We present spectral hole-burning measurements of the 4I9/2 → 4F3/2 transition in Nd3+:YLiF4. The isotope shifts of Nd3+ can be directly resolved in the optical absorption spectrum. We report atomic frequency comb storage with an echo efficiency of up to 35% and a memory bandwidth of 60 MHz in this material. The interesting properties show the potential of this material for use in both quantum and classical information processing.
The Gauss-Seidel method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the Gauss-Seidel method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of CPUs. In contrast to other existing solutions, our method does not require any assumptions and is equally applicable for solving linear and nonlinear equations. This approach is implemented in the DelPhi program, which is a finite difference Poisson-Boltzmann equation solver to model electrostatics in molecular biology. This development makes the iterative procedure on obtaining the electrostatic potential distribution in the parallelized DelPhi several folds faster than that in the serial code. Further we demonstrate the advantages of the new parallelized DelPhi by computing the electrostatic potential and the corresponding energies of large supramolecular structures.
electrostatics; DelPhi; Poisson- Boltzmann equation; Gauss-Seidel iteration; parallel computing
The purpose of this study was to investigate in vivo three- dimensional tibiofemoral kinematics and femoral condylar motion in knees with anterior cruciate ligament (ACL) deficiency during a knee bend activity. Ten patients with unilateral ACL rupture were enrolled. Both the injured and contralateral normal knees were imaged using biplane radiography at extension and at 15°, 30°, 60°, 90°, and 120° of flexion. Bilateral knees were next scanned by computed tomography, from which bilateral three-dimensional knee models were created. The in vivo tibiofemoral motion at each flexion position was reproduced through image registration using the knee models and biplane radiographs. A joint coordinate system containing the geometric center axis of the femur was used to measure the tibiofemoral motion. In ACL deficiency, the lateral femoral condyle was located significantly more posteriorly at extension and at 15° (p < 0.05), whereas the medial condylar position was changed only slightly. This constituted greater posterior translation and external rotation of the femur relative to the tibia at extension and at 15° (p < 0.05). Furthermore, ACL deficiency led to a significantly reduced extent of posterior movement of the lateral condyle during flexion from 15° to 60° (p < 0.05). Coupled with an insignificant change in the motion of the medial condyle, the femur moved less posteriorly with reduced extent of external rotation during flexion from 15° to 60° in ACL deficiency (p < 0.05). The medial- lateral and proximal-distal translations of the medial and lateral condyles and the femoral adduction-abduction rotation were insignificantly changed after ACL deficiency. The results demonstrated that ACL deficiency primarily changed the anterior-posterior motion of the lateral condyle, producing not only posterior subluxation at low flexion positions but also reduced extent of posterior movement during flexion from 15° to 60°.
Three-dimensional tibiofemoral kinematics and femoral condylar motion in ACL-deficient knees during upright weight-bearing flexion were measured using biplane radiography with the geometric center axis.
ACL deficiency caused posterior subluxation of the lateral condyle with excess external femoral rotation at early flexion positions.
On flexion from 15° to 60°, the lateral condyle moved slightly posteriorly in ACL deficiency leading to reduced extent of external femoral rotation.
anterior cruciate ligament; injury; kinematics; tibiofemoral; femoral condyle; radiography
The selection criteria for patients with hepatocellular carcinoma (HCC) to undergo liver transplantation should accurately predict posttransplant recurrence while not denying potential beneficiaries. In the present study, we attempted to identify risk factors associated with posttransplant recurrence and to expand the selection criteria.
Patients and Methods
Adult patients with HCC who underwent liver transplantation between November 2004 and September 2012 at our centre were recruited into the current study (N = 241). Clinical and pathological data were retrospectively reviewed. Patients who died during the perioperative period or died of non-recurrence causes were excluded from this study (N = 25). All potential risk factors were analysed using uni- and multi-variate analyses.
