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SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6Δ17-65 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6Δ17-65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6Δ17-65 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan β-blocker propranolol or by using mice lacking the β2-adrenergic receptor (β2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking β-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced β-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or β-AR signaling in combination with immunotherapy.The San Andreas fault has the highest calculated time-dependent probability for large-magnitude earthquakes in southern California. However, where the fault is multistranded east of the Los Angeles metropolitan area, it has been uncertain which strand has the fastest slip rate and, therefore, which has the highest probability of a destructive earthquake. Reconstruction of offset Pleistocene-Holocene landforms dated using the uranium-thorium soil carbonate and beryllium-10 surface exposure techniques indicates slip rates of 24.1 ± 3 millimeter per year for the San Andreas fault, with 21.6 ± 2 and 2.5 ± 1 millimeters per year for the Mission Creek and Banning strands, respectively. These data establish the Mission Creek strand as the primary fault bounding the Pacific and North American plates at this latitude and imply that 6 to 9 meters of elastic strain has accumulated along the fault since the most recent surface-rupturing earthquake, highlighting the potential for large earthquakes along this strand.A new cancer vaccine technology builds a network of local lymphatic vessels that paves the way to stronger responses to immunotherapy.Retromer is a master regulator of cargo retrieval from endosomes, which is critical for many cellular processes including signaling, immunity, neuroprotection, and virus infection. The retromer core (VPS26/VPS29/VPS35) is present on cargo-transporting, tubular carriers along with a range of sorting nexins. Here, we elucidate the structural basis of membrane tubulation and coupled cargo recognition by metazoan and fungal retromer coats assembled with the non-Bin1/Amphiphysin/Rvs (BAR) sorting nexin SNX3 using cryo-electron tomography. The retromer core retains its arched, scaffolding structure but changes its mode of membrane recruitment when assembled with different SNX adaptors, allowing cargo recognition at subunit interfaces. Thus, membrane bending and cargo incorporation can be modulated to allow retromer to traffic cargoes along different cellular transport routes.Polymer electrolyte membrane unitized regenerative fuel cells (PEM-URFCs) require bifunctional porous transport layers (PTLs) to play contradictory roles in a single unitized system hydrophobicity for water drainage in the fuel cell (FC) mode and hydrophilicity for water supplement in the electrolysis cell (EC) mode. Here, we report a high-performance amphiphilic Ti PTL suitable for both FC and EC modes, thanks to alternating hydrophobic and hydrophilic channels. To fabricate the amphiphilic PTL, we used a shadow mask patterning process using ultrathin polydimethylsiloxane (PDMS) brush as a hydrophobic surface modifier, which can change the Ti PTL's surface polarity without decreasing its electrical conductivity. Consequently, performance improved by 4.3 times in FC (@ 0.6 V) and 1.9 times in EC (@ 1.8 V) from amphiphilic PTL. To elucidate reason for performance enhancement, discrete gas emission through the hydrophobic channels in amphiphilic PTL was verified under scanning electrochemical microscopy.In the 1970s, the Shumagin Islands region of the Alaska subduction zone was identified as a seismic gap expected to host a future great [moment magnitude (M w) ≥8.0] earthquake. More recent geodetic data indicate that this region is weakly coupled, and the geologic record shows little evidence of past large events. From July to October 2020, a series of earthquakes occurred in this region, raising the possibility of greater coupling. selleck chemicals The initial M w 7.8 thrust faulting earthquake straddled the eastern edge of the Shumagin Gap and was followed by an M w 7.6 strike-slip earthquake within the Shumagin Gap. Stress modeling indicates that this strike-slip earthquake is in fact favored if the Shumagin Gap has low coupling, whereas a highly coupled Shumagin Gap inhibits that type and location of earthquake. The initial thrust earthquake and its afterslip enhanced the strike-slip loading within the subducting slab, helping to trigger the October event.