Publicly available microarray data suggests that the expression of FAM83D (Family with sequence similarity 83, member D) is elevated in a wide variety of tumor types, including hepatocellular carcinoma (HCC). However, its role in the pathogenesis of HCC has not been elucidated. Here, we showed that FAM83D was frequently up-regulated in HCC samples. Forced FAM83D expression in HCC cell lines significantly promoted their proliferation and colony formation while FAM83D knockdown resulted in the opposite effects. Mechanistic analyses indicated that FAM83D was able to activate the MEK/ERK signaling pathway and promote the entry into S phase of cell cycle progression. Taken together, these results demonstrate that FAM83D is a novel oncogene in HCC development and may constitute a potential therapeutic target in HCC.

Aberrant activation of NF-κB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-κB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-κB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKα/β and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-κB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKα/β to block NF-κB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.

The brainstem plays an important role in controlling sodium and water homeostasis. It is a major regulatory site for autonomic and motor functions. Moreover, it integrates cerebrospinal fluid (CSF) signals with neuronal and hormonal signals. Evidence suggests that the CSF-contacting nucleus (CSF-CN) transmits and integrates CSF signals, but, the definitive role of CSF-CN in sodium homeostasis is poorly understood. In this study, we used c-Fos as a marker of neuronal activity and causing colocalization of Nax channel and 5-HT. This proved that CSF-CN played a role in sensing the increase of CSF sodium level. Then, we determined the role of the CSF-contacting nucleus in increasing the sodium appetite of rats. So, we performed targeted lesion of the CSF-contacting nucleus in the brainstem using the cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The lesion of the CSF-CN showed decreased and degenerative neurons, while sodium appetite have increased and Fos immunocytochemistry detected neuronal activity in the lateral parabrachial nucleus (LPBN), but not in the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT). These results indicate that the CSF-CN plays an important role in sensing CSF sodium level and satiating sodium appetite by influencing the LPBN but not SFO and OVLT. The Nax channel and 5-HT might be the molecular mechanisms through which contribute to sodium homeostasis.

Little is known about the interactions between the default mode network (DMN) subregions in relapsing-remitting multiple sclerosis (RRMS). This study used diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) to examine alterations of long white matter tracts in paired DMN subregions and their functional connectivity in RRMS patients.

Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

Visual cortical prostheses have the potential to restore partial vision. Still limited by the low-resolution visual percepts provided by visual cortical prostheses, implant wearers can currently only "see" pixelized images, and how to obtain the specific brain responses to different pixelized images in the primary visual cortex (the implant area) is still unknown. We conducted a functional magnetic resonance imaging experiment on normal human participants to investigate the brain activation patterns in response to 18 different pixelized images. There were 100 voxels in the brain activation pattern that were selected from the primary visual cortex, and voxel size was 4 mm × 4 mm × 4 mm. Multi-voxel pattern analysis was used to test if these 18 different brain activation patterns were specific. We chose a Linear Support Vector Machine (LSVM) as the classifier in this study. The results showed that the classification accuracies of different brain activation patterns were significantly above chance level, which suggests that the classifier can successfully distinguish the brain activation patterns. Our results suggest that the specific brain activation patterns to different pixelized images can be obtained in the primary visual cortex using a 4 mm × 4 mm × 4 mm voxel size and a 100-voxel pattern.

Chromosomal fusions are common in normal and cancer cells and can produce aberrant gene products that promote transformation. The mechanisms driving these fusions are poorly understood, but recurrent fusions are widespread. This suggests an underlying mechanism, and some authors have proposed a possible role for RNA in this process. The unicellular eukaryote Oxytricha trifallax displays an exorbitant capacity for natural genome editing, when it rewrites its germline genome to form a somatic epigenome. This developmental process provides a powerful model system to directly test the influence of small noncoding RNAs on chromosome fusion events during somatic differentiation. Here we show that small RNAs are capable of inducing chromosome fusions in 4 distinct cases (out of 4 tested), including one fusion of 3 chromosomes. We further show that these RNA-mediated chromosome fusions are heritable over multiple sexual generations and that transmission of the acquired fusion is associated with endogenous production of novel piRNA molecules that target the fused junction. We also demonstrate the capacity of a long noncoding RNA (lncRNA) to induce chromosome fusion of 2 distal germline loci. These results underscore the ability of short-lived, aberrant RNAs to act as drivers of chromosome fusion events that can be stably transmitted to future generations.

