Temporal Unit Interval Independent Sets

Temporal graphs have been recently introduced to model changes to a given network that occur throughout a fixed period of time. We introduce and investigate the Temporal ? Independent Set problem, a temporal variant of the well known Independent Set problem. This problem is e.g. motivated in the context of finding conflict-free schedules for maximum subsets of tasks, that have certain (changing) constraints on each day they need to be performed. We are specifically interested in the case where each task needs to be performed in a certain time-interval on each day and two tasks are in conflict on a day if their time-intervals overlap on that day. This leads us to considering Temporal ? Independent Set on the restricted class of temporal unit interval graphs, i.e., temporal graphs where each layer is unit interval. We present several hardness results for this problem, as well as two algorithms: The first is a constant-factor approximation algorithm for instances where ?, the total number of time steps (layers) of the temporal graph, and ?, a parameter that allows us to model some tolerance in the conflicts, are constants. For the second result we use the notion of order preservation for temporal unit interval graphs that, informally, requires the intervals of every layer to obey a common ordering. We provide an FPT algorithm parameterized by the size of minimum vertex deletion set to order preservation

Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy

BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR or CAR induces a strong antitumor response in a proportion of patients with cancer; however, the therapeutic efficacy is often limited by rapid decline in T cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that cytokines can be anchored to the cell membrane in a functional fashion and that cytokine receptor signaling can synergize with TLR4 and CD40 signaling. Here, we aimed at augmenting T cell activation by simultaneous signaling through the cytokine receptor, toll-like receptor and TNF-type receptor using IL-18, TLR4 and CD40 as prototypes. METHODS: Genes were expressed on electroporation of in vitro-transcribed mRNA in CD4(+) and CD8(+) T cells from healthy donors redirected against melanoma cells with an anti-melanotransferrin CAR and in TILs derived from melanoma patients. Functional assays included the activation of signaling pathways, expression of activation and differentiation markers, cytokine secretion and killing of melanoma target cells. RESULTS: To provide IL-18 costimulation to T cells in-cis while avoiding systemic effects, we genetically anchored IL-18 to the T cell membrane, either alone (memIL-18) or fused with constitutively active (ca)TLR4 and caCD40 signaling domains arranged in tandem, creating a synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered strong NF-κB activation in cells lacking the IL-18 receptor, attesting to functionality of the TLR-CD40 moiety. While the membrane-anchored cytokine was found to act mainly in-cis, some T cell activation in-trans was also observed. The electroporated T cells exhibited spontaneous T-bet upregulation and IFN-γ and TNF-α secretion. Melanoma-induced activation of CAR-T cells and TILs as manifested by cytokine secretion and cytolytic activity was substantially augmented by both constructs, with memIL-18-TLR4-CD40 exerting stronger effects than memIL-18 alone. CONCLUSIONS: Linking membrane anchored IL-18 with caTLR4 and caCD40 signaling in one hybrid transmembrane protein provides simultaneous activation of three T cell costimulatory pathways through one genetically engineered membrane molecule, strongly amplifying T cell functions for adoptive T cell therapy of cancer

Engineering of Doxorubicin-Encapsulating and TRAIL-Conjugated Poly(RGD) Proteinoid Nanocapsules for Drug Delivery Applications

Proteinoids are non-toxic biodegradable polymers prepared by thermal step-growth polymerization of amino acids. Here, P(RGD) proteinoids and proteinoid nanocapsules (NCs) based on D-arginine, glycine, and L-aspartic acid were synthesized and characterized for targeted tumor therapy. Doxorubicin (Dox), a chemotherapeutic drug used for treatment of a wide range of cancers, known for its adverse side effects, was encapsulated during self-assembly to form Dox/P(RGD) NCs. In addition, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which can initiate apoptosis in most tumor cells but undergoes fast enzyme degradation, was stabilized by covalent conjugation to hollow P(RGD) NCs. The effect of polyethylene glycol (PEG) conjugation was also studied. Cytotoxicity tests on CAOV-3 ovarian cancer cells demonstrated that Dox/P(RGD) and TRAIL-P(RGD) NCs were as effective as free Dox and TRAIL with cell viability of 2% and 10%, respectively, while PEGylated NCs were less effective. Drug-bearing P(RGD) NCs offer controlled release with reduced side effects for improved therapy

Ethical considerations of medical nutritional therapy at end of life: the Israel perspective

Summary: The major ethical dilemma regarding feeding a person at the end of their life in Israel is related to the medical team's ability to not provide food. In addition to the medical indications, the decision-making process needs to include ethnic considerations, religious positions and a strong collective memory related to the Holocaust and post-Holocaust behavior. An Expert group of professionals regularly faced with these dilemmas gathered to address this issue. The group included Nutrition Specialists, Neurologists, Geriatricians, Oncologists and Specialists in palliative care, Nurses, Dieticians, Speech therapists but also Lawyers and Religion experts.The conclusions suggested: 1) One should evaluate the patient's ability to eat safely and sufficiently, assessed by speech therapist and dietician evaluations. 2) If not successful, a discussion between the team, the patient, if available, and the family is initiated. 3) If oral nutrition is possible it is encouraged. 4) If not, artificial nutrition should be discussed. 5) The family's will to never stop providing food and water according to Jewish law has to be acknowledged when the medical team does not suggest nutritional therapy. Emotional aspects, religious beliefs and nutritional indications have to be reconciled and a consensus should be reached

Community-Wide Assessment of Protein-Interface Modeling Suggests Improvements to Design Methodology.

International audienceThe CAPRI (Critical Assessment of Predicted Interactions) and CASP (Critical Assessment of protein Structure Prediction) experiments have demonstrated the power of community-wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community-wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting that there may be important physical chemistry missing in the energy calculations. A total of 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the nonpolar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were, on average, structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a nonbinder