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Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8 + T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy. The regulatory mechanisms of PD-L1 posttranslational modifications are not completely understood. Here the authors show that USP8 negatively regulates PD-L1 protein abundance by removing the K63-linked ubiquitination of PD-L1; while USP8 inhibition increases MHC-I expression and triggers anti-tumour immune responses through activating NF-κB signalling.

Knowledge and research tying the environmental impact and embodied energy together is a largely unexplored area in the building industry. The aim of this study is to investigate the practicality of using the ratio between embodied energy and embodied carbon to measure the building’s impact. This study is based on life-cycle assessment and proposes a new measure: life-cycle embodied performance (LCEP), in order to evaluate building performance. In this project, eight buildings located in the same climate zone with similar construction types are studied to test the proposed method. For each case, the embodied energy intensities and embodied carbon coefficients are calculated, and four environmental impact categories are quantified. The following observations can be drawn from the findings: (a) the ozone depletion potential could be used as an indicator to predict the value of LCEP; (b) the use of embodied energy and embodied carbon independently from each other could lead to incomplete assessments; and (c) the exterior wall system is a common significant factor influencing embodied energy and embodied carbon. The results lead to several conclusions: firstly, the proposed LCEP ratio, between embodied energy and embodied carbon, can serve as a genuine indicator of embodied performance. Secondly, environmental impact categories are not dependent on embodied energy, nor embodied carbon. Rather, they are proportional to LCEP. Lastly, among the different building materials studied, metal and concrete express the highest contribution towards embodied energy and embodied carbon.

Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.

Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus. cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson’s disease, Huntington’s disease, major depression, schizophrenia, and drug addiction. The ventral tegmental area (VTA) has been identified as an important relay nucleus that modulates homeostatic plasticity in the midbrain dopamine system. Due to the complexity of synaptic transmissions and input–output connections in the VTA, the structure and function of this crucial brain region are still not fully understood. In this review article, we mainly focus on the cell types, neurotransmitters, neuropeptides, ion channels, receptors, and neural circuits of the VTA dopamine system, with the hope of obtaining new insight into the formation and function of this vital brain region.

When assessed using the difference between urban and rural air temperatures, the urban heat island (UHI) is most prominent during the nighttime. Typically, nocturnal UHI intensity is maintained throughout the night. The UHI intensity over Dallas–Fort Worth (DFW), Texas, however, experienced frequent “collapses” (sudden decreases) around midnight during August 2011, while the region was experiencing an intense heat wave. Observational and modeling studies were conducted to understand this unique phenomenon. Sea-breeze passage was found to be ultimately responsible for the collapses of the nocturnal UHI. Sea-breeze circulation developed along the coast of the Gulf of Mexico during the daytime. During the nighttime, the sea-breeze circulation was advected inland (as far as ~400 km) by the low-level jet-enhanced southerly flow, maintaining the characteristics of sea-breeze fronts, including the enhanced wind shear and vertical mixing. Ahead of the front, surface radiative cooling enhanced the near-surface temperature inversion in rural areas through the night with calm winds. During the frontal passage (around midnight at DFW), the enhanced vertical mixing at the leading edge of the fronts brought warmer air to the surface, leading to rural surface warming events. In contrast, urban effects led to a nearly neutral urban boundary layer. The enhanced mechanical mixing associated with sea-breeze fronts, therefore, did not increase urban surface temperature. The different responses to the sea-breeze frontal passages between rural (warming) and urban areas (no warming) led to the collapse of the UHI. The inland penetration of sea-breeze fronts at such large distances from the coast and their effects on UHI have not been documented in the literature.

