Novel histone-derived antimicrobial peptides use different antimicrobial mechanisms

The increase in multidrug resistant bacteria has sparked an interest in the development of novel antibiotics. Antimicrobial peptides that operate by crossing the cell membrane may also have the potential to deliver drugs to intracellular targets. Buforin 2 (BF2) is an antimicrobial peptide that shares sequence identity with a fragment of histone subunit H2A and whose bactericidal mechanism depends on membrane translocation and DNA binding. Previously, novel histone-derived antimicrobial peptides (HDAPs) were designed based on properties of BF2, and DesHDAP1 and DesHDAP3 showed significant antibacterial activity. In this study, their DNA binding, permeabilization, and translocation abilities were assessed independently and compared to antibacterial activity to determine whether they share a mechanism with BF2. To investigate the importance of proline in determining the peptides' mechanisms of action, proline to alanine mutants of the novel peptides were generated. DesHDAP1, which shows significant similarities to BF2 in terms of secondary structure, translocates effectively across lipid vesicle and bacterial membranes, while the DesHDAP1 proline mutant shows reduced translocation abilities and antimicrobial potency. In contrast, both DesHDAP3 and its proline mutant translocate poorly, though the DesHDAP3 proline mutant is more potent. Our findings suggest that a proline hinge can promote membrane translocation in some peptides, but that the extent of its effect on permeabilization depends on the peptide's amphipathic properties. Our results also highlight the different antimicrobial mechanisms exhibited by histone-derived peptides and suggest that histones may serve as a source of novel antimicrobial peptides with varied properties.     

Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGFβ-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection

Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection.     

17th Chromosome‐Centric Human Proteome Project Symposium in Tehran

This report describes the 17th Chromosome‐Centric Human Proteome Project which was held in Tehran, Iran, April 27 and 28, 2017. A brief summary of the symposium's talks including new technical and computational approaches for the identification of novel proteins from non‐coding genomic regions, physicochemical and biological causes of missing proteins, and the close interactions between Chromosome‐ and Biology/Disease‐driven Human Proteome Project are presented. A synopsis of decisions made on the prospective programs to maintain collaborative works, share resources and information, and establishment of a newly organized working group, the task force for missing protein analysis are discussed.     

Plenty of rooftops with few neighbours occupied by young breeding Yellow-legged Gulls (Larus michahellis): Does this occur at the expense of their health condition?

Gulls, as largely flexible opportunistic individuals, have been increasingly breeding in many cities around the world, but it is still unclear whether urban habitats are of equal or higher quality than traditional natural habitats or represent an ecological trap with immediate reproductive benefits but longer-term detrimental consequences to health. Here we present a study of breeding parameters (nest density, egg dimensions, clutch size, hatching success and adult body condition) and physiological parameters (erythrocyte sedimentation rate, heterophil/lymphocyte ratio, haemoglobin concentration and measurements of oxidative stress) as indicators of the general health condition of Yellow-legged Gull Larus michahellis adults and chicks from natural and urban colonies. Yellow-legged Gulls in the largest urban area (Porto) laid smaller eggs and clutches, showed a significantly lower occurrence of inflammatory processes in chicks, and showed a slower early chick growth than in the natural colony of Deserta. This suggests that urban gulls might be facing important trade-offs between the advantages of breeding in lower density urban colonies, with fewer intraspecific interactions and a lower disease transmission probability, and the disadvantages of having an anthropogenic diet usually lower in nutritional value.     