Sixty-one recipients of 216 qualified patients suffered from recurrence. Similar recurrence-free and long-term survival rates were observed between living donor liver transplant recipients (N = 60) and deceased donor liver transplant recipients (N = 156). Total tumour volume (TTV) and preoperative percentage of lymphocytes (L%) were two independent risk factors in the multivariate analysis. We propose a prognostic score model based on these two risk factors. Patients within our criteria achieved a similar recurrence-free survival to patients within the Milan criteria. Seventy-one patients who were beyond the Milan criteria but within our criteria also had comparable survival to patients within the Milan criteria.
TTV and L% are two risk factors that contribute to posttransplant recurrence. Selection criteria based on these two factors, which are proposed by our study, expanded the Milan criteria without increasing the risk of posttransplant recurrence.
Human monocytes/macrophages (M/MФ) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/MØ can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/MØ, and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/MØ remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/MØ to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways—a novel mechanism underlying cellular responses to external or internal cues.
To assess the relationship between cognitive decline of older patients (≥65 years) and utilization of primary care physician (PCP) services over 24-months.
Retrospective analysis of prospectively collected data from a cluster randomized trial that took place from 2006 to 2010 and investigated the relationship between formal neuropsychological evaluation and patient outcomes in primary care.
Twenty-four PCPs in 11 practices in southwestern Pennsylvania. Most practices were suburban and included more than 5 PCPs.
A sample of 423 primary care patients 65 years or older.
The association between the number of PCP visits and a decline in cognitive status, as determined by multivariable analyses that controlled for patient-level, physician-level, and practice-level factors (e.g., patient age, comorbidities, and symptoms of depression; practice location and size; PCP age and sex) and used a linear mixed model with a random intercept to adjust for clustering.
Over a two year follow-up, 199 patients (47.0%) experienced a decline in cognitive status. Patients with a cognitive decline had a mean of 0.69 more PCP visits than did patients without a cognitive decline (P<0.05).
Early signs of cognitive decline may be an indicator of greater utilization of primary care. Given the demographic trends, more PCPs are likely to be needed to meet the increasing needs of the older population.
cognitive and psychological function; comorbidity; older adults; primary care; utilization
Huang-lian-jie-du-tang (HLJDT), a traditional Chinese medicine, has been shown to improve insulin resistance (IR) induced by inflammation, a key event in the development of metabolic syndrome (MS). The present study aimed to investigate the protective effects of HLJDT on MS and explore the underlying mechanism. MS rats were established with obese-diets and treated with normal saline, aspirin or HLJDT. The myocardial lesions were identified by echocardiogram, transmission electron microscope, and Sirius-red staining. The inflammatory cytokines were measured by ELISA and real-time PCR. The activation of NF-κB, JNK, SOCS3, IRS1 and AKT in the heart was detected by immunohistochemistry and Western blot analysis. Compared with the controls, MS rats developed obvious obesity, hypertension, dyslipidemia, IR, inflammation, and cardiac damage. Moreover, phosphorylated IRS-1 at Ser307 was correlated with the activation of NF-κB, JNK and SOCS3 and the inhibition of AKT in the heart from MS rats. These data suggest that serine phosphorylation of IRS-1 in response to inflammation is mediated, in part, by NF-κB, JNK and SOCS3. Notably, HLJDT inhibited the activation of NF-κB and reduced serine phosphorylation of IRS-1. In summary, HLJDT protects myocardium from IR-mediated injury by inhibiting serine phosphorylation of IRS-1 in MS rats.
AIM: To analyze the prognostic factors of 5-year survival and 10-year survival in hepatocellular carcinoma (HCC) patients, and to explore the reasons for long-term survival and provide choice of treatment modalities for HCC patients.
