work. Quadrupole interactions caused by nearby Ag-solute atoms were measured at nuclei of 111In/Cd solute probe atoms in the binary compound GdAl2 using the method of perturbed angular correlation of gamma rays (PAC). Locations of In-probes and Ag-solutes on both Gd- and Al-sublattices were identified by comparing site fractions in Gd-poor and Gd-rich GdAl2(Ag) samples. Interaction enthalpies between solute-atom pairs were determined from temperature dependences of observed site fractions. Repulsive interactions were observed for close-neighbor complexes In/Gd/+Ag/Gd/ and In/Gd/+Ag/Al/ pairs, whereas a slightly attractive interaction was observed for In/Al/+Ag/Al/. Interaction enthalpies were all in the range +/- 0.15 eV. Temperature dependences of site fractions of In-probes on locally defect-free Gd- and Al-sites yields a transfer enthalpy that was found to be 0.343 eV in a previous study of undoped GdAl2. The corresponding values in GdAl2(Ag) samples are much smaller. This is attributed to competition of In- and Ag-solutes to occupy sites of the same sublattice. While the difference in site-enthalpies of In-solutes on Gd- and Al-sites is temperature independent, it is proposed that the transfer of Ag-solutes from Gd- to Al-sites leads to a large temperature dependence of degeneracies of levels available to In-solutes, resulting in an effective transfer enthalpy that is much smaller than the difference in site-enthalpies., Comment: 17 pages, 6 figures, 2 tables. To be presented at the International Conference on Hyperfine Interactions and Their Applications, July 3-8, 2016, Leuven, Belgium; www.hyperfine2016.be/

We examined the implicit acquisition and mental representation of a novel verb in patients with probable Alzheimer’s disease (AD). Patients were exposed to the new verb in a naturalistic manner as part of a simple picture story. We probed grammatical, semantic and thematic matrix knowledge of the verb soon after presentation and again one week later. We found partial verb acquisition that was retained over one week. AD patients did not differ from controls in their acquisition and retention of a new verb’s major grammatical subcategory, although they acquired little of its semantic properties and displayed minimal acquisition of the new word’s thematic matrix. Moreover, AD patients appeared to maintain their acquired grammatical knowledge over one week. We discuss the implications of these findings from several perspectives, including the modularity of the language processing system, the relationship between episodic memory and semantic memory, and the role of the preserved implicit memory system in AD patients’ partially successful lexical acquisition.

Numerous immune-suppressive mechanisms exist within the tumor microenvironment that may hinder chimeric antigen receptor (CAR) T cell efficacy. One such mechanism is mediated by TGF-β, a cytokine secreted by tumor cells and infiltrating suppressive immune cells that directly inhibits effector T cell activity. Effector T cells express the TGF-β receptors TGFBR1 and TGFBR2, and exposure of T cells to TGF-β induces phosphorylation of the major TGF-β signal mediators SMAD2 and SMAD3. Phosphorylated SMAD proteins (pSMADs) induce a suppressive transcriptional program that ultimately leads to reduced cytokine production, reduced cytotoxicity, and a failure to proliferate in response to antigen stimulation. A dominant negative receptor version (DNR) of TGFBR2 that does not contain signaling domains protects T cells from the impacts of TGF-β by blocking the ability of TGF-β to induce pSMADs. Here, we report the development of a novel TGF-β signal conversion platform that provides a T cell stimulatory signal upon exposure to TGF-β. This platform utilizes co-expression of chimeric variants of TGFBR2 and TGFBR1 where the TGF-β-binding domain of each receptor is fused to the transmembrane and intracellular signaling domains of the T cell simulating IL-12 receptors IL-12R-β2 and IL-12R-β1, respectively. Using a single lentiviral vector encoding both chimeric TGF-β receptors (CTBR) and a CAR, we demonstrated that CAR-CTBR T cells were completely protected from TGF-β-mediated SMAD phosphorylation. In addition, CAR-CTBR T cells generated significant amounts of pSTAT4 and pSTAT5 in response to TGF-β exposure, a response that mimics the T cell stimulation effects of IL-12. To further demonstrate successful signal conversion, we evaluated the impact of TGF-β exposure on the secretion of IFNγ, a major downstream target of IL-12 signaling. CAR-CTBR cells secreted significantly greater amounts of IFNγ than either control CAR T or CAR-DNR T cells following activation in the presence of TGF-β. Lastly, we utilized a serial restimulation assay to expand CAR, CAR-DNR, and CAR-CTBR T cells in the presence or absence of TGF-β. As expected, TGF-β exposure resulted in a significant inhibition of T cell proliferation in control CAR T cells. By contrast, both CAR-DNR and CAR-CTBR cells were protected from TGF-β-mediated inhibition of expansion. Gene expression analysis following 21 days of weekly antigen-driven expansion revealed specific TGF-β-mediated gene expression changes in CAR-CTBR cells consistent with increased T cell potency, including significant upregulation of IFNγ, IL10, IL18RAP, IL18R1, IL21R and CD62L transcripts. These data demonstrate the successful development of a TGF-β signal conversion platform that transforms the inhibitory effects of TGF-β exposure into an IL-12R-like T cell stimulatory signal that has the potential to produce superior CAR T cell responses in vivo. Note: This abstract was not presented at the meeting. Citation Format: Benjamin Boyerinas, Sara Miller, Ryan Murray, Stacie Seidel, Geoffrey Parsons, Kathy Seidl, Kevin Friedman, Richard Morgan. A novel TGF-β/IL-12R signal conversion platform that protects CAR T cells from TGF-β-mediated immune suppression and concurrently amplifies effector function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 602. doi:10.1158/1538-7445.AM2017-602

