Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys

Though immune correlates for protection are still under investigation, potent cytotoxic T lymphocyte responses are desirable for an ideal HIV-1 vaccine. PD-1 blockade enhances SIV-specific CD8+ T cells. However, little information has been reported about how it affects the immunogenicity and protection of prophylactic SIV vaccines in nonhuman primates. Here, we show that PD-1 blockade during vaccination substantially improved protective efficacy in SIV challenged macaques. The PD-1 pathway was blocked using a monoclonal antibody specific to human PD-1. Administration of this antibody effectively augmented and sustained vaccine-induced SIV-specific T cell responses for more than 42 weeks after first immunization in rhesus monkeys, as compared with SIV vaccination only. Importantly, after intrarectally repeated low-dosage challenge with highly pathogenic SIVmac239, monkeys with PD-1 blockade during vaccination achieved full protection against incremental viral doses of up to 50,000 TICD50. These findings highlight the importance of PD-1 blockade during vaccination for the development of HIV vaccines

Recognition of cavitation characteristics in non-clogging pumps based on the improved Lévy flight bat algorithm

The performance and operational stability of non-clogging pumps can be affected by cavitation. To accurately identify the cavitation state of the non-clogging pump and provide technical references for monitoring its operation, a study was conducted on the optimization of Elman neural networks for cavitation monitoring and identification using the Improved Lévy Flight Bat Algorithm (ILBA) on the basis of the traditional Bat Algorithm (BA). The ILBA employs multiple bats to interact and search for targets and utilizes the local search strategy of Lévy flight, effectively avoiding local minima by taking advantage of the non-uniform random walk characteristics of large jumps. The ILBA algorithm demonstrates superior performance compared to other traditional algorithms through simulation testing and comparative calculations with eight benchmark test functions. On this basis, the optimization of the weights and thresholds of the Elman neural network was carried out by the improved bat algorithm. This leads to an enhancement in the accuracy of the neural network for identifying and classifying cavitation data, and the establishment of the ILBA-Elman cavitation diagnosis model was achieved. Collect pressure pulsation signals at the tongue of the non-clogging pump volute through cavitation tests. Through the cavitation feature extraction method based on Variational Mode Decomposition (VMD) and Multi-scale Dispersion Entropy (MDE), the interference signal can be effectively suppressed and the complexity of the time series can be measured from multiple angles, thereby creating a cavitation feature data set. The improved cavitation diagnosis model (ILBA-Elman) can realize the effective identification of the cavitation characteristics of non-clogging pumps through a variety of algorithm comparison experiments

Lepidopteran wing scales contain abundant cross-linked film-forming histidine-rich cuticular proteins

Scales are symbolic characteristic of Lepidoptera; however, nothing is known about the contribution of cuticular proteins (CPs) to the complex patterning of lepidopteran scales. This is because scales are resistant to solubilization, thus hindering molecular studies. Here we succeeded in dissolving developing wing scales from Bombyx mori, allowing analysis of their protein composition. We identified a distinctive class of histidine rich (His-rich) CPs (6%–45%) from developing lepidopteran scales by LC-MS/MS. Functional studies using RNAi revealed CPs with different histidine content play distinct and critical roles in constructing the microstructure of the scale surface. Moreover, we successfully synthesized films in vitro by crosslinking a 45% His-rich CP (BmorCPR152) with laccase2 using N-acetyl- dopamine or N-β-alanyl-dopamine as the substrate. This molecular study of scales provides fundamental information about how such a fine microstructure is constructed and insights into the potential application of CPs as new biomaterials

Regulating Innate and Adaptive Immunity for Controlling SIV Infection by 25-Hydroxycholesterol

Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon-dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-γ-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-α cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection

Inhibition of 26S Protease Regulatory Subunit 7 (MSS1) Suppresses Neuroinflammation

Recently, researchers have focused on immunosuppression induced by rifampicin. Our previous investigation found that rifampicin was neuroprotective by inhibiting the production of pro-inflammatory mediators, thereby suppressing microglial activation. In this study, using 2-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS), we discovered that 26S protease regulatory subunit 7 (MSS1) was decreased in rifampicin-treated microglia. Western blot analysis verified the downregulation of MSS1 expression by rifampicin. As it is indicated that the modulation of the ubiquitin-26S proteasome system (UPS) with proteasome inhibitors is efficacious for the treatment of neuro-inflammatory disorders, we next hypothesized that silencing MSS1 gene expression might inhibit microglial inflammation. Using RNA interference (RNAi), we showed significant reduction of IkBα degradation and NF-kB activation. The production of lipopolysaccharides-induced pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide, cyclooxygenase-2, and prostaglandin E2 were also reduced by MSS1 gene knockdown. Taken together, our findings suggested that rifampicin inhibited microglial inflammation by suppressing MSS1 protein production. Silencing MSS1 gene expression decreased neuroinflammation. We concluded that MSS1 inhibition, in addition to anti-inflammatory rifampicin, might represent a novel mechanism for the treatment of neuroinflammatory disorders

