Battling for Ribosomes: Translational Control at the Forefront of the Antiviral Response

In the early stages of infection, gaining control of the cellular protein synthesis machinery including its ribosomes is the ultimate combat objective for a virus. To successfully replicate, viruses unequivocally need to usurp and redeploy this machinery for translation of their own mRNA. In response, the host triggers global shutdown of translation while paradoxically allowing swift synthesis of antiviral proteins as a strategy to limit collateral damage. This fundamental conflict at the level of translational control defines the outcome of infection. As part of this special issue on molecular mechanisms of early virus–host cell interactions, we review the current state of knowledge regarding translational control during viral infection with specific emphasis on protein kinase RNA-activated and mammalian target of rapamycin-mediated mechanisms. We also describe recent technological advances that will allow unprecedented insight into how viruses and host cells battle for ribosomes.     

Negotiated Bonds: The Practice of Childfree Pet Parenting

The American Pet Products Association reports a decade-long increase of pet spending, estimated to reach over $69 billion in 2017. In some cases, these owners apply traditional parenting practices while nurturing their pets. Relatedly, a growing number of pet owners identify themselves as “pet parents.” This study is the first known work to investigate how identity plays a role in the growing population of pet parents. While previous research into the pet parenting phenomenon has sought to quantify the demographics, spending, and frequency of this population, less work seeks to understand what pet parenting looks like in practice. Sampling a population of childfree pet parents, the current study utilized semi-structured interviews and identified two common themes in their daily practice of the identity: 1) Despite the use of parent–child terms and strategies, childfree pet parents are acutely aware of the differences between raising children and raising pets, and 2) pet parents ascribe agency to their pet, identifying individual pet wants and needs to fulfill. This may further inform future research on human–animal relationships by establishing a human identity that connects directly to pet practices in the United States, asking us to consider the lived experiences of this growing population and their pets including spending, lifestyle, and attachment concerns.     

Predicting CO2 adsorption and reactivity on transition metal surfaces using popular density functional theory methods

ABSTRACT

In this work, with Ni (110) as a model catalyst surface and CO₂ as an adsorbate, a performance study of Density Functional Theory methods (functionals) is performed. CO being a possible intermediate in CO₂ conversion reactions, binding energies of both, CO₂ and CO, are calculated on the Ni surface and are compared with experimental data. OptPBE-vdW functional correctly predicts CO₂ binding energy on Ni (?62?kJ/mol), whereas CO binding energy is correctly predicted by the rPBE-vdW functional (?138?kJ/mol). The difference in computed adsorption energies by different functionals is attributed to the calculation of gas phase CO₂. Three alternate reaction systems based on a different number of C=O double bonds present in the gas phase molecule are considered to replace CO₂. The error in computed adsorption energy is directly proportional to the number of C=O double bonds present in the gas phase molecule. Additionally, both functionals predict similar carbon–oxygen activation barrier (40?kJ/mol) and equivalent C1s shifts for probe species (?2.6?eV for CCH₃ and +1.5?eV CO₃^?), with respect to adsorbed CO₂. Thus, by including a correction factor of 28?kJ/mol for the computed CO₂ gas phase energy, we suggest using rPBE-vdW functional to investigate CO₂ conversion reactions on different metals.     

High TMPRSS4 expression is a predictor of poor prognosis in cervical squamous cell carcinoma

Objective The aim of this study was to clarify the clinical role of TMPRSS4 expression in cervical squamous cell carcinoma (CSCC) and to investigate the role of TMPRSS4 in predicting outcomes of patients with CSCC. Methods The retrospective study enrolled 87 patients diagnosed with CSCC between 2004 and 2006. TMPRSS4 expression in CSCC was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. The impact of TMPRSS4 expression on 5-year disease-free survival (DFS) and 5-year overall survival (OS) was assessed by Kaplan–Meier analysis and Cox proportional hazards modeling. Results The high expression of TMPRSS4 was 63.2% in 87 patients with CSCC, and 17.5% in 40 patients with benign cervical disease (P < 0.001). High TMPRSS4 expression was significantly associated with tumor grade (P = 0.005), lymph node metastasis (P = 0.004), and deep cervical stromal invasion (P = 0.025). Patients with high expression of TMPRSS4 had shorter OS and DFS than those with low expression (P = 0.0205 and P = 0.0318, respectively). In multivariate Cox regression analysis, high expression of TMPRSS4 was a potential prognostic indicator for OS (P = 0.041) and DFS (P = 0.015). Conclusion Our findings suggest that TMPRSS4 might play an important role in the progression of CSCC. TMPRSS4 could be a potential prognostic marker of CSCC.     

