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The human serotonin transporter (hSERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process plays an important role in depression. In addition to substrate serotonin, hSERT is also the target of drugs of abuse like cocaine and clinically used antidepressants such as escitalopram and paroxetine. To date, few studies attempt to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of hSERT. The high-resolution X-ray structure of hSERT resolved recently enables us to theoretically study the unbinding of the above four ligands against the S1 or S2 site of hSERT, by means of molecular docking, molecular dynamics (MD) and potential of mean force (PMF) simulations. We proved that for either the S1 or S2 site, the other three ligands (cocaine, escitalopram and paroxetine) are much more favorable than the original substrate serotonin, whether in kinetics along the unbinding pathways or in thermodynamics at the equilibrium states. Furthermore, the S1 site is much more favorable than the S2 site, for each ligand. Interestingly, inspection revealed that there are ~ 3Å lengths between the allosteric site of serotonin and cocaine, and an unseen un-binding pathway for escitalopram at the S1 site except for verification of the broadest trail.

BackgroundTumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown.MethodsHCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10high(Siglec-10hi) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh human tumor tissues.ResultsOur data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan–Meier curves and Cox regression analysis showed that intratumoral Siglec-10+cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10hiTAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hiTAMs. High infiltration of Siglec-10hiTAMs was associated with impaired CD8+T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8+T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab.ConclusionsSiglec-10hiTAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hiTAMs may serve as a promising immunotherapy approach for HCC.

CD74 was initially thought to participate mainly in antigen presentation as an MHC class II chaperone. Recent studies have shown that CD74 plays an important role within the cell and throughout the immune system in a wide spectrum of neoplasms. However, the role of CD74 in hepatocellular carcinoma (HCC) remains elusive. In this study, HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas (TCGA) were obtained and analyzed. Immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq) were performed to detect the characteristics of CD74+ cells and explore their impact on the tumor microenvironment (TME) of HCC. Our data revealed that stromal CD74+ cell enrichment was associated with favorable prognosis in patients with HCC. CD74 was abundant in a large portion of HCC specimens and prominently distributed on stromal macrophages. scRNA-seq data also indicated that the pathways related to immune response were significantly upregulated in CD74+ macrophages. High infiltration of CD74+ macrophages was associated with increased infiltration of CD8+ cytotoxic T lymphocytes (CTLs) with enhanced effector functions in HCC. Besides, blocking CD74 weakened the antitumor activity and proliferation ability of CD8+ CTLs in HCC. Our findings highlight the critical role of CD74 in HCC. New drugs and antibodies targeting CD74 may be effective strategies for HCC therapy.

Objective The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. Methods Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated. Results A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. Discussion Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. Clinical trial registration ClinicalTrials.gov number: NCT02430259

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

Cytomegalovirus (CMV) is a β-herpesvirus that establishes lifelong latency in infected hosts. Following transplantation of a latently infected organ, reactivation can occur and consists of a spectrum of clinically apparent syndromes from mild symptoms to tissue-invasive, resulting in both direct and indirect sequelae. Before the advent of effective antiviral agents, the primary treatment was reduction in immunosuppression (IS). While antiviral agents provide effective prophylaxis, there are several important caveats associated with their use, including drug toxicity and resistance. The traditional view attributes CMV reactivation and the ensuing clinical disease primarily to IS, either intrinsic to disease-related immune compromise or from the extrinsic administration of IS agents. However, previous data from both animal models and human subjects showed that inflammatory signals could induce upregulation of latent viral gene expression. New data demonstrate that ischemia/reperfusion is necessary and sufficient to induce CMV reactivation following murine transplantation of a latently infected graft. In this article, we review a growing body of evidence that suggests that reactivation of both human CMV and murine CMV is first triggered by molecular events that activate CMV gene expression and lytic infection and viral dissemination are then facilitated by IS. The initial activation of viral gene expression may be mediated by oxidative stress, DNA damage, or inflammatory cytokines, and these factors may act synergistically. New therapeutic approaches are needed to capture this complex array of targets.

Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.

