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Immune checkpoint blockade (ICB) has emerged as a novel therapeutic tool for cancer therapy in the last decade. Unfortunately, a small number of patients benefit from approved immune checkpoint inhibitors (ICIs). Therefore, multiple studies are being conducted to find new ICIs and combination strategies to improve the current ICIs. In this review, we discuss some approved immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and also highlight newer emerging ICIs. For instance, HLA-E, overexpressed by tumor cells, represents an immune-suppressive feature by binding CD94/NKG2A, on NK and T cells. NKG2A blockade recruits CD8+ T cells and activates NK cells to decrease the tumor burden. NKG2D acts as an NK cell activating receptor that can also be a potential ICI. The adenosine A2A and A2B receptors, CD47-SIRPα, TIM-3, LAG-3, TIGIT, and VISTA are targets that also contribute to cancer immunoresistance and have been considered for clinical trials. Their antitumor immunosuppressive functions can be used to develop blocking antibodies. PARPs, mARTs, and B7-H3 are also other potential targets for immunosuppression. Additionally, miRNA, mRNA, and CRISPR-Cas9-mediated immunotherapeutic approaches are being investigated with great interest. Pre-clinical and clinical studies project these targets as potential immunotherapeutic candidates in different cancer types for their robust antitumor modulation.

Discontinuous (first-order) quantum phase transitions and the associated metastability play central roles in diverse areas of physics, ranging from ferromagnetism to the false-vacuum decay in the early Universe 1 , 2 ; yet, their dynamics are not well understood. Ultracold atoms provide an ideal platform for experimental simulations of quantum phase transitions 3 , 4 ; so far, however, studies of first-order phase transitions have been limited to systems with weak interactions 5 – 8 , where quantum effects are exponentially suppressed. Here we realize a strongly correlated driven many-body system whose transition can be tuned from continuous to discontinuous. Resonant shaking of a one-dimensional optical lattice hybridizes the two lowest Bloch bands 9 , 10 , driving a novel transition from a Mott insulator to a superfluid with a staggered phase order. For weak shaking amplitudes, this transition is discontinuous and the system can remain frozen in a metastable state, whereas for strong shaking, it undergoes a continuous transition towards a superfluid. Our observations of this metastability and hysteresis agree with numerical simulations and pave the way for exploring the crucial role of quantum fluctuations in discontinuous transitions. Studies of first-order phase transitions in quantum simulators have so far been restricted to the weakly interacting regime. A tunable discontinuous phase transition has now been realized with strongly correlated atoms in a driven optical lattice.

Suppression of human megakaryocytes by dengue virus (DENV) infection significantly reduces the platelet count that eventually leads to thrombocytopenia, severe dengue and death. To understand DENV interactions with megakaryocytes, we investigated the cell cycle in leukemic human megakaryocytic in vitro cell line (MEG-01 cells). Megakaryocytes are known for complex endomitotic cell cycle leading to their polyploidy state. Our study shows that DENV uses these polyploid cells for its replication. Understanding the modulation of DENV-mediated cell cycle regulation in megakaryocytes is therefore highly important. We show that DENV2 (serotype 2) infection significantly modulates cell cycle signaling. Our protein profile microarray data showed significant upregulation of several cell cycle regulatory proteins including CDK4, CDK1, Cyclin B1 and others or downregulation of Chk1, GSK3-beta, CUL-3, and E2F-3. Quantitative real-time PCR and immunoblotting analyses further confirmed the upregulation of CDK4, CDK1, and Cyclin B1 upon DENV2 infection. Gene silencing of CDK4, CDK1 and Cyclin B1 showed significant reduction in DENV2 loads. Immunoprecipitation analysis further revealed an enhanced interaction between Cyclin B1 and CDK1 upon DENV2 infection that perhaps suggest the substantial changes noted in cell cycle regulation. Overall, our study suggests that DENV2 modulates cell cycle signaling in megakaryocytes and interferes with the critical regulatory proteins that may eventually lead to changes in endomitosis process. In conclusion, we report an important molecular insight regarding DENV2-mediated cell cycle modulation in human megakaryocytes.

We report experimental measurements showing how one can combine quantum interference and thermal Doppler shifts at room temperature to detect weak magnetic fields. We pump 87 Rb atoms to a highly-excited, Rydberg level using a probe and a coupling laser, leading to narrow transmission peaks of the probe due to destructive interference of transition amplitudes, known as Electromagnetically Induced Transparency. While it is customary in such setups to use counterpropagating lasers to minimize the effect of Doppler shifts, here we show, on the contrary, that one can harness Doppler shifts in a copropagating arrangement to produce an enhanced response to a magnetic field. In particular, we demonstrate an order-of-magnitude bigger splitting in the transmission spectrum as compared to the counterpropagating case. We explain and generalize our findings with theoretical modeling and simulations based on a Lindblad master equation. Our results pave the way to using quantum effects for magnetometry in readily deployable room-temperature platforms.