METHODS: From January 1990 to October 2012, 8450 HCC patients were included in a prospective database compiled by the Information Center after hospital admission. Long-term surviving patients were included in a 10-year survival group (520 patients) and a 5-year survival group (1516 patients) for analysis.The long-term survival of HCC patients was defined as the survival of 5 years or longer. Clinical and biologic variables were assessed using univariate and multivariate analyses. The survival of patients was evaluated by follow-up data.
RESULTS: The long-term survival of HCC patients was associated with the number of lesions, liver cirrhosis and Child-Pugh classification. It was not found to be associated with tumor diameter, histological stage, and pretreatment level of serum α-fetoprotein. The differences in clinical factors between the 5-year survival and the 10-year survival were found to be the number of lesions, liver cirrhosis, Child-Pugh classification, and time elapsed until first recurrence or metastasis. The survival period of different treatment modalities in the patients who survived for 5 years and 10 years showed significant differences: (in order of significance) surgery alone > surgery-transcatheter arterial chemoembolization (TACE) > TACE-radiofrequency ablation (RFA) > TACE alone > surgery-TACE-RFA. The 10-year survival of HCC patients was not associated with the choice of treatment modality.
CONCLUSION: This retrospective study elucidated survival outcomes, prognostic factors affecting survival and treatment modalities in HCC patients.
Hepatocellular carcinoma; Surgery; Radiofrequency ablation; Transcatheter arterial chemoembolization; Statistical analysis; Clinical study
Summary: A new edition of the DelPhi web server, DelPhi web server v2, is released to include atomic presentation of geometrical figures. These geometrical objects can be used to model nano-size objects together with real biological macromolecules. The position and size of the object can be manipulated by the user in real time until desired results are achieved. The server fixes structural defects, adds hydrogen atoms and calculates electrostatic energies and the corresponding electrostatic potential and ionic distributions.
Availability and implementation: The web server follows a client–server architecture built on PHP and HTML and utilizes DelPhi software. The computation is carried out on supercomputer cluster and results are given back to the user via http protocol, including the ability to visualize the structure and corresponding electrostatic potential via Jmol implementation. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
Supplementary data are available at Bioinformatics online.
The Bateson–Dobzhansky–Muller (BDM) model of reproductive isolation by genetic incompatibility is a widely accepted model of speciation. Because of the exceptionally rich biological information about the budding yeast Saccharomyces cerevisiae, the identification of BDM incompatibilities in yeast would greatly deepen our understanding of the molecular genetic basis of reproductive isolation and speciation. However, despite repeated efforts, BDM incompatibilities between nuclear genes have never been identified between S. cerevisiae and its sister species S. paradoxus. Such negative results have led to the belief that simple nuclear BDM incompatibilities do not exist between the two yeast species. Here, we explore an alternative explanation that such incompatibilities exist but were undetectable due to limited statistical power. We discover that previously employed statistical methods were not ideal and that a redesigned method improves the statistical power. We determine, under various sample sizes, the probabilities of identifying BDM incompatibilities that cause F1 spore inviability with incomplete penetrance, and confirm that the previously used samples were too small to detect such incompatibilities. Our findings call for an expanded experimental search for yeast BDM incompatibilities, which has become possible with the decreasing cost of genome sequencing. The improved methodology developed here is, in principle, applicable to other organisms and can help detect epistasis in general.
genetic incompatibility; reproductive isolation; yeast; speciation; simulation; odds ratio
Background and Aims
The glycoprotein (G protein) and fusion protein (F protein) of respiratory syncytial virus (RSV) both show genetic variability, but few studies have examined the F protein gene. This study aimed to characterize the molecular epidemiology and phylodynamics of the F protein gene in clinical RSV strains isolated in northern Taiwan from 2000–2011.
RSV isolates from children presenting with acute respiratory symptoms between July 2000 and June 2011 were typed based on F protein gene sequences. Phylogeny construction and evaluation were performed using the neighbor-joining (NJ) and maximum likelihood (ML) methods. Phylodynamic patterns in RSV F protein genes were analyzed using the Bayesian Markov Chain Monte Carlo framework. Selection pressure on the F protein gene was detected using the Datamonkey website interface.
From a total of 325 clinical RSV strains studied, phylogenetic analysis showed that 83 subgroup A strains (RSV-A) could be further divided into three clusters, whereas 58 subgroup B strains (RSV-B) had no significant clustering. Three amino acids were observed to differ between RSV-A and -B (positions 111, 113, and 114) in CTL HLA-B*57- and HLA-A*01-restricted epitopes. One positive selection site was observed in RSV-B, while none was observed in RSV-A. The evolution rate of the virus had very little change before 2000, then slowed down between 2000 and 2005, and evolved significantly faster after 2005. The dominant subtypes of RSV-A in each epidemic were replaced by different subtypes in the subsequent epidemic.
Before 2004, RSV-A infections were involved in several small epidemics and only very limited numbers of strains evolved and re-emerged in subsequent years. After 2005, the circulating RSV-A strains were different from those of the previous years and continued evolving through 2010. Phylodynamic pattern showed the evolutionary divergence of RSV increased significantly in the recent 5 years in northern Taiwan.
Cranial radiation therapy has been used for the treatment of primary and metastatic brain tumors. A prominent feature of brain injury induced by the radiation therapy is hippocampal dysfunction, characterized by a decline in memory. Cdk5 plays an important role in memory formation. Abnormal Cdk5 activity is associated with neuronal apoptosis induced by neurotoxic stimuli. However, the roles of Cdk5 in hippocampal apoptosis in response to X-ray irradiation have not been explored.
The expression of Cdk5 activators, p35 and p25, in hippocampal neurons was tested in both in vivo animal and in vitro couture after X-ray irradiation.
After X-ray irradiation at 20 Gy and 30 Gy in rats, the number of hippocampal neuronal pyknosis was increased, but the number of hippocampal neuron was decreased, in the hippocampal CA1 region of rats. In these animals undergone with X-ray irradiation, the expression of p35 was significantly down-regulated, but it was up-regulated in p25. These opposite expressions were also shown in the primary cultured hippocampal neurons with 30 Gy irradiation. The apoptosis induced by X-ray irradiation were significantly prevented by the pretreatment of Cdk5 inhibitor, roscovitine, in both in vivo and in vitro settings.
X-ray irradiation resulted in a hippocampal neuronal apoptosis through up-regulation of p25, the Cdk5 activator. Hyperactivity of Cdk5 was involved in the pathogenesis of X-ray irradiation-induced hippocampal neuronal apoptosis. Blockade of Cdk5 signal pathway effectively protected neurons from the irradiation-induced brain injury.
Cdk5; p35; p25; Apoptosis; Irradiation; Hippocampus
Interleukin-6, a multifunctional cytokine, contributes to tumor cell proliferation and differentiation. However, the biological mechanisms that are affected by the expression of interleukin-6 in bladder cancer cells remain unclear. We evaluated the effects of interleukin-6 expression in human bladder carcinoma cells in vitro and in vivo. The results of interleukin-6-knockdown experiments in T24 cells and interleukin-6-overexpression experiments in HT1376 cells revealed that interleukin-6 reduced cell proliferation, migration, and invasion in vitro. Xenograft animal studies indicated that the overexpression of interleukin-6 downregulated tumorigenesis of bladder cells and that interleukin-6 knockdown reversed this effect. The results of RT-PCR, immunoblotting, and reporter assays indicated that the overexpression of interleukin-6 upregulated the expression of the mammary serine protease inhibitor (MASPIN), N-myc downstream gene 1 (NDRG1), and KAI1 proteins in HT1376 cells and that interleukin-6 knockdown reduced the expression of these proteins in T24 cells. In addition, results of immunoblotting assays revealed that interleukin-6 modulated epithelial-mesenchymal transitions by upregulating the expression of the E-cadherin, while downregulation N-cadherin and vimentin proteins. Our results suggest that the effects of interleukin-6 on the regulation of epithelial-mesenchymal transitions and the expressions of the MASPIN, NDRG1, and KAI1 genes attribute to the modulation of tumorigenesis in human bladder carcinoma cells.
The study of open quantum systems is important for fundamental issues of quantum physics as well as for technological applications such as quantum information processing. Recent developments in this field have increased our basic understanding on how non-Markovian effects influence the dynamics of an open quantum system, paving the way to exploit memory effects for various quantum control tasks. Most often, the environment of an open system is thought to act as a sink for the system information. However, here we demonstrate experimentally that a photonic open system can exploit the information initially held by its environment. Correlations in the environmental degrees of freedom induce nonlocal memory effects where the bipartite open system displays, counterintuitively, local Markovian and global non-Markovian character. Our results also provide novel methods to protect and distribute entanglement, and to experimentally quantify correlations in photonic environments.
Antibodies against spliceosome Sm proteins (anti-Sm autoantibodies) are specific to the autoimmune disease systemic lupus erythematosus (SLE). Anti-Sm autosera have been reported to specifically recognize Sm D1 and D3 with symmetric di-methylarginines (sDMA). We investigated if anti-Sm sera from local SLE patients can differentially recognize Sm proteins or any other proteins due to their methylation states.
We prepared HeLa cell proteins at normal or hypomethylation states (treated with an indirect methyltransferase inhibitor adenosine dialdehyde, AdOx). A few signals detected by the anti-Sm positive sera from typical SLE patients decreased consistently in the immunoblots of hypomethylated cell extracts. The differentially detected signals by one serum (Sm1) were pinpointed by two-dimensional electrophoresis and identified by mass spectrometry. Three identified proteins: splicing factor, proline- and glutamine-rich (SFPQ), heterogeneous nuclear ribonucleoprotein D-like (hnRNP DL) and cellular nucleic acid binding protein (CNBP) are known to contain methylarginines in their glycine and arginine rich (GAR) sequences. We showed that recombinant hnRNP DL and CNBP expressed in Escherichia coli can be detected by all anti-Sm positive sera we tested. As CNBP appeared to be differentially detected by the SLE sera in the pilot study, differential recognition of arginine methylated CNBP protein by the anti-Sm positive sera were further examined. Hypomethylated FLAG-CNBP protein immunopurified from AdOx-treated HeLa cells was less recognized by Sm1 compared to the CNBP protein expressed in untreated cells. Two of 20 other anti-Sm positive sera specifically differentiated the FLAG-CNBP protein expressed in HeLa cells due to the methylation. We also observed deferential recognition of methylated recombinant CNBP proteins expressed from E. coli by some of the autosera.
Our study showed that hnRNP DL and CNBP are novel antigens for SLE patients and the recognition of CNBP might be differentiated dependent on the level of arginine methylation.
SLE; Anti-Sm; Arginine methylation; CNBP; hnRNP DL
To investigate the infections of severe fever with thrombocytopenia syndrome virus (SFTSV) in domesticated animals, we sampled a total of 3,039 animals in 2 counties in Shandong Province, People’s Republic of China, from April to November 2011. SFTSV-specific antibodies were detected in 328 (69.5%) of 472 sheep, 509 (60.5%) of 842 cattle, 136 (37.9%) of 359 dogs, 26 (3.1%) of 839 pigs, and 250 (47.4%) of 527 chickens. SFTSV RNA was detected in all sampled animal species, but the prevalence was low, ranging from 1.7% to 5.3%. A cohort study in 38 sheep was conducted to determine when seroconversion to SFTSV occured. SFTSVs were isolated from sheep, cattle, and dogs and shared >95% sequence homology with human isolates from the same disease-endemic regions. These findings demonstrate that natural infections of SFTSV occur in several domesticated animal hosts in disease-endemic areas and that the virus has a wide host range.
severe fever with thrombocytopenia syndrome virus; SFTSV; infection; domesticated animals; host; China; Phlebovirus; family Bunyaviridae; pathogenic disease; transmission; viruses; zoonoses; prevalence
Background and Objectives
Analysis of positively-selected genes can help us understand how human evolved, especially the evolution of highly developed cognitive functions. However, previous works have reached conflicting conclusions regarding whether human neuronal genes are over-represented among genes under positive selection.
Methods and Results
We divided positively-selected genes into four groups according to the identification approaches, compiling a comprehensive list from 27 previous studies. We showed that genes that are highly expressed in the central nervous system are enriched in recent positive selection events in human history identified by intra-species genomic scan, especially in brain regions related to cognitive functions. This pattern holds when different datasets, parameters and analysis pipelines were used. Functional category enrichment analysis supported these findings, showing that synapse-related functions are enriched in genes under recent positive selection. In contrast, immune-related functions, for instance, are enriched in genes under ancient positive selection revealed by inter-species coding region comparison. We further demonstrated that most of these patterns still hold even after controlling for genomic characteristics that might bias genome-wide identification of positively-selected genes including gene length, gene density, GC composition, and intensity of negative selection.
Our rigorous analysis resolved previous conflicting conclusions and revealed recent adaptation of human brain functions.
Molecular imaging is a rapidly advancing field that allows cancer biologists to look deeper into the complex inner workings of tumor cells, or whole tumors, in a non-invasive manner. In this review, we will summarize some recent advances that enable investigators to study various important biological processes in tumors in vivo. We will discuss novel imaging approaches that allow investigators to visualize and quantify molecular pathways, such as receptor tyrosine kinase activation, hypoxia signal transduction, apoptosis, and DNA double-strand breaks. Select examples of these applications will be discussed. Because of the limited scope of this review, we will only focus on natural reporters, such as bioluminescence and fluorescent proteins.
Protein arginine methyltransferase (PRMT) 1 is the most conserved and widely distributed PRMT in eukaryotes. PRMT8 is a vertebrate-restricted paralogue of PRMT1 with an extra N-terminal sequence and brain-specific expression. We use zebrafish (Danio rerio) as a vertebrate model to study PRMT8 function and putative redundancy with PRMT1. The transcripts of zebrafish prmt8 were specifically expressed in adult zebrafish brain and ubiquitously expressed from zygotic to early segmentation stage before the neuronal development. Whole-mount in situ hybridization revealed ubiquitous prmt8 expression pattern during early embryonic stages, similar to that of prmt1. Knockdown of prmt8 with antisense morpholino oligonucleotide phenocopied prmt1-knockdown, with convergence/extension defects at gastrulation. Other abnormalities observed later include short body axis, curled tails, small and malformed brain and eyes. Catalytically inactive prmt8 failed to complement the morphants, indicating the importance of methyltransferase activity. Full-length prmt8 but not prmt1 cRNA can rescue the phenotypic changes. Nevertheless, cRNA encoding Prmt1 fused with the N-terminus of Prmt8 can rescue the prmt8 morphants. In contrast, N-terminus- deleted but not full-length prmt8 cRNA can rescue the prmt1 morphants as efficiently as prmt1 cRNA. Abnormal brain morphologies illustrated with brain markers and loss of fluorescent neurons in a transgenic fish upon prmt8 knockdown confirm the critical roles of prmt8 in neural development. In summery, our study is the first report showing the expression and function of prmt8 in early zebrafish embryogenesis. Our results indicate that prmt8 may play important roles non-overlapping with prmt1 in embryonic and neural development depending on its specific N-terminus.