Background: Whether T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens can be influenced by tuberculosis preventive treatment in a high-endemic country is uncertain. Methods: In this prospective, open-label, controlled study, 513 individuals with silicosis were randomly selected for TB preventive treatment with rifapentine and isoniazid or for observation. QuantiFERON-TB Gold in-tube (QFT-GIT) assay was used to measure IFN-γ response to M. tuberculosis antigens at baseline (T0) and at 6 (T1) and 33 (T2) months after completion of therapy. Results: A total of 220 subjects were included in the final analysis: 105 and 115 in the prevention and observation arms, respectively. The proportions of QFT-GIT reversion from baseline to T1 were similar in the prevention and observation arms (18.4% vs 12.8%, P = 0.566). However, reversion from baseline to T2 was more frequent in the prevention arm than in the observation arm, but the difference was not significant (24.2% vs 6.3%, P = 0.881). No significant difference was observed in the quantitative responses of QFT-GIT between the two arms during follow-up at T1 (P = 0.648) and T2 (P = 0.918). Conclusions: Preventive tuberculosis treatment has no effect on interferon-γ responses measured by serial QFT-GIT assays in a high tuberculosis-endemic country. Clinical Trials Registration: http://www.clinicaltrials.gov NCT02430259. Keywords: QuantiFERON TB-Gold in-tube, Tuberculosis preventive treatment, Serial tests, Randomized clinical trial

CD34+ myeloid lineage progenitor cells are an important reservoir of latent human cytomegalovirus (HCMV), and differentiation to macrophages or dendritic cells (DCs) is known to cause reactivation of latent virus. Due to its species-specificity, murine models have been used to study mouse CMV (MCMV) latency and reactivation in vivo. While previous studies have shown that MCMV genomic DNA can be detected in the bone marrow (BM) of latently infected mice, the identity of these cells has not been defined. Therefore, we sought to identify and enrich for cellular sites of MCMV latency in the BM haematopoietic system, and to explore the potential for establishing an in vitro model for reactivation of latent MCMV. We studied the kinetics and cellular characteristics of acute infection and establishment of latency in the BM of mice. We found that while MCMV can infect a broad range of haematopoietic BM cells (BMCs), latent virus is only detectable in haematopoietic stem cells (HSCs), myeloid progenitor cells, monocytes and DC-enriched cell subsets. Using three separate approaches, MCMV reactivation was detected in association with differentiation into DC-enriched BMCs cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) followed by lipopolysaccharide (LPS) treatment. In summary, we have defined the kinetics and cellular profile of MCMV infection followed by the natural establishment of latency in vivo in the mouse BM haematopoietic system, including the haematopoietic phenotypes of cells that are permissive to acute infection, establish and harbour detectable latent virus, and can be stimulated to reactivate following DC enrichment and differentiation, followed by treatment with LPS.

Background: Adaptive resistance is one of the major hinderances for unresectable hepatocellular carcinoma (HCC) treated with lenvatinib and anti-programmed cell death protein 1 (anti-PD-1) therapy. Physical activity is known to have anti-cancer effects, including immunomodulatory actions, influencing patients’ outcomes. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC.Methods: The physical activity levels of patients with unresectable HCC treated with combination therapy using lenvatinib plus anti-PD-1 antibodies were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS), analyzed using the Kaplan-Meier method with a log-rank test. Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). Factors associated with survival and ORR were analyzed using regression analyses. A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter. Results: Fifty-nine patients with unresectable HCC were categorized to active (n=28) or sedentary (n=31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI, 0.060-0.799) and PFS (HR = 0.158, 95% CI, 0.044-0.562) and higher ORR (OR = 4.571, 95% CI, 1.482-14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy. Conclusions: Regular physical activity was associated with improved outcomes in patients receiving combined lenvatinib plus anti-PD-1 therapy for unresectable HCC. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

The incidence of ulcerative colitis (UC), an inflammatory bowel disease (IBD), is drastically increasing globally, leading to greater economic hardship and patient morbidity. This study evaluated the effects of chelerythrine on acetic acid (AA)-induced UC in a mouse model. Mice received chelerythrine (25, 50, and 100 mg/kg, i.g.) and sulfasalazine (SASP) (500 mg/kg, i.g.) for 7 consecutive days following the induction of colitis via the intrarectal administration of AA (5% v/v). Disease activity index (DAI), tissue morphology, tissue damage, oxidative stress (OS), and inflammatory markers were then evaluated. The results revealed that the colonic levels of total antioxidant capacity (T-AOC), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) had decreased, while colonic myeloperoxidase (MPO), malondialdehyde (MDA), lipid peroxide (LPO) activity, colonic and serum interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) levels, and serum lactate dehydrogenase (LDH) had all increased significantly in the colitis untreated group compared to that of the normal control. Treatment with chelerythrine considerably improved most of these parameters, and a dose of 100 mg/kg, was found to be comparable to that of 500 mg/kg SASP. This alkaloid also markedly reversed body weight (BW), clinical activity score, gross lesion score, mucosal edema, and colon weight/length in a dose-dependent manner. In conclusion, the protective effect of chelerythrine could be attributed to its anti-inflammatory and antioxidant activities.