Transmembrane helix 6 observed at the interface of β2AR homodimers in blind docking studies

Peptide– and protein–protein dockings were carried out on β₂-adrenergic receptor (β₂AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two β₂AR monomers, thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially, a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to β₂AR monomer using a rigid body approach. Interestingly, all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore, longer peptides generated from a whole TM region were blindly docked to β₂AR using the same rigid body approach. This yielded a total of seven docked peptides, each derived from one TM helix. Most interestingly, for each peptide, TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings, two β₂AR monomers were blindly docked to each other using a full rigid-body search of docking orientations, which yielded a total of 16,000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements, 102 conformers were composed of two monomers oriented in opposite directions, whereas in the remaining 47, the monomers were arranged in parallel. Lastly, all 149 conformers were clustered based on a root mean-squared distance value of 6 Å. In agreement with the peptide results, the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.     

Role of differential adhesion in cell cluster evolution: from vasculogenesis to cancer metastasis

Cell–cell and cell–matrix adhesions are fundamental to numerous physiological processes, including angiogenesis, tumourigenesis, metastatic spreading and wound healing. We use cellular potts model to computationally predict the organisation of cells within a 3D matrix. The energy potentials regulating cell–cell (J_CC) and cell–matrix (J_MC) adhesive interactions are systematically varied to represent different, biologically relevant adhesive conditions. Chemotactically induced cell migration is also addressed. Starting from a cluster of cells, variations in relative cell adhesion alone lead to different cellular patterns such as spreading of metastatic tumours and angiogenesis. The combination of low cell–cell adhesion (high J_CC) and high heterotypic adhesion (low J_MC) favours the fragmentation of the original cluster into multiple, smaller cell clusters (metastasis). Conversely, cellular systems exhibiting high-homotypic affinity (low J_CC) preserve their original configuration, avoiding fragmentation (organogenesis). For intermediate values of J_CC and J_MC (i.e. J_CC/J_MC ～ 1), tubular and corrugated structures form. Fully developed vascular trees are assembled only in systems in which contact-inhibited chemotaxis is activated upon cell contact. Also, the rate of secretion, diffusion and sequestration of chemotactic factors, cell deformability and motility do not significantly affect these trends. Further developments of this computational model will predict the efficacy of therapeutic interventions to modulate the diseased microenvironment by directly altering cell cohesion.     

Emerging liquid chromatography–mass spectrometry technologies improving dried blood spot analysis

Dried blood spots (DBS), a micro blood sampling technique, has recently gained interest in drug discovery and development due to its inherent advantages over the conventional whole blood, plasma or serum sample collection. Since the regulatory authorities have agreed to the use of blood as an acceptable biological matrix for drug exposure measurements, its applications have been extended not only to therapeutic drug monitoring but also to toxicokinetic and pharmacokinetic studies. The pharmaceutical industry is keen to promote DBS as a prominent tool in bioanalytical applications due to the financial, ethical and organizational issues involved in clinical trials. This could be accomplished due to the latest advances in modern analytical technology, particularly liquid chromatography–mass spectrometry. The present review discusses some of the emerging liquid chromatography–mass spectrometry technologies in improving DBS analysis for its innovative applications in the development of new drugs.     

Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect

Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration–oxidation of dienes followed by Buchwald–Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.     

Th1/Th2/Th17/Treg cytokines in Guillain–Barré syndrome and experimental autoimmune neuritis

Guillain–Barré syndrome (GBS) is an immune-mediated acute inflammatory disorder in the peripheral nervous system (PNS) of humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for GBS. Although GBS and EAN have been widely studied, the pathophysiological basis of GBS/EAN remains largely unknown. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of EAN by acting as mediators or effectors. Both GBS and EAN have hitherto been attributed to T helper (Th)1 cells-mediated disorders, however, some changes in GBS and EAN could not be explained by the pathogenic role of Th1 cells and a disturbance of the Th1/Th2 balance, which has previously been considered to be important for the homeostatic maintenance of the immune responses and to explain the adaptive immunity and autoimmune diseases. The Th1/Th2 paradigm in autoimmune diseases has been greatly challenged in recent years, with the identification of a particular T cell subset Th17 cells. Studies on the associations between Th17 cells/cytokines and GBS/EAN are reviewed. But some of them occasionally yield conflicting results, indicating an intricate network of cytokines in immune response.