Pinocembrin-7-O-β-D-glucoside (PCBG), a flavonoid isolated from Penthorum chinense Pursh., has significant liver-protecting effects. The pharmacokinetics of PCBG and its major metabolite pinocembrin (PCB) in rats were investigated in this study. A sensitive and accurate UPLC-MS/MS method was developed and validated for the simultaneous quantitative determination of PCBG and PCB in rat plasma after oral and intravenous administration of PCBG. After intravenous administration, PCBG was the main form in plasma. In contrast, after oral administration, the concentration of PCB was about 4-fold higher than that of PCBG, indicating that PCBG was metabolized to PCB. We also investigated the biotransformation of PCBG in vitro in order to understand whether the pH and the intestinal flora of gastrointestinal tract could affect the metabolism of PCBG. PCBG was incubated in rat plasma, liver homogenization, gastrointestial contents, liver microsomes (RLM) and hepatocytes in vitro. The data showed that PCB was quickly formed in the gastrointestinal incubation but PCBG was converted to PCB gradually in other incubations. The results indicated that the majority of PCBG was converted to its aglycone PCB in digestive system after oral administration, and PCB could be the active ingredient in the body.

To investigate the effects and mechanisms of hydroxytyrosol (HT) during the pathogenesis of myocardial ischemia reperfusion (I/R) in rat hearts.

Previous studies indicated that food consumption was associated with Helicobacter pylori infection, but no study has yet investigated the association between Helicobacter pylori infection and dietary patterns. The aim of this study was to evaluate the associations between Helicobacter pylori infection and dietary patterns in Tianjin, China. The final cross-sectional study population comprised 10407 participants. Dietary consumption of participants was assessed via food frequency questionnaire. Factor analysis was used to identify dietary patterns, and Helicobacter pylori infection status was diagnosis by H. pylori urease Immunogold Testing kit. Participants in the highest quartile of the high-carbohydrate/sweet pattern showed a multivariable-adjusted OR (95% CI) of 1.65 (1.27-2.17) for the prevalence of H. pylori infection compared with those in the lowest quartile. The multiple adjusted OR for scores of the extreme quartile of high-protein/cholesterol pattern was 0.75 (95% CI, 0.57-0.98). This study demonstrated that a diet rich in carbohydrates and sweets was positively associated with the prevalence of H. pylori infection; interestingly, a diet characterized by high intake of animal offal, animal blood, fish, seafood, and poultry was associated with a reduction of prevalence of H. pylori infection.

The higher order chromatin structure has recently been revealed as a critical new layer of gene transcriptional control. Changes in higher order chromatin structures were shown to correlate with the availability of transcriptional factors and/or MAR (matrix attachment region) binding proteins, which tether genomic DNA to the nuclear matrix. How posttranslational modification to these protein organizers may affect higher order chromatin structure still pending experimental investigation. The type III histone deacetylase silent mating type information regulator 2, S. cerevisiae, homolog 1 (SIRT1) participates in many physiological processes through targeting both histone and transcriptional factors. We show that MAR binding protein SATB1, which mediates chromatin looping in cytokine, MHC-I and β-globin gene loci, as a new type of SIRT1 substrate. SIRT1 expression increased accompanying erythroid differentiation and the strengthening of β-globin cluster higher order chromatin structure, while knockdown of SIRT1 in erythroid k562 cells weakened the long-range interaction between two SATB1 binding sites in the β-globin locus, MAR(HS2) and MAR(ε). We also show that SIRT1 activity significantly affects ε-globin gene expression in a SATB1-dependent manner and that knockdown of SIRT1 largely blocks ε-globin gene activation during erythroid differentiation. Our work proposes that SIRT1 orchestrates changes in higher order chromatin structure during erythropoiesis, and reveals the dynamic higher order chromatin structure regulation at posttranslational modification level.

