miRNAs have been found to repress gene expression at posttranscriptional level in cells. Studies have shown that expression of miRNAs is tissue-specific and developmental-stage-specific. The mechanism behind this could be explained by miRNA pathways. In this study, totally 54 miRNAs were analysed in 7 matched human foetal and adult organs (brain, colon, heart, kidney, liver, lung and spleen) using real-time PCR. Quantitative analysis showed that a big proportion of the 54 miRNAs have higher general expression in the organs of the foetal period than the adult period, with the exception of the heart. The miRNA gene promoter methylation level in the adult stages was higher than in the foetal stages. Moreover, there is a high general expression level of several miRNAs in both stages of brain, kidney, liver, lung and spleen, but not seen in colon and heart. Our results indicate that the miRNAs may play a bigger role in the foetal stage than the adult stage of brain, colon, kidney, liver, lung and spleen. The majority of the miRNAs analysed may play an important role in the growth and development of brain, kidney, liver, lung and spleen. However, a minority of the miRNAs may be functional in colon and heart.

It has been shown that reward motivation can facilitate proactive control, a cognitive control mode that is characterized of prior preparation and sustained holding of the goal-relevant information in working memory. However, it remains to be established the neural networks that may be involved in this promotion effect. In this study, participants underwent the AX-Continuous Performance Task (AX-CPT) that measures relative proactive control during functional magnetic resonance imaging (fMRI) scanning. We employed independent component analysis to decompose multiple brain networks and identified the task related network. Results showed that the salience network (SN) was engaged in the AX-CPT protocol. Importantly, our data demonstrated that reward modulated the association between task engagement of SN and proactive control, whereby the positive correlation was particularly observed in the reward condition. Moreover, reward modulated task engagement of the SN in a proactive manner, which may contribute to the behavioral proactive performance. Overall, our data suggest the involvement of SN in the reward facilitation effect of proactive control.

Porcine circovirus 2 (PCV2) is the causative agent of porcine circovirus-associated diseases (PCVADs). The infection of PCV2 is widespread and has serious consequence, thereby causing significant economic losses in the swine industry worldwide. Previously, we found that a strain named YiY-3-2-3 has a naturally occurring point mutation (G710 to A710) in ORF1 region, which leads to a shorten product of the rep gene (945 to 660 base pair). Importantly, the Rep protein is responsible for genome replication of PCV2. To explore the effects of this mutation on the PCV2 replication, in the current study we constructed infectious clone of this IF-YiY-3-2-3, as well as those of its two parental strains of IF-YiY-3-2-1 and IF-YiY-3-2-10. Subsequently, these infectious clones which have 1.1 copy of PCV2 genome of their corresponding strains were transfected into PK15 cells to obtain rescued viruses, respectively.

China's TB control system has been transforming its service delivery model from CDC (Centers for Disease Control and Prevention)-led model to the designated hospital-led model to combat the high disease burden of TB. The implications of the new service model on TB health workforce development remained unclear. This study aims to identify implications of the new service model on TB health workforce development and to analyze whether the new service model has been well equipped with appropriate health workforce.

Pb is a potential risk factor for cognition, mainly mediated by enhanced oxidative stress. Resveratrol, a natural polyphenol with crucial anti-oxidative property, is recently implicated in preventing cognitive deficits in normal aging and neurodegenerative disorders. Its beneficial effects have been linked to sirtuin 1(SIRT1) activation. The aim of this work is to investigate the possible linkage between alterations in Pb-induced oxidative damage and cognitive impairment by prolonged treatment of resveratrol. Male C57BL/6 mice were given Pb(Ac)2 treatment or deionized H2O for 12 weeks, and subjected to resveratrol gavage at the dose of 50 mg/kgBw•d or vehicle after Pb exposure. Results from biochemical analysis and immunohistofluorescence showed that Pb induced oxidative DNA damage and decreased cortical antioxidant biomarker. As expected, these abnormalities were improved by resveratrol treatment. Morris water maze test, Western blotting, immunohistofluorescence staining and RT-qPCR indicated that resveratrol ameliorated spatial learning and memory deficits with alterations in hippocampal BDNF-TrkB signaling, promoted nuclear localization and phosphorylation of hippocampal SIRT1, partly increased protein levels of AMPK and PGC-1α involving in modulation of antioxidant response in Pb-exposed mice. Our results support the hypothesis that resveratrol could attenuate Pb-induced cognitive impairment which was associated with activating SIRT1 via modulation of oxidative stress. Additionally, resveratrol also repressed the Pb-induce amyloidogenic processing with resultant decline in cortical Aβ1--40. Noteworthy, such effects were not mediated by resveratrol treatment alone. These findings emphasize the potential of SIRT1 activator as an efficacious dietary intervention to downgrade the Pb-induced neurotoxic lesion.

