Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.
Background. As one of the most widely researched consequence of traumatic events, the prevalence of post-traumatic stress symptoms among people exposed to the trauma resulting from coronavirus disease 2019 (COVID-19) outbreak varies greatly across studies. This review aimed at examining the pooled prevalence of post-traumatic stress symptoms among people exposed to the trauma resulting from COVID-19 outbreak. Methods. Systematic searches of databases were conducted for literature published on PubMed, EMBASE, Web of Science, the Cochrane Library, PsycArticle, and Chinese National Knowledge Infrastructure until October 14, 2020. Statistical analyses were performed using R software (PROSPERO registration number: CRD42020180309). Results. A total of 106,713 people exposed to the trauma resulting from the COVID-19 outbreak were identified in the 76 articles, of which 33,810 were reported with post-traumatic stress symptoms. The pooled prevalence of post-traumatic stress symptoms among people exposed to the trauma resulting from COVID-19 outbreak was 28.34%, with a 95% confidence interval of 23.03-34.32%. Subgroup analysis indicated that older age, male and bigger sample size were associated with higher prevalence of post-traumatic stress symptoms. After controlling for other factors, the results of meta-regression showed that the influence of gender and sample size on prevalence is no longer significant. Conclusions. Symptoms of post-traumatic stress disorder (PTSD) were very common among people exposed to the trauma resulting from COVID-19 outbreak. Further research is needed to explore more possible risk factors for post-traumatic stress symptoms and identify effective strategies for preventing PTSD-related symptoms among people exposed to the trauma resulting from COVID-19 outbreak. BackgroundAs of December 14, 2020, 70.4 million confirmed cases of coronavirus disease 2019 (COVID-19) and 1.6 million deaths have been reported to the World Health Organization [1]. The outbreak of COVID-19 spread rapidly, caused enormous losses to individual health, national economy, and social wellbeing [2,3]. Currently, control of the epidemic of COVID-19 is still the dominant task across the world, millions of people are scared and even panic of the possible loss of health, life, and wealth. Although it is too early to predict how many people worldwide will be infected with this emerging virus, it is believed that the numbers of case and death will continue to increase in the forthcoming months. Some psychologists draw attention toward post-traumatic stress disorder (PTSD) as the second tsunami of the COVID-19 pandemic [4]. According to the Diagnostic and Statistics of Mental Disorders, the fifth edition (DSM-5), the clinical features of PTSD include persistent avoidance of stimuli, persistent intrusion symptoms, negative alterations in cognition or mood and marked alterations in arousal and reactivity, all of which are related to traumatic events [5]. PTSD could cause clinically significant distress or impairment in occupational, ...
Ribosomal protein S6 kinase (S6K) functions as a key component in the target of rapamycin (TOR) pathway involved in multiple processes in eukaryotes. The role and regulation of TOR-S6K in lipid metabolism remained unknown in plants. Here we provide genetic and pharmacological evidence that TOR-Raptor2-S6K1 is important for thylakoid galactolipid biosynthesis and thylakoid grana modeling in rice (Oryza sativa L.). Genetic suppression of S6K1 caused pale yellow-green leaves, defective thylakoid grana architecture. S6K1 directly interacts with Raptor2, a core component in TOR signaling, and S6K1 activity is regulated by Raptor2 and TOR. Plants with suppressed Raptor2 expression or reduced TOR activity by inhibitors mimicked the S6K1-deficient phenotype. A significant reduction in galactolipid content was found in the s6k1, raptor2 mutant or TOR-inhibited plants, which was accompanied by decreased transcript levels of the set of genes such as lipid phosphate phosphatase α5 (LPPα5), MGDG synthase 1 (MGD1), and DGDG synthase 1 (DGD1) involved in galactolipid synthesis, compared to the control plants. Moreover, loss of LPPα5 exhibited a similar phenotype with pale yellow-green leaves. These results suggest that TOR-Raptor2-S6K1 is important for modulating thylakoid membrane lipid biosynthesis, homeostasis, thus enhancing thylakoid grana architecture and normal photosynthesis ability in rice.
Response errors often cause individuals to slow down their subsequent reactions (posterror slowing [PES]). Despite intensive investigations on PES, the adaptive nature of PES remains unresolved. Here, we systematically examined this issue by manipulating response-stimulus intervals (RSIs) and examining their influence on behaviors and neural dynamics of PES. Behavioral and electrophysiological (EEG) measures were recorded while male and female human participants performed a four-choice flanker task as RSIs were manipulated. Behaviorally, PES showed maladaptive features at short RSIs but some adaptive features at long RSIs. EEG results indicated that RSIs did not affect basic error-related processing, indexed by the same pattern in the contrasts between flanker errors and correct responses on the error-related negativity (ERN), error positivity (Pe), or theta band, no matter at short or long RSIs. However, RSIs significantly influenced postflanker error attentional adjustment, motor inhibition, and sensory sensitivity. At short RSIs, compared with postcorrect trials, postflanker error trials elicited larger beta band power and smaller P1 amplitude but did not affect alpha band power, suggesting that motor processing was inhibited, and subsequent sensory processing was impaired, but no attentional adjustment occurred. By contrast, at long RSIs, postflanker error trials led to smaller alpha and beta band power but did not affect P1 amplitude, indicating that attentional adjustment but not motor inhibition occurred, and sensory processing was not impaired. Together with behavioral results, the current study demonstrated that PES was adaptive at long RSIs but maladaptive at short RSIs. We further discuss the role of central resources in the adaptability of PES.
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