Serine/threonine kinases are involved in gene regulation and signal transduction in prokaryotes and eukaryotes. Here, we investigated the role of the serine/threonine kinase Stk in the opportunistic pathogen Staphylococcus epidermidis.

Staphylococcus aureus is known as an invasive human pathogen, resulting in significant morbidity and mortality worldwide; however, information on community-associated S. aureus (CA-SA) from bloodstream infections (BSI) in children in China remains scarce. This study aimed to investigate the molecular characteristics of 78 CA-SA isolates recovered from pediatric patients with BSI between 2012 and 2017 in Shanghai. All isolates including 51 (65.4%) methicillin-susceptible S. aureus (MSSA) and 27 (34.6%) methicillin-resistant S. aureus (MRSA) isolates were characterized based on antimicrobial resistance, virulence genes, multilocus sequence typing (MLST), spa, and SCCmec typing. A total of 18 distinct sequence types (STs) and 44 spa types were identified. ST188 and ST7 were the predominant MSSA clones and ST59-MRSA-SCCmecIV/V was the most common MRSA clone. Spa t189 (9.0%, 7/78) was the most common spa type. SCCmec types IV and V were observed at frequencies of 59.3 and 40.7%, respectively. Notably, 40 (51.3%) S. aureus BSI strains were multidrug resistant (MDR), and these were mostly resistant to penicillin, erythromycin, and clindamycin. MRSA strains were associated with substantially higher rates of resistance to multiple antibiotics than MSSA strains. Fifty (64.1%, 50/78) isolates, including 19 (70.3%) MRSA isolates, harbored ≥ 10 tested virulence genes, as evaluated in this study. Ten (37.0%) MRSA isolates and four (7.8%) MSSA isolates harbored the gene encoding Panton-Valentine leukocidin (PVL). Virulence genes analysis showed diversity in different clones; the seb-sek-seq genes were present in all ST59 strains, whereas the seg-sei-sem-sen-seo genes were present in different clones including ST5, ST20, ST22, ST25, ST26, ST30, ST121, and ST487 strains. In conclusion, this study revealed that community-associated S. aureus strains from BSI in children demonstrated considerable genetic diversity, and identified major genotypes of CA-MRSA and CA-MSSA, with a high prevalence of CA-MRSA. Furthermore, major genotypes were frequently associated with specific antimicrobial resistance and toxin gene profiles. Understanding the molecular characteristics of those strains might provide further insights regarding the spread of BSI S. aureus among children between communities in China.

Human infections with the H7N9 virus could lead to lung damage and even multiple organ failure, which is closely associated with a high mortality rate. However, the metabolic basis of such systemic alterations remains unknown.

Recent advances in the preparation of shape-shifting and size-growing nanostructures are hot topics in development of nanoscience, because many intelligent functions are always relied on their shape and dimension. Here we report a tunable manipulation of sequential self-assembled transformation in situ via a hierarchical assembly strategy based on a living thiol-disulfide exchange reaction. By tailoring the external stimuli, the reactive points can be generated at the ends of initially unimolecular micelles, which subsequently drive the pre-assemblies to periodically proceed into the hierarchically micellar connection, axial growth, bending, and cyclization processes from nanoscopic assemblies to macroscopic particles. Of particular interest would be systems that acquired the shape control and size adjustment of self-assemblies after termination or reactivation of disulfide reshuffling reaction by regulating external stimuli whenever needed. Such a hierarchical strategy for self-assembled evolution is universally applicable not only for other disulfide-linked dendritic polymers but also for exploitation of biological applications.

