Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses.

Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT's ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic

General requirements for protein secretion by the F-like conjugation system R1

► Mechanism of protein transfer by plasmid R1 conjugative T4 system requires relaxosome. ► Protein translocation depends on concomitant DNA transfer. ► Required functions of T4 coupling protein correlate for protein and DNA transfer

Financial conditions and financial sustainability in higher education: A literature review

This chapter offers a necessary summary of the key concepts of the financial conditions in the higher education (HE) sector, through a close examination of different approaches. Focusing on a review of current literature, the chapter provides an overview of the transformation and main uses of performance information in the HE sector as the result of public policy changes. The chapter also defines some of the key theoretical and practical elements to describe the financial conditions and distress of public universities, while also clarifying the distinctive features of financial sustainability. The authors highlight in their closing remarks the implications for future research developments. These issues touch the core of the financial challenges in the HE sector and require thought and resolution to ensure the long-term success of public universities worldwide

Boreal lakes moderate seasonal and diurnal temperature variation and perturb atmospheric circulation: analyses in the Community Earth System Model 1 (CESM1)

We used a lake thermal physics model recently coupled into the Community Earth System Model 1 (CESM1) to study the effects of lake distribution in present and future climate. Under present climate, correcting the large underestimation of lake area in CESM1 (denoted CCSM4 in the configuration used here) caused 1 °C spring decreases and fall increases in surface air temperature throughout large areas of Canada and the US. Simulated summer surface diurnal air temperature range decreased by up to 4 °C, reducing CCSM4 biases. These changes were much larger than those resulting from prescribed lake disappearance in some present-day permafrost regions under doubled-CO2 conditions. Correcting the underestimation of lake area in present climate caused widespread high-latitude summer cooling at 850 hPa. Significant remote changes included decreases in the strength of fall Southern Ocean westerlies. We found significantly different winter responses when separately analysing 45-yr subperiods, indicating that relatively long simulations are required to discern the impacts of surface changes on remote conditions. We also investigated the surface forcing of lakes using idealised aqua-planet experiments which showed that surface changes of 2 °C in the Northern Hemisphere extra-tropics could cause substantial changes in precipitation and winds in the tropics and Southern Hemisphere. Shifts in the Inter-Tropical Convergence Zone were opposite in sign to those predicted by some previous studies. Zonal mean circulation changes were consistent in character but much larger than those occurring in the lake distribution experiments, due to the larger magnitude and more uniform surface forcing in the idealised aqua-planet experiments