Overflow metabolism-caused acetate accumulation is a major problem that restricts industrial applications of various bacteria. 2,3-Butanediol (2,3-BD) synthesis in microorganisms is an ancient metabolic process with unidentified functions. We demonstrate here that acetate increases and then decreases during the growth of a bacterium Enterobacter cloacae subsp. dissolvens SDM. Both bifunctional acetaldehyde/ethanol dehydrogenase AdhE-catalyzed ethanol production and acetate-induced 2,3-BD biosynthesis are indispensable for the elimination of acetate generated during overflow metabolism. 2,3-BD biosynthesis from glucose supplies NADH required for acetate elimination via AdhE-catalyzed ethanol production. The coupling strategy involving 2,3-BD biosynthesis and ethanol production is widely distributed in bacteria and is important for toxic acetate elimination. Finally, we realized the co-production of ethanol and acetoin from chitin, the second most abundant natural biopolymer whose catabolism involves inevitable acetate production through the coupling acetate elimination strategy. The synthesis of a non-toxic chemical such as 2,3-BD may be viewed as a unique overflow metabolism with desirable metabolic functions.

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune "checkpoint" inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

Human control is characterized by its flexibility and adaptability in response to the conditional probability in the environment. Previous studies have revealed that efficient conflict control could be attained by predicting and adapting to the changing control demand. However, it is unclear whether cognitive flexibility could also be gained by predicting and adapting to the changing control demand. The present study aimed to explore this issue by combining the model-based analyses of behavioral and neuroimaging data with a probabilistic cued task switching paradigm. We demonstrated that the Bayesian surprise (i.e. unsigned precision-weighted prediction error [PE]) negatively modulated the connections among stimulus processing brain regions and control regions/networks. The effect of Bayesian surprise modulation on these connections guided control engagement as reflected by the control PE effect on behavior, which in turn facilitated cognitive flexibility. These results bridge a gap in the literature by illustrating the neural and behavioral effect of control demand prediction (or PE) on cognitive flexibility and offer novel insights into the source of switch cost and the mechanism of cognitive flexibility.

Ovarian cancer (OvCa) is a malignant disease of the female reproductive system with a high mortality rate. LncRNA has been confirmed to play a crucial role in the development and progression of various cancer types. Novel lncRNA ZFHX4-AS1 has been reported in several cancers, albeit its functional mechanisms in OvCa remain unclear.

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.

The pathogenesis of head and neck squamous cell carcinoma (HNSCC) is associated with human papillomavirus (HPV) infection. However, the molecular mechanisms underlying the interactions between HNSCC and HPV remain unclear. Bioinformatics was used to analyze the gene expression dataset of HPV-associated HNSCC based on the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) in HPV-positive and HPV-negative HNSCC were screened. Gene function enrichment, protein-protein interactions (PPI), survival analysis, and immune cell infiltration of DEGs were performed. Furthermore, the clinical data of HNSCC tissue samples were analyzed using immunohistochemistry. In total, 194 DEGs were identified. A PPI network was constructed and 10 hub genes (EREG, PLCG1, ERBB4, HBEGF, ZFP42, CBX6, NFKBIA, SOCS1, ATP2B2, and CEND1) were identified. Survival analysis indicated that low expression of SOCS1 was associated with worse overall survival. Immunohistochemistry demonstrated that SOCS1 expression was higher in HPV-negative HNSCC than in HPV-positive HNSCC, and there was a positive correlation between SOCS1 expression and patient survival. This study provides new information on biological targets that may be relevant to the molecular mechanisms underpinning the occurrence and development of HNSCC. SOCS1 may play an important role in the interaction between HPV and HNSCC and serve as a potential biomarker for future therapeutic targets.