Nonlocality is one unique property of quantum mechanics that differs from the classical world. One of its quantifications can be properly described as the maximum global effect caused by locally invariant measurements, known as measurement-induced nonlocality (MIN) (2011 Phys. Rev. Lett. 106 120401). Here, we propose quantifying the MIN by the trace norm. We show explicitly that this measure is monotonically decreasing under the action of a completely positive trace-preserving map, which is the general local quantum operation, on the unmeasured party for the bipartite state. This property avoids the undesirable characteristic appearing in the known measure of MIN defined by the Hilbert-Schmidt norm which may be increased or decreased by trivial local reversible operations on the unmeasured party. We obtain analytical formulas of the trace-norm MIN for any -dimensional pure state, two-qubit state, and certain high-dimensional states. As with other quantum correlation measures, the newly defined MIN can be directly applied to various models for physical interpretations.

Addictive substances are known to increase dopaminergic signaling in the mesocorticolimbic system. The origin of this dopamine (DA) signaling originates in the ventral tegmental area (VTA), which sends afferents to various targets, including the nucleus accumbens, the medial prefrontal cortex, and the basolateral amygdala. VTA DA neurons mediate stimuli saliency and goal-directed behaviors. These neurons undergo robust drug-induced intrinsic and extrinsic synaptic mechanisms following acute and chronic drug exposure, which are part of brain-wide adaptations that ultimately lead to the transition into a drug-dependent state. Interestingly, recent investigations of the differential subpopulations of VTA DA neurons have revealed projection-specific functional roles in mediating reward, aversion, and stress. It is now critical to view drug-induced neuroadaptations from a circuit-level perspective to gain insight into how differential dopaminergic adaptations and signaling to targets of the mesocorticolimbic system mediates drug reward. This review hopes to describe the projection-specific intrinsic characteristics of these subpopulations, the differential afferent inputs onto these VTA DA neuron subpopulations, and consolidate findings of drug-induced plasticity of VTA DA neurons and highlight the importance of future projection-based studies of this system.

In many chemical reactions, the transformation from reactants to products is mediated by transient intermediate complexes. For gas-phase reactions involving molecules with a few atoms, these complexes typically live on the order of 10 ps or less before dissociating, and are therefore rarely influenced by external processes. Here, we demonstrate that the transient intermediate complex K 2 Rb 2 *, formed from collisions between ultracold KRb molecules, undergoes rapid photo-excitation in the presence of a continuous-wave laser source at 1,064 nm, a wavelength commonly used to confine ultracold molecules. These excitations are facilitated by the exceptionally long lifetime of the complex under ultracold conditions. Indeed, by monitoring the change in the complex population after the sudden removal of the excitation light, we directly measure the lifetime of the complex to be 360 ± 30 ns, in agreement with our calculations based on the Rice–Ramsperger–Kassel–Marcus (RRKM) statistical theory. Our results shed light on the origin of the two-body loss widely observed in ultracold molecule experiments. Additionally, the long complex lifetime, coupled with the observed photo-excitation pathway, opens up the possibility to spectroscopically probe the structure of the complex with high resolution, thus elucidating the reaction dynamics. A transient intermediate complex in a chemical reaction—formed from collisions between molecules with a few atoms—is observed under ultracold conditions. Its lifetime can be directly measured after suppression of the photo-excitation process.

Toll-like receptor (TLR)-mediated signaling are critical for host defense against pathogen invasion. However, excessive responses would cause harmful damages to the host. Here we show that deficiency of the E3 ubiquitin ligase TRIM32 increases poly(I:C)- and LPS-induced transcription of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines in both primary mouse immune cells and in mice. Trim32-/- mice produced higher levels of serum inflammatory cytokines and were more sensitive to loss of body weight and inflammatory death upon Salmonella typhimurium infection. TRIM32 interacts with and mediates the degradation of TRIF, a critical adaptor protein for TLR3/4, in an E3 activity-independent manner. TRIM32-mediated as well as poly(I:C)- and LPS-induced degradation of TRIF is inhibited by deficiency of TAX1BP1, a receptor for selective autophagy. Furthermore, TRIM32 links TRIF and TAX1BP1 through distinct domains. These findings suggest that TRIM32 negatively regulates TLR3/4-mediated immune responses by targeting TRIF to TAX1BP1-mediated selective autophagic degradation.