Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.

Archaeological studies have revealed a series of cultural changes around the Last Glacial Maximum in East Asia; whether these changes left any signatures in the gene pool of East Asians remains poorly indicated. To achieve deeper insights into the demographic history of modern humans in East Asia around the Last Glacial Maximum, we extensively analyzed mitochondrial DNA haplogroup M9a'b, a specific haplogroup that was suggested to have some potential for tracing the migration around the Last Glacial Maximum in East Eurasia.

We have previously shown that Toll-like receptor (TLR) agonists contribute to the control of viral infection by augmenting virus-specific CD8(+) T-cell responses. It is also well established that signaling by TLRs results in the production of pro-inflammatory cytokines such as interleukin 6 (IL-6). However, how these pro-inflammatory cytokines influence the virus-specific CD8(+) T-cell response during the TLR agonist stimulation remained largely unknown. Here, we investigated the role of TLR-induced IL-6 in shaping virus-specific CD8(+) T-cell responses in the Friend retrovirus (FV) mouse model. We show that the TLR agonist induced IL-6 counter-regulates effector CD8(+) T-cell responses. IL-6 potently inhibited activation and cytokine production of CD8(+) T cells in vitro. This effect was mediated by a direct stimulation of CD8(+) T cells by IL-6, which induced upregulation of STAT3 phosphorylation and SOCS3 and downregulated STAT4 phosphorylation and T-bet. Moreover, combining TLR stimulation and IL-6 blockade during an acute FV infection resulted in enhanced virus-specific CD8(+) T-cell immunity and better control of viral replication. These results have implications for our understanding of the role of TLR induced pro-inflammatory cytokines in regulating effector T cell responses and for the development of therapeutic strategies to overcome T cell dysfunction in chronic viral infections.

Intravascular coronary stenting has been used in the treatment of coronary artery disease (CAD), with a major limitation of in-stent restenosis (ISR). The 316 stainless steel has been widely used for coronary stents. In this study, we developed a novel coating method to reduce ISR by simultaneously coating vascular endothelial growth factor (VEGF) and anti-CD34 antibody on 316L stainless steel.

We built a cohort study of HIV patients taking long-term first-line Antiretroviral Therapy in 2003. In this assay, we focused on the development of primary drug resistance mutations against Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), K103N, Y181C and G190A.

Epithelial to mesenchymal transition (EMT) of alveolar epithelial cells occurs in lung fibrotic diseases. Tanshinone IIA (Tan IIA) has been reported to exert anti-inflammatory effects in pulmonary fibrosis. Nonetheless, whether Tan IIA affects lung fibrosis-related EMT remains unknown and requires for further investigations.

Periostin (POSTN), a recently characterised matricellular protein, is frequently dysregulated in various malignant cancers and promotes tumor metastatic growth. POSTN plays a critical role in the crosstalk between murine breast cancer stem cells (CSCs) and their niche to permit metastatic colonization. However, whether pro-metastatic capability of POSTN is associated with multipotent potentials of mesenchymal stem cells (MSCs) has not been documented. Here we demonstrate that POSTN promotes a stem cell-like trait and a mesenchymal phenotype in human mammary epithelial cells and breast cancer cells. Interestingly, ectopic overexpression of POSTN or recombinant POSTN treatment can induce human mammary epithelial cells and breast cancer cells differentiation into multiple cell lineages that recapitulate part of the multilineage differentiation potentials of MSCs. Moreover, POSTN is highly expressed in bone marrow-derived MSCs and their derived adipocytes, chondrocytes, and osteoblasts in vitro. Furthermore, POSTN promotes the growth of xenograft tumors in vivo. POSTN-overexpressing human mammary epithelial cells enhance breast tumor growth and metastasis. These data thus provide evidence of a new role for POSTN in mammary epithelial neoplasia and metastasis, suggesting that epithelial cancer cells might acquire CSC-like traits and a mesenchymal phenotype, as well as the multipotent potentials of MSCs to promote tumorigenesis and metastasis. Therefore, targeting POSTN and other extracellular matrix components of tumor microenvironment may help to develop new therapeutical strategies to inhibit tumor metastasis.

High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT).

Sarcoidosis is a systemic granulomatous disease, which is thought to result from an aberrant immune response. CD4+ T lymphocytes play an important role in the development of granulomas. Previously, the immunopathogenesis of sarcoidosis was focused on Th1/Th2 disturbances. The aim of this study was to evaluate the balance between newer CD4+ T lymphocytes, i.e., Treg and Th17 cells. In our studies, a decrease in Treg cells and an increase in Th17 cells were observed in the peripheral blood and BALF of sarcoidosis patients. A significant increase in the Th17/Treg cell ratio was observed in sarcoidosis patients. After treatment with prednisone, the expression of Foxp3 mRNA was elevated in the peripheral blood, and expression of (ROR)γt mRNA showed a downward trend. These findings suggest that sarcoidosis is associated with an imbalance between Th17 and Treg cells in peripheral blood and BALF. Therefore, targeting the cytokines that affect the Th17/Treg ratio could provide a new promising therapy for pulmonary sarcoidosis.