One-pot synthesis of bioactive cyclopentenones from α-linolenic acid and docosahexaenoic acid

Oxidation products of the poly-unsaturated fatty acids (PUFAs) arachidonic acid, α-linolenic acid and docosahexaenoic acid are bioactive in plants and animals as shown for the cyclopentenones prostaglandin 15d-PGJ₂ and PGA₂, cis-(+)-12-oxophytodienoic acid (12-OPDA), and 14-A-4 neuroprostane. In this study an inexpensive and simple enzymatic multi-step one-pot synthesis is presented for 12-OPDA, which is derived from α-linolenic acid, and the analogous docosahexaenoic acid (DHA)-derived cyclopentenone [(4Z,7Z,10Z)-12-[[-(1S,5S)-4-oxo-5-(2Z)-pent-2-en-1yl]-cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid, OCPD]. The three enzymes utilized in this multi-step cascade were crude soybean lipoxygenase or a recombinant lipoxygenase, allene oxide synthase and allene oxide cyclase from Arabidopsis thaliana. The DHA-derived 12-OPDA analog OCPD is predicted to have medicinal potential and signaling properties in planta. With OCPD in hand, it is shown that this compound interacts with chloroplast cyclophilin 20-3 and can be metabolized by 12-oxophytodienoic acid reductase (OPR3) which is an enzyme relevant for substrate bioactivity modulation in planta.     

Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis

Background

The diagnosis of idiopathic pulmonary fibrosis can be quite challenging, even after careful clinical evaluation, imaging and pathological tests. This case report intends to demonstrate and discuss these difficulties, especially those concerning the differential diagnosis with chronic hypersensitivity pneumonitis.

Case presentation

A 58-year-old white male presented with shortness of breath, dry cough, fatigue and weight loss for two months. He was a former smoker and had regular exposure to a parakeet and poultry. Physical examination revealed bilateral basal crackles and chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance. Auto-antibodies and IgG immunoglobulins to parakeet and fungal proteins were negative. Lung function tests displayed moderate restriction, low diffusion capacity and resting hypoxaemia. Bronchoalveolar lavage showed increased lymphocytes (28%) and neutrophils (12%) and surgical lung biopsy was compatible with a pattern of usual interstitial pneumonia. According to the possibility of either idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, treatment included prednisolone, azathioprine, acetylcysteine and avoidance of contact with the parakeet, but there was an unfavorable response and the patient was subsequently referred for lung transplant.

Conclusion

Chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis can present with the same clinical and radiological manifestations In this case, despite careful evaluation, no definite diagnosis could be achieved.

     

Aging aggravates ischemic stroke‐induced brain damage in mice with chronic peripheral infection

Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1‐polarized chronic systemic infection was induced in 18–22 month and 4‐month‐old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin‐17α and tumor necrosis factor‐α levels. Neither age nor infection status alone or in combination altered the ischemia‐induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.     

Parental effects in a partially self-incompatible herb Campanula rapunculoides L. (Campanulaceae): influence of variation in the strength of self-incompatibility on seed set and progeny performance

We employ a full reciprocal diallel design between 10 parental plants that differed in their strength of self-incompatibility (SI; strong, intermediate, and weak) to examine parental effects on seed set and 10 components of fitness of progeny performance in Campanula rapunculoides. We perform ANOVAs to separate the influence of the strength of SI and the identity of the maternal and paternal parent on family performance. We calculate the phenotypic and genetic correlations between traits to determine potentially evolutionary constraints. Finally, we employ maximum likelihood methods to estimate the components of quantitative genetic variance, as defined by Cockerham and Weir in their BioModel c. Our most significant finding is that weak SI plants have high outcrossed seed set as maternal parents. We argue that direct or pleiotropic effects of modifiers of SI probably cause this. Second, we find that extranuclear interactions, as defined by the BioModel, have strong effects on seed set and several vegetative and flowering traits. These findings indicate that some maternal plants selectively provision seeds sired by specific paternal donors and that some of this variation appears to be associated with modifiers of the strength of SI. We find other sources of significant quantitative genetic variation for all of the traits we examine and discuss the possible role these play in the evolution of the reproductive system. Taken together, our findings show that variation in the strength of SI may influence levels of quantitative genetic variation that, in turn, can influence the reproductive success of individuals in C. rapunculoides