A new biflavonoid, (2″ S)-8″-C-methyl-2″,3″-dihydrorobustaflavone-4′-methyl ether (1) and 5 known robustaflavones (2-6) were isolated from the 70% EtOH extract of Selaginella braunii for the first time. The structures of 1 and the known compounds were identified by performing a comprehensive analysis of spectroscopic data including ultraviolet-visible, high-resolution electrospray ionization mass spectrometry, 1-dimensional and 2-dimensional nuclear magnetic resonance, and circular dichroism spectra. Compounds 1-6 were determined for cytotoxic activity against 3 human cancer cell lines (SMMC-7721, MCF-7, and A549). Compound 1 exerted apparent antiproliferative effects on SMMC-7721, MCF-7, and A549 cells, with IC50 values of 18.6, 16.7, and 25.5 μM, respectively.

This report derives the exact solutions for the problem of a magneto-electro-elastic cylinder with a penny-shaped and embedded crack subjected to transient thermal load. Thermal cracking is analysed in the theoretical framework of linear magneto-electro-thermo-elasticity. The heat conduction equation for a magneto-electro-thermo-elastic cylinder with a finite size is solved using the standard method of separation variables. The coupling magneto-electro-thermo-elastic fields are determined in a stationary case via the Hankel integral transform. Based on Abel’s integral equation and the dual integral equation, the mathematical formulations for the permeable crack conditions are derived. Solutions to the elastic, electric, and magnetic intensity factors are obtained. Due to the explicitness of these solutions, they are very interesting for the design and analysis of magneto-electro-thermo-elastic composites.

High-flux measurement characteristics of compressed sensing (CS) imaging causes the imaging system prone to be disturbed by quantization. To realize high-quality CS imaging with limited detector bits, an improved imaging method combining sparse measurements and multiple dithers is proposed to reduce the dynamic range of the measured signals and increase that of effective detection. Simulations and experiments show that compared with traditional CS imaging, the proposed system decreases reconstruction errors caused by quantization distortions and may reduce the required number of detector bits to 1. The effects of detector noise and system parameters are discussed to validate the feasibility and performance of this method.

Sequential double extension twinning in AZ31 Mg alloy happens easily during sequential biaxial compressions. Widespread twin-twin interaction leads to the formation of intragranular cross-level twin pairs, each of which can be defined by a primary twin variant PVi (i = 1–6) and its nearby secondary twin variant PVj-SVk (j, k = 1–6, j ≠ i, k) across the twin-twin boundary between them. Theoretically, 9 possible misorientations exist between the two variants. Misorientation between two crystals can be expressed by a pair of rotation axis (r) and the minimum rotation angle (θ). The crystallography of a cross-level twin pair can be described unanimously by the misorientations between PVi and PVj-SVk (i.e., r1-θ1), PVi and PVj (i.e., r2-θ2), and the host grain and PVj-SVk (i.e., r3-θ3), resulting in 13 possible orientation relationships (ORs) that can be expressed explicitly by the three misorientation angles (θ1, θ2, θ3). A cross-level twin pair is a key element of a crossing or crossed twin structure, which is common in the deformed microstructure. Statistical electron backscatter diffraction analysis reveals that OR2 of (49.7°, 60°, 60°) appears the most frequently. Twinning shear transmission is almost irrelevant to the formation of a cross-level twin pair. Although the majority of the identified twins are high Schmid factor (SF) ones with SF > 0.3 and SF ratio > 0.8, SF analysis fails to explain the highly preference of OR2 and the abnormal absence of OR8 of (44.0°, 60°, 60.4°), probably due to the complexity of the formation of a cross-level twin pair.