Repetitive anodal transcranial direct current stimulation (tDCS) in a rat model of Alzheimer's disease (AD) has been shown to have distinct neuroprotective effects. Moreover, the effects of anodal tDCS not only occur during the stimulation but also persist after the stimulation has ended (after-effects). Here, the duration of the after-effects induced by repetitive anodal tDCS was investigated based on our previous studies. Adult male Sprague-Dawley rats were divided into three groups: a sham group, a β-amyloid (Aβ) group (AD group) and a stimulation group (ATD group). Aβ was injected into the bilateral hippocampi of the rats in the AD and ATD groups to produce the AD model. Rats in the ATD group underwent 10 sessions of anodal tDCS, and the after-effects of repetitive anodal tDCS were evaluated by behavioral and histological analyses. A Morris water maze (MWM) was utilized on a monthly basis to assess spatial learning and memory abilities. The ATD group showed shorter escape latencies and more platform region crossings than the AD group. Hippocampal choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) immunohistochemical analyses were carried out after the last MWM assessment. The immunohistochemistry results showed notable differences among the groups, particularly between the AD and ATD groups. This study reveals that repetitive anodal tDCS can not only improve cognitive function and memory performance but also has long-term after-effects that persist for 2 months.

Mucus secretion accumulation in the airways may act as a contributing factor for the development of airflow limitation in severe fetal asthma patients. Accumulated evidences showed that transforming growth factor beta (TGF-β) plays a regulatory role in airway remodeling including mucus hyper-secretion in asthma. However, the detailed molecular mechanisms of TGF-β3 induced MUC5AC hyper-expression in airway epithelium remains unclear. Here, we demonstrated the pivotal roles of autophagy in regulation of MUC5AC hyper-production induced by TGF-β3 in airway epithelium. Our experimental data showed that inhibiting autophagy pathway in repeated ovalbumin (OVA) exposed mice exhibited decreased airway hyper-response and airway inflammation, diminishing the expression of Muc5ac and TGF-β3. Furthermore, our studies demonstrated that autophagy was induced upon exposure to TGF-β3 and then mediated MUC5AC hyper-expression by activating the activator protein-1 (AP-1) in human bronchial epithelial cells. Finally, Smad2/3 pathway was involved in TGF-β3-induced MUC5AC hyper-expressions by promoting autophagy. These data indicated that autophagy was required for TGF-β3 induced airway mucous hyper-production, and that inhibition of autophagy exerted therapeutic benefits for TGF-β3 induced airway mucus secretion.

With increasing interest in ab initio protein design, there is a desire to be able to fully explore the design space of insertions and deletions. Nature inserts and deletes residues to optimize energy and function, but allowing variable length indels in the context of an interactive protein design session presents challenges with regard to speed and accuracy.

Spleen tyrosine kinase (Syk) is a critical target protein for treating immunoreceptor signalling-mediated allergies. In this study, a virtual screening of an in-house Chinese medicine database followed by biological assays was carried out to identify novel Syk inhibitors. A molecular docking method was employed to screen for compounds with potential Syk inhibitory activity. Then, an in vitro kinase inhibition assay was performed to verify the Syk inhibitory activity of the virtual screening hits. Subsequently, a β-hexosaminidase release assay was conducted to evaluate the anti-mast cell degranulation activity of the active compounds. Finally, tanshinone I was confirmed as a Syk inhibitor (IC50 = 1.64 μM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.76 μM). Docking studies showed that Pro455, Gln462, Leu377, and Lys458 were key amino acid residues for Syk inhibitory activity. This study demonstrated that tanshinone I is a Syk inhibitor with mast cell degranulation inhibitory activity. Tanshinone I may be a potential lead compound for developing effective and safe Syk-inhibiting drugs.