The black-legged tick Ixodes scapularis transmits the human anaplasmosis agent, Anaplasma phagocytophilum . In this study, we show that A. phagocytophilum specifically up-regulates I. scapularis organic anion transporting polypeptide, isoatp4056 and kynurenine amino transferase ( kat ), a gene involved in the production of tryptophan metabolite xanthurenic acid (XA), for its survival in ticks. RNAi analysis revealed that knockdown of isoatp4056 expression had no effect on A. phagocytophilum acquisition from the murine host but affected the bacterial survival in tick cells. Knockdown of the expression of kat mRNA alone or in combination with isoatp4056 mRNA significantly affected A. phagocytophilum survival and isoatp4056 expression in tick cells. Exogenous addition of XA induces isoatp4056 expression and A. phagocytophilum burden in both tick salivary glands and tick cells. Electrophoretic mobility shift assays provide further evidence that A. phagocytophilum and XA influences isoatp4056 expression. Collectively, this study provides important novel information in understanding the interplay between molecular pathways manipulated by a rickettsial pathogen to survive in its arthropod vector.

Motivated by rapid experimental progress in the fields of ultracold atoms and quantum optics, I present a series of theoretical studies which explore collective phenomena in quantum gases of atoms and photons. In Chapter 1, I highlight the major developments in the research field and identify the overarching themes and motivations. I also provide a roadmap for the rest of the thesis and summarize the main results. The remaining eight chapters contain original studies, organized along three broad motifs. In Chapters 2 through 5, I investigate how the nature of collective excitations and quasiparticles can be explored in modern experiments. More specifically, I model the dynamics of a spin impurity in a Bose lattice gas, develop a protocol for observing fractionalized excitations or anyons in an optical cavity, and characterize the collective dynamics of Bogoliubov quasiparticles and domain walls in a Fermi superfluid. In Chapters 6 and 7, I examine unconventional superfluid phases in spin-imbalanced Fermi gases. In particular, I propose a novel technique for engineering the long-sought-after Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase and study the relative stability of exotic phases across a dimensional crossover. Finally, Chapters 8 and 9 are devoted to studies of kinetics in out-of-equilibrium systems. I model the formation of a Bose-Einstein condensate in a dimple trap and characterize the approach to thermal equilibrium in quasi-one-dimensional geometries.

Kinetically constrained spin chains serve as a prototype for structured ergodicity breaking in isolated quantum systems. We show that such a system exhibits a hierarchy of degenerate steady states when driven by incoherent pump and loss at the boundary. By tuning the relative pump and loss and how local the constraints are, one can stabilize mixed steady states, noiseless subsystems, and various decoherence-free subspaces, all of which preserve large amounts of information. We also find that a dipole-conserving bulk suppresses current in steady state. These exact results based on the flow in Hilbert space hold regardless of the specific Hamiltonian or drive mechanism. Our findings show that a competition of kinetic constraints and local drives can induce different forms of ergodicity breaking in open systems, which should be accessible in quantum simulators.

Consider equal antiferromagnetic Heisenberg interactions between qubits sitting at the nodes of a complex, nonbipartite network. We ask the question: How does the network topology determine the net magnetization of the ground state and to what extent is it tunable? By examining various network families with tunable properties, we demonstrate that (i) graph heterogeneity, i.e., spread in the number of neighbors, is essential for a nonzero total spin, and (ii) other than the average number of neighbors, the key structure governing the total spin is the presence of (disassortative) hubs, as opposed to the level of frustration. We also show how to construct simple networks where the magnetization can be tuned over its entire range across both abrupt and continuous transitions, which may be realizable on existing platforms. Our findings pose a number of fundamental questions and strongly motivate wider exploration of quantum many-body phenomena beyond regular lattices.

We show that a simple experimental setting of a locally pumped and lossy array of two-level quantum systems can stabilize states with strong long-range coherence. Indeed, by explicit analytic construction, we show there is an extensive set of steady-state density operators, from minimally to maximally entangled, despite this being an interacting open many-body problem. Such nonequilibrium steady states arise from a hidden symmetry that stabilizes Bell pairs over arbitrarily long distances, with unique experimental signatures. We demonstrate a protocol by which one can selectively prepare these states using dissipation. Our findings are accessible in present-day experiments.

We find a rich variety of counterintuitive features in the steady states of a qubit array coupled to a dissipative source and sink at two arbitrary sites, using a master equation approach. We show there are setups where increasing the pump and loss rates establishes long-range coherence. At sufficiently strong dissipation, the source or sink effectively generates correlation between its neighboring sites, leading to a striking density-wave order for a class of \"resonant\" geometries. This effect can be used more widely to engineer nonequilibrium phases. We show the steady states are generically distinct for hard-core bosons and free fermions, and differ significantly from the ones found before in special cases. They are explained by generally applicable ansatzes for the long-time dynamics at weak and strong dissipation. Our findings are relevant for existing photonic setups.