MoS2 is a promising two-dimensional material that is being considered as a replacement for Si in sub-5 nm device technologies. Integration could include the growth or transfer of large areas of MoS2 films onto Si wafers. Subsequent isolation of devices fabricated on MoS2 films is an open research area that has received little attention. Although reactive ion etching or chemical etching can be used to create isolated channels, these techniques are problematic due to the weak van der Waals interaction between the two-dimensional films and their substrates. Subsequent wet processing during lithography can cause delamination from the substrate, resulting in mechanical damage to the films or even displacement of the channels. An alternative to physical isolation of MoS2 was the focus of this study. It is known that, in many semiconductors, radiation damage can be used for isolation. In this study, large-area 3-5 layer MoS2 films were grown on sapphire and subsequently transferred onto SiO2/Si wafers. The MoS2 was then exposed to low energy phosphorus plasma implantation at biases of 100, 200, and 300 V and a dose of 1 x 1014 cm-2. Electrical measurements using patterned Ni/Au contacts show that after implantation, independent of bias, there is a 105 increase in resistivity and a similar increase in specific contact resistivity of the MoS2. TEM shows that the film is still crystalline and there is no measurable etching of the films after implantation, suggesting that the increase in resistivity is likely the result of radiation damage in the MoS2. The thermal stability of the increase in electrical resistivity was assessed by a series of 15 minute anneals beginning at 325°C in a sulfur overpressure and progressing up to 525°C under an Al2O3 ALD cap. The resistivity increase remained unchanged after annealing, suggesting that this is a stable alternative to physical isolation in MoS2 devices.

Sepsis is an aggressive inflammatory syndrome and a global health burden estimated to kill 7.3 million people annually. Single-target molecular therapies have not addressed the multiple disease pathways triggered by septic injury. Cell therapies might offer a broader set of mechanisms of action that benefit complex, multifocal disease processes. We describe a population of immune-specialized myofibroblasts derived from lymph node tissue, termed fibroblastic reticular cells (FRCs). Because FRCs have an immunoregulatory function in lymph nodes, we hypothesized that ex vivo-expanded FRCs would control inflammation when administered therapeutically. Indeed, a single injection of ex vivo-expanded allogeneic FRCs reduced mortality in mouse models of sepsis when administered at early or late time points after septic onset. Mice treated with FRCs exhibited lower local and systemic concentrations of proinflammatory cytokines and reduced bacteremia. When administered 4 hours after induction of lipopolysaccharide endotoxemia, or cecal ligation and puncture (CLP) sepsis in mice, FRCs reduced deaths by at least 70%. When administered late in disease (16 hours after CLP), FRCs still conveyed a robust survival advantage (44% survival compared to 0% for controls). FRC therapy was dependent on the metabolic activity of nitric oxide synthase 2 (NOS2) as the primary molecular mechanism of drug action in the mice. Together, these data describe a new anti-inflammatory cell type and provide preclinical evidence for therapeutic efficacy in severe sepsis that warrants further translational study.

An infant with a ventricular septal defect; Vertebral anomalies, Anal atresia, Cardiac anomalies, Tracho Esophageal fistula (TEF), Renal anomalies, Limb anomalies syndrome; and tracheal stenosis with a bridging bronchus underwent repair of the ventricular septal defect and trachea-bronchial reconstruction at age 11 months. Herein we describe our surgical approach to resection of the bridging bronchus and a technique using a modified end-to-end tracheal anastomosis for the correction of this complex anomaly.

Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.