Approximate Strong Equilibrium in Job Scheduling Games

A Nash Equilibrium (NE) is a strategy profile resilient to unilateral deviations, and is predominantly used in the analysis of multiagent systems. A downside of NE is that it is not necessarily stable against deviations by coalitions. Yet, as we show in this paper, in some cases, NE does exhibit stability against coalitional deviations, in that the benefits from a joint deviation are bounded. In this sense, NE approximates strong equilibrium. Coalition formation is a key issue in multiagent systems. We provide a framework for quantifying the stability and the performance of various assignment policies and solution concepts in the face of coalitional deviations. Within this framework we evaluate a given configuration according to three measures: (i) IR_min: the maximal number alpha, such that there exists a coalition in which the minimal improvement ratio among the coalition members is alpha, (ii) IR_max: the maximal number alpha, such that there exists a coalition in which the maximal improvement ratio among the coalition members is alpha, and (iii) DR_max: the maximal possible damage ratio of an agent outside the coalition. We analyze these measures in job scheduling games on identical machines. In particular, we provide upper and lower bounds for the above three measures for both NE and the well-known assignment rule Longest Processing Time (LPT). Our results indicate that LPT performs better than a general NE. However, LPT is not the best possible approximation. In particular, we present a polynomial time approximation scheme (PTAS) for the makespan minimization problem which provides a schedule with IR_min of 1+epsilon for any given epsilon. With respect to computational complexity, we show that given an NE on m >= 3 identical machines or m >= 2 unrelated machines, it is NP-hard to determine whether a given coalition can deviate such that every member decreases its cost

DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity

BACKGROUND: Treatment of Diffuse Large B Cell Lymphoma (DLBCL) patients with rituximab and the CHOP treatment regimen is associated with frequent intrinsic and acquired resistance. However, treatment with a CD47 monoclonal antibody in combination with rituximab yielded high objective response rates in patients with relapsed/refractory DLBCL in a phase I trial. Here, we report on a new bispecific and fully human fusion protein comprising the extracellular domains of SIRPα and 4-1BBL, termed DSP107, for the treatment of DLBCL. DSP107 blocks the CD47:SIRPα ‘don’t eat me’ signaling axis on phagocytes and promotes innate anticancer immunity. At the same time, CD47-specific binding of DSP107 enables activation of the costimulatory receptor 4-1BB on activated T cells, thereby, augmenting anticancer T cell immunity. METHODS: Using macrophages, polymorphonuclear neutrophils (PMNs), and T cells of healthy donors and DLBCL patients, DSP107-mediated reactivation of immune cells against B cell lymphoma cell lines and primary patient-derived blasts was studied with phagocytosis assays, T cell activation and cytotoxicity assays. DSP107 anticancer activity was further evaluated in a DLBCL xenograft mouse model and safety was evaluated in cynomolgus monkey. RESULTS: Treatment with DSP107 alone or in combination with rituximab significantly increased macrophage- and PMN-mediated phagocytosis and trogocytosis, respectively, of DLBCL cell lines and primary patient-derived blasts. Further, prolonged treatment of in vitro macrophage/cancer cell co-cultures with DSP107 and rituximab decreased cancer cell number by up to 85%. DSP107 treatment activated 4-1BB-mediated costimulatory signaling by HT1080.4-1BB reporter cells, which was strictly dependent on the SIRPα-mediated binding of DSP107 to CD47. In mixed cultures with CD47-expressing cancer cells, DSP107 augmented T cell cytotoxicity in vitro in an effector-to-target ratio-dependent manner. In mice with established SUDHL6 xenografts, the treatment with human PBMCs and DSP107 strongly reduced tumor size compared to treatment with PBMCs alone and increased the number of tumor-infiltrated T cells. Finally, DSP107 had an excellent safety profile in cynomolgus monkeys. CONCLUSIONS: DSP107 effectively (re)activated innate and adaptive anticancer immune responses and may be of therapeutic use alone and in combination with rituximab for the treatment of DLBCL patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02256-x

Neuroprotective Effect of Transplanted Human Embryonic Stem Cell-Derived Neural Precursors in an Animal Model of Multiple Sclerosis

BACKGROUND: Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC)-derived early multipotent neural precursors (NPs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes

Nudging the Criminal Justice System into Listening to Crime Victims in Plea Agreements

The Crime Victim’s Rights Act has given victims “the right to participate in the system.” However, crime victims remain marginalized as their involvement in plea agreements is yet under enforced. This article reveals the largely unnoticed gap between the victim’s rights and the disadvantaged reality they experience in plea agreements. Further, the paper identifies the legal causes that led to this gap; namely, the broad discretion and dominance of the prosecution on the one hand, and the victim’s lack of enforcement mechanisms to participate on the other. The article provides a solution whose novelty is twofold. First, the solution advocated by this article embodies the nudge theory; a theory, explained in this article, which is unfortunately yet to be adequately utilized in the context of criminal law. Second, the article demonstrates a choice architecture mechanism that leaves the prosecutor’s discretion intact; while at the same time nudges the participation of the crime victims. The rightreality gap identified in this article threatens to leave crime victims unheard. This article analyzes the importance of victims’ voice in plea bargains, identifies the causes of this entrenched gap, and provides a unique and practical solution to the problem