PERILIPIN5 (PLIN5) is a newly discovered member of the PAT family that regulates cellular neutral lipid stores and use. It is expressed in highly oxidative tissues and is induced during fasting. Like other members of the PAT family, PERILIPIN5 expression is also regulated by PPARα. However, its induction by fasting is PPARα-independent. So far, the transcriptional regulation of perilipin5, apart from PPARα, remains unclear. In the present study, we investigated the transcriptional regulation of pig perilipin5 and revealed that its promoter activity was up-regulated by C/EBPα. By constructing various progressive deletions and mutants, the binding region of C/EBPα was discovered. Furthermore, the binding site was identified by chromatin immunoprecipitation and luciferase reporter assays. Moreover, over-expression of C/EBPα induced endogenous perilipin5 expression in the pig kidney cell line IBRS2. Data from arrays showed that C/EBPα expression was induced during fasting. Taken together, our results indicate that C/EBPα is an essential regulatory factor for perilipin5 transcription and suggest that fasting stimulates perilipin5 transcription through influencing C/EBPα expression.

Diacetyl, a high value product that can be extensively used as a food ingredient, could be produced from the non-enzymatic oxidative decarboxylation of α-acetolactate during 2,3-butanediol fermentation. In this study, the 2,3-butanediol biosynthetic pathway in Enterobacter cloacae subsp. dissolvens strain SDM, a good candidate for microbial 2,3-butanediol production, was reconstructed for diacetyl production. To enhance the accumulation of the precursor of diacetyl, the α-acetolactate decarboxylase encoding gene (budA) was knocked out in strain SDM. Subsequently, the two diacetyl reductases DR-I (gdh) and DR-II (budC) encoding genes were inactivated in strain SDM individually or in combination to decrease the reduction of diacetyl. Although the engineered strain E. cloacae SDM (ΔbudAΔbudC) was found to have a good ability for diacetyl production, more α-acetolactate than diacetyl was produced simultaneously. In order to enhance the nonenzymatic oxidative decarboxylation of α-acetolactate to diacetyl, 20 mM Fe(3+) was added to the fermentation broth at the optimal time. In the end, by using the metabolically engineered strain E. cloacae SDM (ΔbudAΔbudC), diacetyl at a concentration of 1.45 g/L was obtained with a high productivity (0.13 g/(L·h)). The method developed here may be a promising process for biotechnological production of diacetyl.

Studies on the association between two single nucleotide polymorphisms (SNPs) in estrogen receptor α (ERα), PvuII (rs2234693 T>C) and XbaI (rs9340799 A>G), and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship.

TRAF family member-associated NF-κB activator (TANK) is a scaffold protein that assembles into the interferon (IFN) regulator factor 3 (IRF3)-phosphorylating TANK-binding kinase 1 (TBK1)-(IκB) kinase ε (IKKε) complex, where it is involved in regulating phosphorylation of the IRF3 and IFN production. However, the functions of TANK in encephalomyocarditis virus (EMCV) infection-induced type I IFN production are not fully understood. Here, we demonstrated that, instead of stimulating type I IFN production, the EMCV-HB10 strain infection potently inhibited Sendai virus- and polyI:C-induced IRF3 phosphorylation and type I IFN production in HEK293T cells. Mechanistically, EMCV 3C protease (EMCV 3C) cleaved TANK and disrupted the TANK-TBK1-IKKε-IRF3 complex, which resulted in the reduction in IRF3 phosphorylation and type I IFN production. Taken together, our findings demonstrate that EMCV adopts a novel strategy to evade host innate immune responses through cleavage of TANK.