Magneto-electro-elastic composite with a penny-shaped crack is analyzed. The exact solution of temperature field based on non-Fourier heat conduction is derived by the method of standard separation of variables. The thermal stress, electrical displacement and magnetic induction in the transversely isotropic and axis-symmetric magneto-electro-elastic cylinder are evaluated by Hankel transform technique. The thermal stress, electrical displacement and magnetic induction intensity factors at the tip of penny-shaped crack are obtained by Abel type integral equation. The influence of the thermal relaxation time, crack length, characteristic length of materials and magneto-electro-thermo-elastic coupling on intensity factors are analyzed. Thermal shock resistance of MEE cylinder is evaluated by associating the stress based failure criterion and fracture mechanics based failure criterion.

With the help of trace analysis, cross-grain boundary (cross-GB) contraction twin (CTW) pairs and bands can be identified more easily in a deformed Mg alloy. Cross-GB CTW pairs can form in two neighboring grains with misorientations from 5° to 60°. Schmid factor (SF) analysis reveals that the majority of them are high SF twin variants, indicating that the applied macro stress plays the most important role in their nucleation. Twinning shear compatibility over GB has been explicitly evaluated by a geometrical compatibility parameter (m′). It is found that nearly half of the cross-GB contraction twin pairs have high m′ values greater than 0.7, indicating that their formation is mainly due to twinning shear transmission over GBs. However, dramatically different from cross-GB extension twin pairs and bands reported before, the rest of the cross-GB contraction twin pairs have low m′ values smaller than 0.4. Their formation is due to the dominance of the applied macro stress near GBs.

Reactivation of latent cytomegalovirus remains an important complication after transplant. Although immunosuppression (IS) has been implicated as a primary cause, we have previously shown that the implantation response of a kidney allograft can lead to early transcriptional activation of latent murine cytomegalovirus (MCMV) genes in an immune-competent host and to MCMV reactivation and dissemination to other organs in a genetically immune-deficient recipient. We now describe a model that allows us to separately analyze the impact of the implantation effect vs that of a clinically relevant IS regimen. Treatment with IS of latently infected mice alone does not induce viral reactivation, but transplant of latently infected allogeneic kidneys combined with IS facilitates MCMV reactivation in the graft and dissemination to other organs. The IS regimen effectively dampens allo-immune inflammatory pathways and depletes recipient anti-MCMV but does not affect ischemia-reperfusion injury pathways. MCMV reactivation similar to that seen in allogeneic transplants combined with also occurs after syngeneic transplants. Thus, our data strongly suggest that while ischemia-reperfusion injury of the implanted graft is sufficient and necessary to initiate transcriptional reactivation of latent MCMV ("first hit"), IS is permissive to the first hit and facilitates dissemination to other organs ("second hit").

Background The use of angiotensin II inhibitors is associated with a low risk of recurrence and metastasis in hepatocellular carcinoma (HCC) patients. Vascular cell adhesion molecule-1 (VCAM-1) is a key factor in tumor metastasis. Methods The effects of angiotensin II and irbesartan (an angiotensin II inhibitor) on HCC were explored with a xenograft model, microarray analysis and cell adhesion experiments. The relationship between the expression of VCAM-1 in HCC tissues and prognosis was analyzed with public and our institutional clinical databases. The effects of angiotensin II, irbesartan and VCAM-1 on adhesion and metastasis in HCC were explored with a xenograft model and cell adhesion experiments. The regulatory mechanisms were analyzed by Western blot analysis. Results Angiotensin II type 1 receptor and VCAM-1 were expressed in HCC tissues. Irbesartan inhibited HCC growth and metastasis in vivo and weakened the adhesion of HCC cells to endothelial cells, an effect that was enhanced by angiotensin II. VCAM-1 was found to be an independent risk factor for recurrence and survival in HCC patients with microvascular invasion. Angiotensin II upregulated VCAM-1 expression, and this upregulation was inhibited by irbesartan. Angiotensin II enhanced adhesion mainly by promoting the expression of VCAM-1 in HCC cells. Irbesartan inhibited the expression of VCAM-1 by reducing p38/MAPK phosphorylation activated by angiotensin II in HCC cells. Conclusions Irbesartan attenuates metastasis by inhibiting angiotensin II-activated VCAM-1 via the p38/MAPK pathway in HCC.

An experiment on compressive microscopic imaging with single-pixel detector and single-arm has been performed on the basis of “positive–negative” (differential) light modulation of a digital micromirror device (DMD). A magnified image of micron-sized objects illuminated by the microscope's own incandescent lamp has been successfully acquired. The image quality is improved by one more orders of magnitude compared with that obtained by conventional single-pixel imaging scheme with normal modulation using the same sampling rate, and moreover, the system is robust against the instability of light source and may be applied to very weak light condition. Its nature and the analysis of noise sources is discussed deeply. The realization of this technique represents a big step to the practical applications of compressive microscopic imaging in the fields of biology and materials science.

Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-κB. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-κB transcription factor family and we demonstrate that canonical NF-κB (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1β, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.

Accurate evaluation of the thermal shock resistance is great importance when estimating both the life and the performance of piezoelectric structures under thermal shock load. Non-Fourier heat conduction law assumed that the speed of heat propagation in a body is finite, which is more exact to evaluate the thermal shock resistance when the thermal shock time reduces to ps/fs scale or the length size of materials reduces to micro/nanoscale. A hyperbolic heat conduction equation was used to study the thermal shock resistance of a cylindrical piezoelectric structure, in which a permeable penny-shaped crack is considered. The analytical solution of non-Fourier temperature filed is determined by the method of separated variable. The formulas of the associating thermal stress and electrical displacement in the piezoelectric cylinder without crack were obtained. The crack problem is solved by the Dual integral equation and Abel integral equation. The thermal shock resistance is evaluated by associating the stress-based and fracture mechanics-based failure criteria.

In order to determine the structure-performance relationship of nonionic-zwitterionic hybrid surfactants, N,N-dimethyl-N-dodecyl polyoxyethylene (n) amine oxides (C12EOnAO) with different polyoxyethylene lengths (EOn, n = 1–4) were synthesized. For homologous C12EOnAO, it was observed that the critical micelle concentration (CMC), the maximum surface excess (Γm), CMC/C20, and the critical micelle aggregation number (Nm,c) decreased on going from 1 to 4 in EOn. However, there were concomitant increases in surface tension at the CMC (γCMC), minimum molecular cross-sectional area (Amin), adsorption efficiency (pC20), and the polarity ([I1/I3]m) based on the locus of solubilization for pyrene. The values of log CMC and Nm,c decreased linearly with EOn lengthening from 1 to 4, although the impact of each EO unit on the CMC of C12EOnAO (n = 1–4) was much smaller than that typically seen for methylene units in the hydrophobic main chains of traditional surfactants. Compared to the structurally related conventional surfactant N,N-dimethyl-N-dodecyl amine oxide (C12AO), C12EOnAO (n = 1–4) have smaller CMC, Amin, and CMC/C20, but larger pC20, Γm, and Nm,c with a higher [I1/I3]m. This may be attributed to the moderately amphiphilic EOn (n = 1–4) between the hydrophobic C12 tail and the hydrophilic AO head group.

Copper foils for flexible printed circuit boards were prepared by double rolling, and the matt surface of double-rolled copper foil was characterized by atomic force microscope, scanning electron microscope, 3D optical interferometer, optical microscope and surface profiler. The morphology characteristics of matt surface were studied, and the formation mechanism of matt surface was discussed. The results showed that the matt surface of the double-rolled copper foil presented rough and relatively homogeneous morphology, and the morphologies of upper and lower matt surfaces were practically coincident. As the copper strips just entered into the deforming zone, the roughening of laminated surface occurred, but the roughness was relatively small. When the copper strips passed through the neutral plane, the roughness of the laminated surface increased significantly. In the backward slip zone, the initial micro-dimples between the two laminated surfaces were connected in the rolling direction, which led to the formation of larger and airtight dimples; when the copper strips moved toward the neutral plane and entered into the forward slip zone, the pressure of fluid in the airtight dimples increased rapidly, which enhanced the depths of the dimples; meanwhile, the depression corrugations with certain depth and larger width were formed on the laminated surface because of the dimple connection in the width direction. The copper foils with thickness of 36–54 μm were fabricated by double rolling, and the R z value of their matt surfaces was 1.0–1.3 μm, which meet the requirements for directly using as adhesive surface of resin substrate, and therefore multiple roughening treatments during the traditional production process of flexible printed circuit board might be omitted. The formation mechanism of the matt surface of double-rolled copper foil proposed on the basis of the metal flow and deformation mechanics theory could explain the representative characteristics of the length direction of corrugations on matt surface being perpendicular to the rolling direction, several corrugations within a grain on the matt surface and the coincident morphologies of the upper and lower matt surfaces.

