Robust joint modeling of longitudinal measurements and time to event data using normal/independent distributions: A Bayesian approach

Joint modeling of longitudinal data and survival data has been used widely for analyzing AIDS clinical trials, where a biological marker such as CD4 count measurement can be an important predictor of survival. In most of these studies, a normal distribution is used for modeling longitudinal responses, which leads to vulnerable inference in the presence of outliers in longitudinal measurements. Powerful distributions for robust analysis are normal/independent distributions, which include univariate and multivariate versions of the Student's t, the slash and the contaminated normal distributions in addition to the normal. In this paper, a linear‐mixed effects model with normal/independent distribution for both random effects and residuals and Cox's model for survival time are used. For estimation, a Bayesian approach using Markov Chain Monte Carlo is adopted. Some simulation studies are performed for illustration of the proposed method. Also, the method is illustrated on a real AIDS data set and the best model is selected using some criteria.     

Experimental Adaptation of Wild-Type Canine Distemper Virus (CDV) to the Human Entry Receptor CD150

Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17^red adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (10² pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (10⁵ pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.     

Achieving energy neutrality in wastewater treatment plants through energy savings and enhancing renewable energy production

Wastewater treatment plants (WWTPs) consume high amounts of energy which is mostly purchased from the grid. During the past years, many ongoing measures have taken place to analyze the possible solutions for both reducing the energy consumption and increasing the renewable energy production in the plants. This review contains all possible aspects which may assist to move towards energy neutrality in WWTPs. The sources of energy in wastewater were introduced and different indicators to express the energy consumption were discussed with examples of the operating WWTPs worldwide. Furthermore, the pathways for energy consumption reductions were reviewed including the operational strategies and the novel technological upgrades of the wastewater treatment processes. Then the methods of recovering the potential energy hidden in wastewater were described along with application of renewable energies in WWTPs. The available assessment methods, which may help in analyzing and comparing WWTPs in terms of energy and greenhouse gas emissions were introduced. Eventually, successful case studies on energy self-sufficiency of WWTPs were listed and the innovative projects in this area were presented.     

The Vital Role of Blood Flow-Induced Proliferation and Migration in Capillary Network Formation in a Multiscale Model of Angiogenesis

Sprouting angiogenesis and capillary network formation are tissue scale phenomena. There are also sub-scale phenomena involved in angiogenesis including at the cellular and intracellular (molecular) scales. In this work, a multiscale model of angiogenesis spanning intracellular, cellular, and tissue scales is developed in detail. The key events that are considered at the tissue scale are formation of closed flow path (that is called loop in this article) and blood flow initiation in the loop. At the cellular scale, growth, migration, and anastomosis of endothelial cells (ECs) are important. At the intracellular scale, cell phenotype determination as well as alteration due to blood flow is included, having pivotal roles in the model. The main feature of the model is to obtain the physical behavior of a closed loop at the tissue scale, relying on the events at the cellular and intracellular scales, and not by imposing physical behavior upon it. Results show that, when blood flow is considered in the loop, the anastomosed sprouts stabilize and elongate. By contrast, when the loop is modeled without consideration of blood flow, the loop collapses. The results obtained in this work show that proper determination of EC phenotype is the key for its survival.     

Strategies toward rheumatoid arthritis therapy; the old and the new

Currently, medications used to treat rheumatoid arthritis (RA) are glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs), predominantly used for controlling the pain and inflammation, disease-modifying antirheumatic drugs (DMARDs), administered as first-line medication for newly diagnosed RA cases, and biological therapies, used to target and inhibit specific molecules of the immune and inflammatory responses. NSAIDs and other GCs are effective in alleviating the pain, inflammation, and stiffness due to RA. DMARDs that are used for RA therapy are hydroxychloroquine, methotrexate, leflunomide, and sulfasalazine. The biological therapies, on the contrary, are chimeric anti-CD20 monoclonal antibody, rituximab, inhibitors of tumor necrosis factor-α (TNF-α) like etanercept, infliximab, and adalimumab, a recombinant inhibitor of interleukin-1 (IL-1), anakinra, and costimulation blocker, abatacept. Moreover, newly under evaluation biological therapies include new TNF-α inhibitors, JAK inhibitors, anti-interleukin-6-receptor monoclonal antibodies (mABs), and antibodies against vital molecules involved in the survival and development of functional B cells. The new strategies to treat RA has improved the course of the disease and most of the patients are successful in remission of the clinical manifestations if the diagnosis of the disease occur early. The probability of remission increase if the diagnosis happens rapidly and treat-to-target approach are implemented. In this review article, we have attempted to go through the treatment strategies for RA therapy both the routine ones and those which have been developed over the past few years and currently under investigation.     

Identification and functional characterization of the CVOMTs and EOMTs genes promoters from Ocimum basilicum L.

Plant Cell, Tissue and Organ Culture (PCTOC) - Methyl chavicol and methyl eugenol are important phenylpropanoid compounds previously purified from basil. These compounds are significantly enhanced...