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Instruction cues are widely employed for research on neural mechanisms during movement preparation. However, their influence on brain connectivity during movement has not received much attention. Herein, 15 healthy subjects completed two experimental tasks including either instructed or voluntary movements; meanwhile electroencephalogram (EEG) data were synchronously recorded. Based on source analysis and related literature, six movement-related brain regions were selected, including the left/right supplementary motor area (SMA), left/right inferior frontal gyrus (iFg), and left/right postcentral gyrus (pCg). After assuming 10 a priori models of regional brain connectivity, we evaluated the optimal connectivity model between brain regions for the two scenarios using the dynamic causality model (DCM). During voluntary movement, the movement originated in the SMA, passed through the iFg of the prefrontal lobe, and then returned to the main sensory cortex of the pCg. In the instructed movement, the movement originated in the iFg, and then was transmitted to the pCg and the SMA, as well as from the pCg to the SMA. In contrast to the preparation process of voluntary movement, there were long-range information interactions between the iFg and pCg. Further, almost the same brain regions were active during movement preparation under both voluntary and instructed movement tasks, which evidences certain similarities in dynamic brain connectivity, that is, the brain has direct connections between the bilateral SMA, bilateral pCg, and bilateral SMA, indicating that the both brain hemispheres work together during the movement preparation phase. The results suggest that the network during the preparation process of instructed movements is more complex than voluntary movements.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has precipitated a global health crisis of unprecedented proportions. Because of its severe impact, multiple COVID-19 vaccines are being rapidly developed, approved and manufactured. Among them, mRNA vaccines are considered as ideal candidates with special advantages to meet this challenge. However, some serious adverse events have been reported after their application, significantly increasing concerns about the safety and efficacy of the vaccines and doubts about the necessity of vaccination. Although several fertility societies have announced that COVID-19 mRNA vaccines are unlikely to affect fertility, there is no denying that the current evidence is very limited, which is one of the reasons for vaccine hesitancy in the population, especially in pregnant women. Herein, we provide an in-depth discussion on the involvement of the male and female reproductive systems during SARS-CoV-2 infection or after vaccination. On one hand, despite the low risk of infection in the male reproductive system or fetus, COVID-19 could pose an enormous threat to human reproductive health. On the other hand, our review indicates that both men and women, especially pregnant women, have no fertility problems or increased adverse pregnancy outcomes after vaccination, and, in particular, the benefits of maternal antibodies transferred through the placenta outweigh any known or potential risks. Thus, in the case of the rapid spread of COVID-19, although further research is still required, especially a larger population-based longitudinal study, it is obviously a wise option to be vaccinated instead of suffering from serious adverse symptoms of virus infection.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently spread worldwide, leading to high morbidity and mortality. As the putative receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is widely distributed in various tissues and organs of the human body. Simultaneously, ACE2 acts as the physiological counterbalance of ACE providing homeostatic regulation of circulating angiotensin II levels. Given that some ACE2 variants are known to cause an increase in the ligand-receptor affinity, their roles in acquisition, progression and severity of COVID-19 disease have aroused widespread concerns. Therefore, we summarized the latest literature and explored how ACE2 variants and epigenetic factors influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome in aspects of ethnicity, gender and age. Meanwhile, the possible mechanisms for these phenomena were discussed. Notably, recombinant human ACE2 and ACE2-derived peptides may have special benefits for combating SARS-CoV-2 variants and further studies are warranted to confirm their effects in later stages of the disease process. As the uncertainty regarding the severity and transmissibility of disease rises, a more in-depth understanding of the host genetics and functional characteristics of ACE2 variants will not only help explain individual clinical differences of the disease, but also contribute to providing effective measures to develop solutions and manage future outbreaks of SARS-CoV-2.

Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD–HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD–HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.

Background: Papillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC. Methods: Clinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, and bioinformatics. Findings: The differentially expressed substances included 146 lipids, 2975 proteins, and 217 metabolites in PTC samples. Multi-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. The key enzymes in the three steps, namely LPL, FATP2, and CPT1A, respectively, were overexpressed. Moreover, their expression was strongly associated with the TNM stage, lymph node metastasis, and PTC prognosis. In addition, the levels of several types of phospholipids and sphingolipids increased significantly in PTC. Interpretation: Our data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for tumour growth, invasion, and metastasis in PTC. This may help elucidate the mechanism underlying PTC pathogenesis and identify the potential therapeutic targets for PTC. Funding Information: Work in the authors' laboratory is supported by grants from National Natural Science Foundation of China (No. 81702647, NO. 81972819), Taishan Scholar Foundation of Shandong Province (No. tspd20181201), Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Natural Science Foundation of Shandong Province (No. ZR201702190483, No. ZR2020YQ57), Key Technology Research and Development Program of Shandong (No. 2016GSF201161). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This prospective study was approved by the institutional ethical committee of Qilu Hospital of Shandong University, Shandong Province, China. All the specimens were collected in the Qilu Hospital of Shandong University. The participants provided written informed consent for the use of thyroid tissue specimens for research.

HBV is considered as a "stealth" virus that does not invoke interferon (IFN) responses; however, the mechanisms by which HBV bypasses innate immune recognition are poorly understood. In this study, we identified adenosine deaminases acting on RNA 1 (ADAR1), which is a key factor in HBV evasion from IFN responses in hepatocytes. Mechanically, ADAR1 interacted with HBV RNAs and deaminated adenosine (A) to generate inosine (I), which disrupted host immune recognition and thus promoted HBV replication. Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes, and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency. Notably, the HBV X protein (HBx) transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation, which in turn enhanced HBV escape from immune recognition, leading to persistent infection. Supplementation with 8-azaadenosine, an ADAR1 inhibitor, efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro. Taken together, our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. METHODS: ZHX2 overexpression and knockdown were introduced into HCC cell lines. BODIPY staining and D-Glucose- 13C6 labeled lipid mass spectrometry were involved to estimate lipogenesis in HCC cell lines. Colony formation and cell proliferation assays were used to determine HCC development. Hepatocytes specific Zhx2 knockout mice (Zhx2-KOhep) were included to induce spontaneous liver tumor. qRT-PCR, western blotting and dual luciferase assays were used to detect gene regulation. FINDINGS: Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC and SCD1. In accordance, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Further studies demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with SREBP1c inhibitor, fatostatin, dampened the spontaneous tumor formation in Zhx2-KOhep mice. Mechanically, ZHX2 transcriptionally increased expression of miR-24-3p, which targets on SREBP1c. INTERPRETATION: ZHX2 inhibits de novo lipogenesis in HCC cells by down-regulating the expression of SREBP1c via miR-24-3p, and further inhibits the development of HCC. These new findings may provide a new strategy for the treatment of HCC. FUNDING STATEMENT: This work was supported by grants from the National Science Foundation of China (Key project 81830017 and 81902443,81702647,81902051,81972819), Taishan Scholarship (No.tspd20181201), National Key Research and Development Program (2018YFE0126500), National Science Foundation for Distinguished Young Scholars of China (81425012), Shandong Provincial Key Innovation project (No.2018FYJH0503), Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Key Research and Development Program of Shandong (2019GSF108238) . DECLARATION OF INTERESTS: All authors declare no potential conflicts of interest. ETHICS APPROVAL STATEMENT: The Medical Ethics Committee of Shandong University approved the use of human specimens in accordance with the Helsinki Declaration. All mice were housed under conditions free of specific pathogens and euthanized according to regulations established by the Animal Care Committee of Shandong University.

Sepsis is a life-threatening condition with limited therapeutic options, characterized as excessive systemic inflammation and multiple organ failure. Macrophages play critical roles in sepsis pathogenesis. Metabolism orchestrates homeostasis of macrophages. However, the precise mechanism of macrophage metabolism during sepsis remains poorly elucidated. In this study, we identified the key role of zinc fingers and homeoboxes (Zhx2), a ubiquitous transcription factor, in macrophage glycolysis and sepsis by enhancing 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) expression. Mice with myeloid Zhx2-specific deletion (abbreviated as MKO) showed more resistance to cecal ligation and puncture and LPS-induced sepsis, exhibiting as prolonged survival, attenuated pulmonary injury, and reduced level of proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β. Interestingly, Zhx2 deletion conferred macrophage tolerance to LPS-induced glycolysis, accompanied by reduced proinflammatory cytokines and lactate. Consistently, treatment of glycolytic inhibitor 2-deoxyglucose almost completely abrogated the protection of mice from LPS-induced sepsis initiated by Zhx2 deletion in macrophages. RNA sequencing and chromatin immunoprecipitation assays confirmed that Zhx2 enhanced transcription of Pfkfb3, the glycolysis rate-limiting enzyme, via binding with Pfkfb3 promoter. Furthermore, Pfkfb3 overexpression not only rescued the reduction of macrophage glycolysis caused by Zhx2 deficiency, displaying as extracellular acidification rates and lactate production but also destroyed the resistance of mice to LPS-induced sepsis initiated by transfer of bone marrow–derived macrophages from MKO mice. These findings highlight the novel role of transcription factor Zhx2 in sepsis via regulating Pfkfb3 expression and reprogramming macrophage metabolism, which would shed new insights into the potential strategy to intervene sepsis.