Myeloid cells are important cell types that carry human cytomegalovirus. Latent viral DNA is present in CD34+ progenitor cells and their derived monocytes. However, differentiation of latently infected monocytes to mature macrophages or dendritic cells causes reactivation of latent viruses. During hematopoietic development, pluripotent genes are repressed, and lineage specific genes are activated in a step-wise manner. This process is governed by cell-type specific chromatin states. Enhancers in the hematopoietic system are highly dynamic and established by pioneer (first tier) transcription factors (TFs), which set the stage for second and third tier TF binding. In this review, we examine the epigenetic mechanisms that regulate myeloid cell development, cell identity, and activation with a special focus on factors that regulate viral gene expression and the status of viral infection in myeloid cells.

Developing ultra-thin copper foils with different surface roughness and microstructure has important significance for improving the service performance and reducing the production cost of high-end circuit boards. In this paper, pure copper strips with initial cube texture were subjected to a double rolling process (deformation amount ranges from 50% to 95%), and the surface textures evolution law and mechanism of double-rolled strips were studied by an X-ray diffraction technique. The results show that when a deformation amount increased from 50% to 70%, the grains of two surfaces rotate away from the cube orientation, and the formed textures of two surfaces mainly consisted of C, S and B orientation components. The orientation density values for these three components on bright surface only had slight difference; the orientation density values for C and S components were much larger than that for B components on a matt surface. When the deformation amount increased to 90%, the increase extents of orientation density values for C and S components were obviously larger than that for B components on a bright surface; the increase extents of orientation density values for these three components were almost the same on the matt surface. It has been found that when deformation amount reaches 95%, the grains orientation of bright surface were relatively concentrated, and the orientation density value for C texture obviously increased to 11.68 and that for B texture was only 3.15; the grains orientation of matt surface were relatively dispersed, and the orientation density value for C texture increased to 9.26 and that for B texture obviously increased to 6.35, and the density values of these two textures had less difference. For the condition of strong compressive and shear stress on the bright surface, grains were mainly rotating to C texture orientation; compared with the bright surface, “semi-free” deformation condition on the matt surface is beneficial to promote much more grains to rotate to the B texture orientation.

Compressive sensing (CS) has been used in LiDAR systems utilizing one single-photon-counting avalanche diode. We demonstrate an unexpected grayscale inversed image of an object at an unchosen depth, which appears in the reconstruction of the infrared single-pixel LiDAR system due to the pile-up effect. A correction algorithm and the sparse measurement are proposed and experimentally verified to effectively reduce the photon pile-up influence, so that the negative images can be completely removed. The correction methods in this research can improve the accuracy and the flexibility of the single-pixel LiDAR systems employing detectors with a low maximum light count.

Nonionic–zwitterionic hybrid surfactants, namely N,N-dimethyl-N-dodecyl polyoxyethylene (3) amine oxide, and the corresponding betaine and/or sulfobetaine, have been synthesized. Their molecule structures were characterized by means of electrospray ionization mass spectrometry and 1H nuclear magnetic resonance. Compared to the structurally related conventional amine oxide, betaine and sulfobetaine, the critical micelle concentrations of the three hybrid surfactants are one order of magnitude smaller than those of traditional ones. The polyoxyethylene segment between the hydrophilic head group and the hydrophobic tail makes the surface activities of the hybrid surfactants superior to their structure-related counterparts.

Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit co-repressor complexes. Kinetic analyses of repressor binding show that these repressors are recruited at the earliest time of infection, suggesting that latency may be the default state. Kidney transplantation leads to epigenetic reprogramming of latent viral chromatin and reactivation of immediate early gene expression. Inflammatory signaling pathways, which activate transcription factors that regulate the major immediate early promoter (MIEP), likely mediate the switch in viral chromatin.

A new theory of two-phase zone continuous casting (TZCC) has been established in order to improve mechanical properties, corrosion resistance and conductivity properties of metals with wide solid–liquid two-phase zone. A Cu–Sn alloy with continuous columnar grains-covered non-columnar small grains of same phase microstructure containing many self-closed grain boundaries were produced by the self-developed TZCC process. Compared with water-cooled mold continuous casting Cu–Sn alloy, the tensile strength and ductility of the TZCC alloy are greatly improved, the corrosion resistance is improved up to fifteenfold, and the conductivity is improved by 12.2%. The excellent high strength may be due to the effective blockage of dislocation motion by numerous self-closed grain boundaries, which suppress the propagation of grain boundary corrosion, and the extremely low electrical resistivity and high ductility may be attributed to continuous columnar grains.