Behavioral research has demonstrated that males have a higher capability of regulating their own and others' emotions than females; however, little is known about the sex-specific brain mechanisms involved in emotion regulation ability. In the present study, we used voxel-based morphometry to investigate the neural basis underlying emotion regulation ability in a large sample of young adults. Assessment of emotion regulation ability was performed using the Wong and Law Emotional Intelligence Scale. As expected, males significantly scored higher in emotion regulation ability than females did. More importantly, we found the sex differences in the neuroanatomical basis of emotion regulation ability. Males showed a stronger positive relation between emotion regulation ability and regional gray matter volume (rGMV) in the right dorsolateral prefrontal cortex. In contrast, females demonstrated a stronger positive relation between emotion regulation ability and rGMV in an anatomical cluster that extends from the left brainstem to the left hippocampus, the left amygdala and the insular cortex. The present study provides the first empirical evidence regarding the sex-linked neuroanatomical correlates of emotion regulation ability. These findings may help understand why there is a higher prevalence of affective disorders in females and maladaptive behaviors in males.

In functional magnetic resonance imaging studies, object selectivity is defined as a higher neural response to an object category than other object categories. Importantly, object selectivity is widely considered as a neural signature of a functionally-specialized area in processing its preferred object category in the human brain. However, the behavioral significance of the object selectivity remains unclear. In the present study, we used the individual differences approach to correlate participants' face selectivity in the face-selective regions with their behavioral performance in face recognition measured outside the scanner in a large sample of healthy adults. Face selectivity was defined as the z score of activation with the contrast of faces vs. non-face objects, and the face recognition ability was indexed as the normalized residual of the accuracy in recognizing previously-learned faces after regressing out that for non-face objects in an old/new memory task. We found that the participants with higher face selectivity in the fusiform face area (FFA) and the occipital face area (OFA), but not in the posterior part of the superior temporal sulcus (pSTS), possessed higher face recognition ability. Importantly, the association of face selectivity in the FFA and face recognition ability cannot be accounted for by FFA response to objects or behavioral performance in object recognition, suggesting that the association is domain-specific. Finally, the association is reliable, confirmed by the replication from another independent participant group. In sum, our finding provides empirical evidence on the validity of using object selectivity as a neural signature in defining object-selective regions in the human brain.

Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15) is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co-expression of IL15 with the α subunit of IL15 receptor (IL15Rα) greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Rα-tdTr), which expresses an IL15Rα-IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13) cells infected with vMyx-IL15Rα-tdTr expressed and secreted the IL15Rα-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY) cell lines were permissive to vMyx-IL15Rα-tdTr infection. In vivo experiments in RAG1-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Rα-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx-tdTr). Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Rα-tdTr treated tumors compared to the controls. In vivo experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8+ T cells in response to vMyx-IL15Rα-tdTr, and prolonged survival. We conclude that delivery of IL15Rα-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system.

Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As a common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression.

The HECT domain-containing ubiquitin E3 ligase NEDD4 is widely expressed in mammalian tissues and plays a crucial role in governing a wide spectrum of cellular processes including cell growth, tissue development and homeostasis. Recent reports have indicated that NEDD4 might facilitate tumorigenesis through targeted degradation of multiple tumor suppressor proteins including PTEN. However, the molecular mechanism by which NEDD4 stability is regulated has not been fully elucidated. Here we report that SCF(β-TRCP) governs NEDD4 protein stability by targeting it for ubiquitination and subsequent degradation in a Casein Kinase-I (CKI) phosphorylation-dependent manner. Specifically, depletion of β-TRCP, or inactivation of CKI, stabilized NEDD4, leading to down-regulation of its ubiquitin target PTEN and subsequent activation of the mTOR/Akt oncogenic pathway. Furthermore, we found that CKIδ-mediated phosphorylation of Ser347 and Ser348 on NEDD4 promoted its interaction with SCF(β-TRCP) for subsequent ubiquitination and degradation. As a result, compared to ectopic expression of wild-type NEDD4, introducing a non-degradable NEDD4 (S347A/S348A-NEDD4) promoted cancer cell growth and migration. Hence, our findings revealed the CKI/SCF(β-TRCP) signaling axis as the upstream negative regulator of NEDD4, and further suggested that enhancing NEDD4 degradation, presumably with CKI or SCF(β-TRCP) agonists, could be a promising strategy for treating human cancers.

Bone marrow mesenchymal stem cell (BMSCs)-based therapy seems to be a promising treatment for acute lung injury, but the therapeutic effects of BMSCs transplantation on acute lung injury induced by brain ischemia and the mechanisms have not been totally elucidated. This study explores the effects of transplantation of BMSCs on acute lung injury induced by focal cerebral ischemia and investigates the underlying mechanism.

Most migraineurs develop cutaneous allodynia (CA) during migraine, and the underlying mechanism of CA in migraine is thought to be sensitization of the third-order trigeminovascular neurons in the posterior thalamic nuclei. This study aimed to investigate whether the ascending/descending pathway associated with the thalamus is disturbed in migraineurs with CA (MWCA) using effective connectivity analysis of resting-state functional magnetic resonance imaging.

Previous studies have demonstrated that patients with posttraumatic stress disorder (PTSD) caused by different types of trauma may show divergence in epidemiology, clinical manifestation and treatment outcome. However, it is still unclear whether this divergence has neuroanatomic correlates in PTSD brains. To elucidate the general and trauma-specific cortical morphometric alterations, we performed a meta-analysis of grey matter (GM) changes in PTSD (N = 246) with different traumas and trauma-exposed controls (TECs, N = 347) using anisotropic effect-size signed differential mapping and its subgroup analysis. Our results revealed general GM reduction (GMR) foci in the prefrontal-limbic-striatal system of PTSD brains when compared with those of TECs. Notably, the GMR patterns were trauma-specific. For PTSD by single-incident traumas, GMR foci were found in bilateral medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), insula, striatum, left hippocampus and amygdala; and for PTSD by prolonged traumas in the left insula, striatum, amygdala and middle temporal gyrus. Moreover, Clinician-Administered PTSD Scale scores were found to be negatively associated with the GM changes in bilateral ACC and mPFC. Our study indicates that the GMR patterns of PTSD are associated with specific traumas, suggesting a stratified diagnosis and treatment for PTSD patients.

Neuroregeneration and apoptosis are two important pathophysiologic changes after spinal cord injury (SCI), but their underlying mechanisms remain unclear. MicroRNAs (miRNAs) play a crucial role in the regulation of neuroregeneration and neuronal apoptosis, research areas that have been greatly expanded in recent years. Here, using miRNA arrays to profile miRNA transcriptomes, we demonstrated that miR-127-3p was significantly down-regulated after spinal cord transection (SCT). Then, bioinformatics analyses and experimental detection showed that miR-127-3p exhibited specific effects on the regulation of neurite outgrowth and the induction of neuronal apoptosis by regulating the expression of the mitochondrial membrane protein mitoNEET. Moreover, knockdown of MitoNEET leaded to neuronal loss and apoptosis in primary cultured spinal neurons. This study therefore revealed that miR-127-3p, which targets mitoNEET, plays a vital role in regulating neurite outgrowth and neuronal apoptosis after SCT. Thus, modificatioin of the mitoNEET expression, such as mitoNEET activition may provide a new strategy for the treatment of SCI in preclinical trials.

Candida glabrata CCTCC M202019 as an industrial yeast strain that is widely used to produce α-oxocarboxylic acid. Strain M202019 has been proven to have a higher pyruvate-producing capacity than the reference strain CBS138. To characterize the genotype of the M202019 strain, we generated a draft sequence of its genome, which has a size of 12.1 Mbp and a GC content of 38.47%. Evidence accumulated during genome annotation suggests that strain M202019 has strong capacities for glucose transport and pyruvate biosynthesis, defects in pyruvate catabolism, as well as variations in genes involved in nutrient and dicarboxylic acid transport, oxidative phosphorylation, and other relevant aspects of carbon metabolism, which might promote pyruvate accumulation. In addition to differences in its central carbon metabolism, a genomic analysis revealed genetic differences in adhesion metabolism. Forty-nine adhesin-like proteins of strain M202019 were identified classified into seven subfamilies. Decreased amounts of adhesive proteins, and deletions or changes of low-complexity repeats and functional domains might lead to lower adhesion and reduced pathogenicity. Further virulence experiments validated the biological safety of strain M202019. Analysis of the C. glabrata CCTCC M202019 genome sequence provides useful insights into its genetic context, physical characteristics, and potential metabolic capacity.

Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8+ T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169+ macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169+ macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus. Lack of CD169+ macrophages also limited the IFN-I-dependent expression of PD-L1. Enhanced viral replication in the absence of PD-L1 led to persistence of virus and prevented CD8+ T-cell exhaustion. As a consequence, mice exhibited severe immunopathology and died quickly after infection. Therefore, CD169+ macrophages are important contributors to the IFN-I response and thereby influence antiviral activity, CD8+ T-cell exhaustion and immunopathology.