Spatio–temporal dynamics and human–land synergistic relationship of urban expansion in Chinese megacities

Megacities play important roles in countries' politics, economy, culture, etc. Exploring the law of urban expansion of megacities has important reference for sustainable urbanization. Here, the spatiotemporal dynamics of urban expansion were quantified analyzed in 21 Chinese megacities from 2000 to 2020 with quantitative measurement indicators and explored the human–land synergistic relationship used the decoupling model. Results are as follows: (1) China's megacities experienced significant expansion, and urban expansion characterized as rapid initially but slowed down thereafter. (2) Urban expansion in megacities was characterized as having significant spatial differences, and rapidly expanding megacity centers moved from eastern to midwestern China. (3) Urban spatial expansion of megacities was mainly an enclave type in 2000–2010 and marginal type in 2010–2020. (4) The main type of human–land synergistic relationship in megacities were weak decoupling, there is a significant increase in expansive coupling and expansive negative decoupling in 2010–2020; (5) Lastly, human–land synergy relationship in most megacities was uncoordinated based on the per capita urban land area and decoupling type. The findings of this study can deepen the understanding of the characteristics and quality of urbanization evolution, and provides reference for high-quality development planning and decision-making in megacities

Agricultural Population Supported in Rural Areas under Traditional Planting Mode Based on Opportunity Cost Analysis

The return of rural migrant workers through increasing agricultural income by expanding farming scale is significant for rural sustainable development without rural population loss. This paper selected six representative counties in Henan Province, China’s major grain-producing province, to conduct a questionnaire survey, investigated the incomes of farmers from farming and migrant workers, calculated moderate farming scale under different opportunity costs, and also estimated the agricultural population that can be supported by arable land resources. Results are as follows: (1) Under the traditional planting mode, annual per capita income of farmers in farming was USD 342.18, which was substantially lower than USD 5255.63 in migrant workers. This huge income gap has led to continuous rural population loss. (2) Under the opportunity cost of farming income equal to migrant workers income, moderate farming scales of the six selected counties were 1.39, 1.17, 1.22, 1.08, 1.34, and 1.01 ha, respectively. Under the 0.8x and 0.6x opportunity cost, corresponding moderate farming scales were 1.11, 0.94, 1.11, 0.86, 1.07, and 1.34 ha; and 0.84, 0.70, 0.73, 0.65, 0.80 and 1.01 ha, respectively. (3) On the basis of the three moderate farming scales and status quo of arable land resources, agricultural populations that can be supported by rural Henan Province were 8.0386 million, 10.0479 million and 13.3942 million, respectively. Findings can guide the formulation of rural revitalization strategic measures and the preparation of village territorial spatial planning

How Leisure Venues Are and Why? A Geospatial Perspective in Wuhan, Central China

Urban leisure venues proffer spatial carriers for citizens’ leisure activities and their functions rely heavily on the spatial configuration, which have largely been ignored. The increasing needs for healthy leisure life and the availability of geospatial open data provide a rising opportunity to fill this gap. To examine the spatial distribution of leisure venues and explore its underlying dominating factors, we adopt geospatial analysis techniques—point pattern analysis and cluster analysis with multi-sources geospatial data in Wuhan, Central China. Results conclude interesting spatial discrepancy based on a three-level clustered pattern of 86520 leisure venues. We find that (1) most clusters are in urban center along the Yangtze River with all 1st-level clusters and plentiful 2nd-level and 3rd-level clusters; (2) There are just sporadic clusters in suburban areas—no 1st-level, merely one 2nd-level and some few 3rd-level ones. Moreover, we demonstrate three underlying dominating factors (i.e., the policy, population and economy) and identify that (1) No systematic (spatial-relevant) leisure policy framework is formed; (2) Population density and commercial centers have positive correlation with the distribution of leisure venues. This study contributes to spatial-relevant leisure policy-making for facilitating healthy leisure life, optimizing leisure space, guiding people-oriented urbanization transition and promoting urban competence

α-Synuclein Induces Neuroinflammation Injury through the <i>IL6ST-AS</i>/STAT3/HIF-1α Axis

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson’s disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD