Ovarian cancer-derived IL-4 promotes immunotherapy resistance.

Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.

2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer.

Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling.

Spontaneous similarity discrimination in the evolution of cooperation.

The similarity discrimination effect occurs when a single gene or gene cluster causes its carriers to display both a variable phenotypic trait and a behavioural predisposition to cooperate preferentially with recognisably similar carriers. We distinguish this from the greenbeard effect, in which cooperation evolves through fixed phenotypic tags and genetically linked cooperative behaviour with others displaying the same tag. Our agent-based simulations show that the evolution of cooperation through similarity discrimination, in contrast to the greenbeard effect, does not depend on population viscosity or other restrictive conditions. Similarity discrimination evolves spontaneously in well mixed populations, not only in the Prisoner's Dilemma game but also across a range of different binary-choice strategic interactions, provided that agents can distinguish reliably between similar and dissimilar co-players.

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress.

Articular cartilage has limited healing capacity and no drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Mesenchymal stromal cell (MSC)-based regenerative therapies for OA are increasingly common, but questions regarding their mechanisms of action remain. Our group recently reported that although cartilage is avascular and relatively metabolically quiescent, injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. MSCs are known to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known to induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When exposed to mechanically injured cartilage, MSCs localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.

Cognitive approaches to insomnia.

Cognition is a broad term that refers to all mental activities and encompasses attention, perception, memory, reasoning, beliefs, attributions and expectations. The aim of the present paper is to draw together the major research findings relating to the importance of cognition in insomnia. Although the research to date has tended to focus on the role of unwanted intrusive thought (also known as worry or cognitive arousal), there is evidence that a broad range of cognitive processes are important for a full understanding of insomnia. These include beliefs, attributions, expectations, perception and attention. The treatment implications of this evidence are discussed, as are priorities for future research.

Evolution of coordinated alternating reciprocity in repeated dyadic games.

A genetic algorithm incorporating mutation and crossing-over was used to investigate the evolution of social behaviour in repeated Prisoner's Dilemma, Chicken (Hawk-Dove), Battle of the Sexes, and Leader games. The results show that the strategic structure of an interaction has a crucial determining effect on the type of social behaviour that evolves. In particular, simulations using repeated Prisoner's Dilemma and Chicken (Hawk-Dove) games lead to the emergence of genes coding for symmetric reciprocity and the evolution of mutual cooperation, whereas simulations using repeated Battle of the Sexes and Leader games lead to near-fixation of genes coding for asymmetric strategic choices and the evolution of coordinated alternating reciprocity. A mechanism is suggested whereby, in games with asymmetric equilibrium points, coordinated alternating reciprocity might evolve without insight or communication between players.