Our previous study reported that both glycoproteins gB and gH of the herpesvirus Marek's disease virus (MDV) contain eleven potential heptad repeat domains. These domains overlap with α-helix-enriched hydrophobic regions, including the gH-derived HR1 (gHH1) and HR3 (gHH3) and gB-derived HR1 (gBH1) regions, which demonstrate effective antiviral activity, with 50% inhibitory concentrations (IC50) of less than 12 µM. Plaque formation and chicken embryo infection assays confirmed these results. In this study, biochemical and biophysical analyses detected potential interactions between these peptides. gHH1, gHH3, and gBH1 were found to interact with each other in pairs. The complex formed by gHH3 and gBH1 showed the most stable interaction at a molar ratio of 1:3, the binding between gHH1 and gBH1 was relatively weak, and no interaction was observed between the three HR peptides. These results indicate that gHH3 and gBH1 are likely the key contributors to the interaction between gB and gH. Furthermore, each HR peptide from herpesvirus glycoproteins did not effectively inhibit virus infection compared with peptides from a class I enveloped virus. In this report, the HR mimic peptide modified with a double glutamic acid (EE) or a double lysine (KK) at the non-interactive sites (i.e., solvent-accessible sites) did not noticeably affect the antiviral activity compared with the wild-type HR peptide, whereas tandem peptides from gH-derived gHH1 and gB-derived gBH1 (i.e., gBH1-Linker-gHH1) produced efficient antiviral effects, unlike the individual peptides. The proposed interpretation of inhibition of entry has been addressed. Our results support the hypothesis that the interaction domain between glycoproteins gH and gB is a critical target in the design of inhibitors of herpesvirus infection.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, multiorgan dysfunction, and a high fatality rate between 12 and 30%. It is caused by SFTS virus (SFTSV), a novel Phlebovirus in family Bunyaviridae. Although the viral pathogenesis remains largely unknown, hemopoietic cells appear to be targeted by the virus. In this study we report that human monocytes were susceptible to SFTSV, which replicated efficiently, as shown by an immunofluorescence assay and real-time reverse transcription-PCR. We examined host responses in the infected cells and found that antiviral interferon (IFN) and IFN-inducible proteins were induced upon infection. However, our data also indicated that downregulation of key molecules such as mitochondrial antiviral signaling protein (MAVS) or weakened activation of interferon regulatory factor (IRF) and NF-κB responses may contribute to a restricted innate immunity against the infection. NSs, the nonstructural protein encoded by the S segment, suppressed the beta interferon (IFN-β) and NF-κB promoter activities, although NF-κB activation appears to facilitate SFTSV replication in human monocytes. NSs was found to be associated with TBK1 and may inhibit the activation of downstream IRF and NF-κB signaling through this interaction. Interestingly, we demonstrated that the nucleoprotein (N), also encoded by the S segment, exhibited a suppressive effect on the activation of IFN-β and NF-κB signaling as well. Infected monocytes, mainly intact and free of apoptosis, may likely be implicated in persistent viral infection, spreading the virus to the circulation and causing primary viremia. Our findings provide the first evidence in dissecting the host responses in monocytes and understanding viral pathogenesis in humans infected with a novel deadly Bunyavirus.
Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.
In the title compound, C14H12ClN3O2, the acylhydrazone base [C(=O)—N—N=C] is essentially planar, with an r.m.s. deviation of 0.0095 Å, and makes a dihedral angle of 12.52 (10)°with the pyridine ring. In the crystal, molecules are linked via pairs of N—H⋯O hydrogen bonds, forming inversion dimers with an R
2(8) graph-set motif. The dimers are linked via C—H⋯π interactions forming chains along .
With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system.
Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style geometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and combined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated, the users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software offers the option to charge the objects with either specified surface or volumetric charge density and to model them with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms can be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The biological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or if a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon (PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot, aptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the barnase-barstar protein complex in its hand.
The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano shapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the atoms in the shapes are assigned according to the user’s preferences allowing various scenarios of modeling. The default output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It can be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz
Biological macromolecules; Electrostatic calculations; Molecular modeling; Nano technology; DelPhi; Poisson-Boltzmann equation