A complete and hardened endocarp is a typical trait of drupe fruits. However, the 'Liehe' (LE) apricot cultivar has a thin, soft, cleavable endocarp that represents 60.39% and 63.76% of the thickness and lignin content, respectively, of the 'Jinxihong' (JG) apricot (with normal hardened-endocarp). To understand the molecular mechanisms behind the LE apricot phenotype, comparative transcriptomes of Prunus armeniaca L. were sequenced using Illumina HiSeq™ 2500.

During June 2-8, 2009, an outbreak of influenza A pandemic (H1N1) 2009 occurred among 31 members of a tour group in China. To identify the mode of transmission and risk factors, we conducted a retrospective cohort investigation. The index case-patient was a female tourist from the United States. Secondary cases developed in 9 (30%) tour group members who had talked with the index case-patient and in 1 airline passenger (not a tour group member) who had sat within 2 rows of her. None of the 14 tour group members who had not talked with the index case-patient became ill. This outbreak was apparently caused by droplet transmission during coughing or talking. That airborne transmission was not a factor is supported by lack of secondary cases among fellow bus and air travelers. Our findings highlight the need to prevent transmission by droplets and fomites during a pandemic.

Evidence indicates the significance of the fronto-parietal regions and inertia sensory processing from previous trials in cognitive flexibility. However, how flexible cognitive performance is achieved by causal interactions between cortical regions, particularly those between the fronto-parietal and stimulus processing regions, remains unknown. In the current study, the effective connectivity between the fronto-parietal and visual regions was examined in the context of a cued task-switching paradigm. We found that the fronto-parietal and visual cortex were differently activated during task transition (task repeat and task switch). Importantly, dynamic causal modeling (DCM) analysis revealed that task transition could modulate the effective connectivity between the fronto-parietal and visual cortex: task repeat decreased, while task switch enhanced, the coupling between the posterior parietal cortex (PPC) and the visual cortex. Furthermore, Granger causality analysis (GCA) showed that the dominant direction of influence was from the fronto-parietal regions to the visual cortex. Finally, individual differences in the top-down influence from the PPC to the visual cortex and the corresponding neural adjustment (task switch‒task repeat) was negatively associated with the behavioral switch cost. Our findings suggest that the interaction between the fronto-parietal and stimulus processing regions, particularly the top-down influence from the PPC to the visual cortex, is of particular importance in flexible cognitive performance.

The genus Tulotis has been classified into the genus Platanthera in the present taxonomic studies since the morphological characteristics of this genus is very similar to that of Platanthera. Platanthera ussuriensis, formerly named as Tulotis ussuriensis, is a small terrestrial orchid species and has been listed as wild plant under State protection (category II) in China. An improved understanding of the genomic information will enable future applications of conservation strategy as well as phylogenetic studies for this rare orchid species. The objective of this research was to characterize and compare the chloroplast genome of P. ussuriensis with other closely related species of Orchidaceae.

One of the most conserved glycosylation sites of neuraminidase (NA) is 146-N-glycan. This site is adjacent to the 150-cavity of NA, which is found within the active site and thought to be a target for rational drug development against the antiviral resistance of influenza. Here, through a total of 2.4 μs molecular dynamics (MD) simulations, we demonstrated that 146-N-glycan can stabilize the conformation of the 150-loop that controls the volume of the 150-cavity. Moreover, with 146-N-glycan, our simulation result was more consistent with crystal structures of NAs than simulations conducted without glycans. Cluster analysis of the MD trajectories showed that 146-N-glycan adopted three distinct conformations: monomer-bridged, dimer-bridged and standing. Of these conformations, the dimer-bridged 146-N-glycan was the most stable one and contributed to stabilization of the 150-loop conformation. Furthermore, our simulation revealed that various standing conformations of 146-N-glycan could block the entrance of the binding pocket. This result was consistent with experimental data and explained the relatively low activity of inhibitors with flexible substituents toward the 150-cavity. Together, our results lead us to hypothesize that rigid and hydrophobic substituents could serve as better inhibitors targeting the 150-cavity.