BACKGROUND The aim of this study was to investigate the value of the mean platelet volume to platelet count (MPV/P) ratio for predicting in-hospital and long-term cardiac mortality in older non-ST elevation-acute coronary syndrome (NSTE-ACS) patients after primary percutaneous coronary intervention (PCI). METHODS We retrospectively reviewed 452 older NSTE-ACS patients who received primary PCI. The patients were divided into two groups based on MPV/P ratios: high MPV/P group (N.=150) defined as a value in the third tertile (>0.056628) and low MPV/P group (N.=302) in the lower two tertiles (≤0.056628). Clinical outcomes included non-fatal reinfarction, heart failure, and cardiac mortality. RESULTS Multivariate analyses showed that high MPV/P and MPV values were independent predictors of cardiac mortality. The in-hospital cardiac mortality of the high MPV/P group was higher than the low MPV/P group (1.3% vs. 14.7%, P

Self-compacting concrete could be poured under the action of gravity, without vibration, and has good working performance. It could reduce the noise during production, and reduce the labor of workers. In recent years, more and more scholars begin to study the concrete. In this paper, ABAQUS finite element software is used to simulate the self-compacted concrete prestressed T-beam under different parameters, using the self-compacting concrete constitutive model. The cooling method is used to simulate the prestress applying, and the performance of beam is analyzed. It is found that the bearing capacity of the member improves with the increasing of the reinforcement ratio, the prestress increases the stiffness of the member, and reduces the deflection of the member, but the ductility is reducing with the increasing of prestress.

Marek's disease (MD) has become increasingly common in China, resulting in considerable economic loss. The etiological agent is unclear. In this study, we isolated a field MD virus (MDV) strain, designated SX1301, from CVI988/Rispens-vaccinated chickens with tumors. Co-infection of avian leukosis virus, reticuloendotheliosis virus, and chicken infectious anemia virus was excluded by polymerase chain reaction, enzyme-linked immunosorbant assay, DNA blotting hybridization, and indirect immunofluorescence assay. As with most strains isolated in China, SX1301 had the same amino acid mutation of meq protein at positions 77(E), 80(Y), and 115(A) Animal experimental results showed development of lethal MD in 57% and MD tumor in 23% of the specific pathogen-free chickens inoculated with SX1301, with tumors mainly distributed in spleen, liver, and kidney. CVI988/Rispens protected 83% of chickens upon challenge with SX1301, with a mortality rate and tumor incidence of 10% and 7%, respectively. These results implicated SX1301 as a virulent MDV strain, with commercial MDV vaccine CVI988/Rispens unable to confer adequate protection against SX1301. There have been no reports of very virulent (vv) plus MDV in China, but frequently occurring virulent MDV may account for the repeated outbreaks of MD. Vaccines with greater efficacy are needed to protect against MDV.

Marek’s disease (MD) has been occurring with increasing frequency in chickens in recent years. To our knowledge, however, there has been no report of the very virulent plus (vv+) MD virus (MDV) field isolate in China. Studies have shown that dual infection with immunosuppressive viruses such as chicken infectious anemia virus (CIAV) occurs frequently in chickens developing MD. In this study, we performed a designed set of in vivo experiments, which comprised five different groups of chickens, including the group of CVI988/Rispens-vaccinated chickens, the groups of CVI988/Rispens-vaccinated chickens infected with MDV or CIAV or both viruses (MDV and CIAV), and the group of MDV-challenged chickens. The effects of CIAV dual infection on the immunization of commercial MDV vaccine CVI988/Rispens were evaluated. The results show that infection of the SD15 strain of CIAV significantly reduced the weight and antibody titers to avian influenza virus (AIV)/Newcastle disease virus (NDV) inactivated vaccines of chickens immunized with the CVI988/Rispens, and resulted in the atrophy of thymus/bursa and the enlargement of spleen. The CVI988/Rispens vaccination conferred good immune protection for chickens challenged with 2000 PFU of the GX0101 strain of MDV. However, dual infection with SD15 significantly reduced the body weight, antibody titers induced by AIV/NDV inactivated vaccines and protective index of CVI988/Rispens, and resulted in the aggravation of the immunosuppression, mortality, and viremia of GX0101 in CVI988/Rispens-immunized/GX0101-challenged chickens. Overall, CIAV infection significantly reduced the protective effects of the CVI988/Rispens vaccine against MDV, implying that concurrent infection with CIAV may be a major contributor in the frequent attacks of MD in China in recent years.

A series of new sulfamide derivatives have been synthesized, their structures were confirmed by 1H NMR and ESI-MS. Some target compounds were assessed by the tool of Dock6, and inhibition effects of all the new compounds on carbonic anhydrase II have been investigated. In addition, some compounds have been investigated for their antihypoxic effects in mice. Results indicated that nine target compounds exhibit as effectively as acetazolamide and 10 compounds have more potent inhibition effects on carbonic anhydrase II than acetazolamide. Three of them (I-8, I-18 and I′-3) can prolong markedly the survival time of mice in hypoxia, which are worth carrying out further studies.