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Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 ( CD276 ) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38 + CD39 + CD4 + T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38 + CD39 + CD4 + T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4 + T cells. B7-H3 is expressed at high levels in several cancer types and can suppress antitumor immune responses. Here the authors show that B7-H3 expression is dependent on mTORC1 activity and that inhibition of B7-H3 promotes antitumor immunity mediated by cytolytic CD4 + T cells in tumor models with mTORC1 hyperactivity.

Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.

Alzheimer’s disease (AD) is a lethal neurodegenerative disorder primarily affecting the aged population. The etiopathogenesis of AD, especially that of the sporadic type, remains elusive. The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. Missense mutations in human TREM2 are determined as genetic risk factors associated with the development of sporadic AD. However, the roles of TREM2 in the pathogenesis of AD are still to be established. In this review, we outlined the influence of Trem2 on balance of pro- and anti-inflammatory microglial activations from a perspective of AD mouse model transcriptomics. On this basis, we further speculated the roles of TREM2 in different stages of AD, which may shed light to the development of TREM2-targeted strategy for the prevention and treatment of this neurodegenerative disorder.

Plasmapause surface waves (PSWs) near the plasmapause boundary are regarded to be the magnetospheric source of ionospheric auroral giant undulations (GUs) located at the equatorward boundary of diffuse aurora. However, the observational evidence of wave‐particle interaction connecting PSWs and GUs is absent. In this letter, we demonstrate GUs are driven by pitch‐angle scattering of time domain structures modulated by the PSWs, based on the conjugated ionospheric and magnetospheric observations. Specifically, ionospheric GUs are lighted by the pitch‐angle scattering of <1 keV thermal electron and ions and energetic ions with energy up to dozens of keV near the plasmapause. Further, the total fluxes during one PSW period and energy of scattered electron and ions determine the size and luminosity of GUs. Our research provides observational evidence that PSWs cause periodic electron precipitation via modulating the time domain structures rather than the previously predicted chorus or electron cyclotron harmonic waves. Plain Language Summary Boundary surface waves usually act as a kind of special oscillation along the boundary layer and are the widely existing physical phenomena in the universe. In our Earth, there are magnetopause surface wave and plasmapause surface wave. For the latter, the plasmapause surface wave has been confirmed to be a kind of sawtooth‐type auroral structures locating on the equatorial edge of aurora oval, named as giant undulations. But how can the plasmapause surface wave produce the auroral giant undulations is still unknown. Based on this question, we have provided the observational evidence of auroral giant undulations being driven by the periodic pitch‐angle scattering of time domain structures modulated by plasmapause surface waves. Our new results in this research would help us to better understand the energy conversion controlled by boundary dynamics and the crucial effect of boundary dynamics on the near‐surface space environment. Key Points Giant undulations (GUs) are lighted by the pitch‐angle scattering of <1 keV thermal electron and ions and energetic ions with energy up to dozens of keV Total fluxes during one plasmapause surface wave (PSW) period and energy of scattered electron and ions determine the size and luminosity of GUs PSWs can cause periodic electron precipitation by modulating time domain structures

Background/Objectives: As zero-dose vaccination has become a global health concern, understanding the practice of self-paid immunizations in migrant and left-behind children in China is crucial to the prevention and control of infectious diseases. Methods: A cross-sectional study was conducted in 1648 children and their caregivers in urban areas in Zhejiang Province and rural areas in Henan Province. The participants were then classified into four groups: urban local, migrant, non-left-behind, and left-behind. Results: Compared to urban local children, migrant (prevalence ratios: 1.29, 95% confidence intervals: 0.69–2.41), non-left-behind (4.72, 3.02–7.37), and left-behind (4.79, 3.03–7.56) children were more likely to be zero-dose vaccinated. Children aged 1–2 years (odds ratio: 1.60, 95% confidence intervals: 1.14–2.23) and born later (1.55, 1.12–2.14), with caregivers aged >35 years (1.49, 1.03–2.15) and less educated (elementary school or lower: 4.22, 2.39–7.45) were less likely to receive self-paid vaccinations, while caregivers other than parents (0.62, 0.41–0.94) and lower household income (0.67, 0.49–0.90) lowered the likelihood of zero-dose vaccination of self-paid vaccines. For migrant and rural zero-dose children, the majority of caregivers reported they “didn’t know where to get a vaccination”, with responses ranging from 82.3% to 93.8%. Conclusions: Migrant and rural children should be prioritized in the promotion of self-paid immunization in order to accomplish the WHO Immunization Agenda 2030’s goal of “leaving no one behind”.

Background and purpose The association between intracranial artery calcification (IAC) and the risk of ischemic stroke occurrence or poor prognosis had not yet been fully understood. In this study, we conducted a meta-analysis of existing studies aimed to assess whether IAC can be used to predict future ischemic stroke and post-stroke mortality. Methods Medline, Cochrane, Web of Science and Google Scholar databases were searched up to June 30, 2022. Studies were included if they reported risk ratio (RR) or odds ratios (OR) and corresponding 95% confidence intervals (CI) of stroke concerning the presence of IAC. Random or fixed effects model meta-analyses were performed. Meta-analysis was conducted by using Stata version 16.0. Results Twelve studies involving 9346 participants were included. Compared with those without IAC, patients with IAC had a higher risk of stroke occurrence (adjusted OR 1.62, 95% CI 1.18–2.23, P  = 0.001) and stroke recurrence (adjusted OR 1.77, 95% CI 1.25–2.51, P  = 0.003). However, we did not find a significant correlation between IAC and post-stroke mortality (pooled OR 1.12, 95% CI 0.80–1.56, P  = 0.504). Conclusions Our meta-analysis demonstrated that the presence of IAC was identified as an independent risk factor for ischemic stroke occurrence and recurrence but is not a predictor of post-stroke mortality.

The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

Based on empirical data of an orthogonal frequency division multiplexing system in realistic environments of next‐generation cellular networks, a new analytical model of phase noise and numerical characteristics of the common phase error and intercarrier interference are derived. Applying an asymptotic theory of probability, analytical expressions are present to approximate the mean vector and the covariance matrix of the intercarrier interference. The approximation expression of the covariance matrix is accurate enough and only has three parameters. When applied to estimate original symbols based on additive white Gaussian noise channel, a Gibbs sampler performs better than the current estimation algorithm following Weiner process phase noise. Based on empirical data of an orthogonal frequency division multiplexing system, a new analytical model of phase noise and numerical characteristics of the common phase error and intercarrier interference are derived. When applied to estimate original symbols based on AWGN channel, the proposed algorithm based on the model performs better than the current algorithm for phase noise.

Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer’s disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β (Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the transgenic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.

F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer’s disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization. F1FO ATP synthase is a critical enzyme for the maintenance of mitochondrial function. Here the authors demonstrate that loss of the F1FO-ATP synthase subunit OSCP and the interaction of OSCP with Aβ peptide in Alzheimer’s disease patients and mouse models lead to F1FO-ATP synthase deregulation and disruption of synaptic mitochondrial function.