Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.     

Probing disorders of the nervous system using reprogramming approaches

The groundbreaking technologies of induced pluripotency and lineage conversion have generated a genuine opportunity to address fundamental aspects of the diseases that affect the nervous system. These approaches have granted us unrestricted access to the brain and spinal cord of patients and have allowed for the study of disease in the context of human cells, expressing physiological levels of proteins and under each patient's unique genetic constellation. Along with this unprecedented opportunity have come significant challenges, particularly in relation to patient variability, experimental design and data interpretation. Nevertheless, significant progress has been achieved over the past few years both in our ability to create the various neural subtypes that comprise the nervous system and in our efforts to develop cellular models of disease that recapitulate clinical findings identified in patients. In this Review, we present tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported, describe the current state of the field, highlight important breakthroughs and discuss the next steps and future challenges.     

Quercetin-induced yeast apoptosis through mitochondrial dysfunction under the accumulation of magnesium in Candida albicans

Latterly, the upsurge in use of antifungal drugs has brought about the emergence of several drug-resistance strains, making it skeptical to continue relying on current therapeutic regime. In the necessity of resistance-free antifungal agent, flavonoids presented possibilities of replacing existing drugs, displaying antifungal activity against pathogenic fungi. Among them, quercetin, one of the most representative flavonoids, exhibited antifungal activity against Candida albicans. To inspect the further understanding regarding quercetin, the antifungal mode of action of quercetin was investigated. In the initial step, the apoptosis was monitored after quercetin treatment. Moreover, intracellular levels of Mg²⁺ was assessed and was determined that Mg²⁺ increase occurred under the influence of quercetin. In addition, several features of mitochondrial dysfunction were monitored. Mitochondrial dysfunction triggers decrease in mitochondrial redox levels and leads to disruption in mitochondrial antioxidant system. Increased intracellular ROS and decreased intracellular redox levels were also displayed, indicating the occurrence of overall disruption in antioxidant systems. Sequentially, DNA fragmentation was observed and this DNA damage in turn induces apoptosis. In analyses, hexaamminecobalt(III) chloride (Cohex) was applied to inhibit Mg²⁺ transport between cytosol and mitochondria. Cohex attenuated the effects induced by quercetin, which demonstrates that the presence of Mg²⁺ is essential in quercetin-induced apoptosis.     

Focus: Addiction: Relapse Prevention and the Five Rules of Recovery

There are four main ideas in relapse prevention. First, relapse is a gradual process with distinct stages. The goal of treatment is to help individuals recognize the early stages, in which the chances of success are greatest. Second, recovery is a process of personal growth with developmental milestones. Each stage of recovery has its own risks of relapse. Third, the main tools of relapse prevention are cognitive therapy and mind-body relaxation, which are used to develop healthy coping skills. Fourth, most relapses can be explained in terms of a few basic rules. Educating clients in these rules can help them focus on what is important: 1) change your life (recovery involves creating a new life where it is easier to not use); 2) be completely honest; 3) ask for help; 4) practice self-care; and 5) don’t bend the rules.     

A genetic and spatial Bayesian analysis of mastitis resistance

A nationwide health card recording system for dairy cattle was introduced in Norway in 1975 (the Norwegian Cattle Health Services). The data base holds information on mastitis occurrences on an individual cow basis. A reduction in mastitis frequency across the population is desired, and for this purpose risk factors are investigated. In this paper a Bayesian proportional hazards model is used for modelling the time to first veterinary treatment of clinical mastitis, including both genetic and environmental covariates. Sire effects were modelled as shared random components, and veterinary district was included as an environmental effect with prior spatial smoothing. A non-informative smoothing prior was assumed for the baseline hazard, and Markov chain Monte Carlo methods (MCMC) were used for inference. We propose a new measure of quality for sires, in terms of their posterior probability of being among the, say 10% best sires. The probability is an easily interpretable measure that can be directly used to rank sires. Estimating these complex probabilities is straightforward in an MCMC setting. The results indicate considerable differences between sires with regards to their daughters disease resistance. A regional effect was also discovered with the lowest risk of disease in the south-eastern parts of Norway.     

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H₂O₂), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H₂O₂-exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury.     

Influence of latitude, water depth, day v. night and wet v. dry periods on the species composition of reef fish communities in tropical Western Australia

Trap sampling over reefs in deep (mean = 20 m) and shallow (mean = 10 m) waters along c. 1500 km of coastline in tropical north‐western Australia during both day and night and in wet and dry periods yielded 23 377 fishes, representing 32 families, 58 genera and 119 species. Individuals of the Serranidae, Lutjanidae, Lethrinidae and Carangidae contributed 88·9% to the total catch. The ichthyofaunal compositions of the Kimberley, Canning and Pilbara bioregions were relatively discrete. Species composition was influenced far more by location (latitude) than by water depth, period and time of day, and underwent a gradational change southwards. The latter change reflected differences in the trends exhibited by the relative abundances of certain species with increasing latitude and the confinement of other species largely to particular regions. The three most abundant species, i.e. Lethrinus sp. 3, Lutjanus carponotatus and Lethrinus laticaudis contributed 34·8, 20·8 and 11·6% to the total catch, respectively. The first species was rarely recorded in the two most northern locations and was abundant in the four most southern locations, whereas the last two species were relatively more abundant in northern than in southern locations. Lutjanus bitaeniatus and Lutjanus johnii were found exclusively at the two locations in the Kimberley region, whereas Abalistes stellatus, Pentapodus emeryii and Lethrinus nebulosus were not caught in this region but were found in both locations of the Canning and Pilbara regions. The species composition in deep and shallow waters at each location almost invariably differed significantly between day and night and between dry and wet periods, with species such as L. bitaeniatus, L. johnii, Lutjanus sebae and A. stellatus being more abundant over deep reefs, whereas L. carponotatus, L. laticaudis, Siganus fuscescens and Lethrinus lentjan were more numerous over shallow reefs. Species such as L. johnii and Lethrinus atkinsoni were relatively more important in night‐time than daytime catches, whereas the reverse applied to Lethrinus lentjan, L. laticaudis and Choerodon cyanodus. Lethrinus sp. 3 and L. laticaudis were relatively more important in catches during the dry than wet period.     

Models for Trypanosoma evansi (surra), its control and economic impact on small-hold livestock owners in the Philippines

Simple demographic and infectious disease models of buffaloes and other domestic hosts for animal trypanosomosis (surra) caused by Trypanosoma evansi were developed. The animal models contained deterministic and stochastic elements and were linked to simulate the benefit of control regimes for surra in village domestic animal populations in Mindanao, Philippines. The impact of the disease on host fertility and mortality were key factors in determining the economic losses and net-benefit from the control regimes. If using a high (99%) efficacy drug in surra-moderate to high risk areas, then treating all animals twice each year yielded low prevalence in 2 years; targeted treatment of clinically sick animals, constantly monitored (monthly), required 75% fewer treatments but took longer to reach a low prevalence than treating all animals twice each year. At high drug efficacy both of these treatment strategies increased the benefit over untreated animals by 81%. If drug efficacy declined then the benefit obtained from twice yearly treatment of all animals declined rapidly compared with regular monitoring and targeting treatment to clinically sick animals. The current control regimen applied in the Philippines of annual sero-testing for surra and only treating sero-positive animals provided the lowest net-benefit of all the control options simulated and would not be regarded as effective control. The total net-benefit from effective surra control for a typical village in a moderate/high risk area was 7.9 million pesos per annum (US $158,000). The value added to buffaloes, cattle, horses, goats/sheep and pigs as a result of this control was US $88, $84, $151, $7, $114 per animal/year, respectively.