Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity

The mammalian alpha/beta T cell receptor (TCR) repertoire plays a pivotal role in adaptive immunity by recognizing short, processed, peptide antigens bound in the context of a highly diverse family of cell-surface major histocompatibility complexes (pMHCs). Despite the extensive TCR-MHC interaction surface, peptide-independent cross-reactivity of native TCRs is generally avoided through cell-mediated selection of molecules with low inherent affinity for MHC. Here we show that, contrary to expectations, the germ line-encoded complementarity determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to contact only the MHC surface and not the bound peptide, can be engineered to yield soluble low nanomolar affinity ligands that retain a surprisingly high degree of specificity for the cognate pMHC target. Structural investigation of one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact interfaces as being a key determinant of the increased affinity. Our results suggest that manipulation of germ line CDR2 loops may provide a useful route to the production of high-affinity TCRs with therapeutic and diagnostic potential.     

Defining disruptive coloration and distinguishing its functions

Disruptive coloration breaks up the shape and destroys the outline of an object, hindering detection. The principle was first suggested approximately a century ago, but, although research has significantly increased, the field remains conceptually unstructured and no unambiguous definition exists. This has resulted in variable use of the term, making it difficult to formulate testable hypotheses that are comparable between studies, slowing down advancement in this field. Related to this, a range of studies do not effectively distinguish between disruption and other forms of camouflage. Here, we give a formal definition of disruptive coloration, reorganize a range of sub-principles involved in camouflage and argue that five in particular are specifically related to disruption: differential blending; maximum disruptive contrast; disruption of surface through false edges; disruptive marginal patterns; and coincident disruptive coloration. We discuss how disruptive coloration can be optimized, how it can relate to other forms of camouflage markings and where future work is particularly needed.     

Concealed by conspicuousness: distractive prey markings and backgrounds

High-contrast markings, called distractive or dazzle markings, have been suggested to draw and hold the attention of a viewer, thus hindering detection or recognition of revealing prey characteristics, such as the body outline. We tested this hypothesis in a predation experiment with blue tits (Cyanistes caeruleus) and artificial prey. We also tested whether this idea can be extrapolated to the background appearance and whether high-contrast markings in the background would improve prey concealment. We compared search times for a high-contrast range prey (HC-P) and a low-contrast range prey (LC-P) in a high-contrast range background (HC-B) and a low-contrast range background (LC-B). The HC-P was more difficult to detect in both backgrounds, although it did not match the LC-B. Also, both prey types were more difficult to find in the HC-B than in the LC-B, in spite of the mismatch of the LC-P. In addition, the HC-P was more difficult to detect, in both backgrounds, when compared with a generalist prey, not mismatching either background. Thus, we conclude that distractive prey pattern markings and selection of microhabitats with distractive features may provide an effective way to improve camouflage. Importantly, high-contrast markings, both as part of the prey coloration and in the background, can indeed increase prey concealment.     

Biodegradation of different molecular-mass polyphenols derived from olive mill wastewaters by Geotrichum candidum

The decolourisation of fresh and stored olive mill wastewaters (OMW) and the biodegradation of three groups (F1, F2 and F3) of phenolic compounds by Geotrichum candidum were investigated. Separated phenolic compounds derived from natural OMW ultrafiltration using membranes with a cutoff 2and 100 kDa. G. candidum growth on fresh OMW decreased pH and reduced COD and colour of 75% and 65%, respectively. However, on the stored-black OMW a failure of COD and colour removal were observed. G. candidum activity on this later substrate was enhanced by the addition of a carbon source easily metabolised, misleading an improvement of the COD reduction and decolourization that reached 58% and 48%, respectively. Growth of G. candidum in the presence of F2 or F3 polyphenolic fractions induced high decolourisation and depolymerisation of phenolic compounds. Whereas, very week decolourisation and biodegradation were observed with F1 fraction. Moreover, the highest levels of lignin peroxidase (LiP) and manganese peroxidase (MnP) activities were obtained in the presence of F2 fraction. These results showed that increasing of molecular-mass of aromatics led to an increase in levels of depolymerisation, decolourisation and COD removal by G. candidum culture.     

Adiponectin and energy homeostasis: consensus and controversy

Adiponectin regulates energy homeostasis through the modulation of glucose and fatty acid metabolism in peripheral tissues. However, its central effect on energy balance remains unclear and controversial. Despite the disparate data, recent advances in our understanding of the signal transduction mechanisms used by adiponectin in the periphery and in the hypothalamus suggest that intracellular cross-talk between adiponectin, leptin and insulin may occur at several levels. The present review will summarize recent reports describing the peripheral and central effects of adiponectin and discuss progress concerning its molecular mechanisms. We will also particularly focus on apparent controversies and related mechanisms associated with the central effects of adiponectin on energy homeostasis.     

Non-classical antifolates. Part 2: Synthesis,biological evaluation,and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

A new series of 2,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 22, 33–37, 39–43, and 45 proved to be active DHFR inhibitors with IC₅₀ range of 0.4–1.0 μM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI₅₀ (MG-MID) concentrations of 11.2, and 24.2 μM, respectively. Molecular modeling study including flexible alignment; electrostatic, hydrophobic mappings; and pharmacophore prediction were performed. A main featured pharmacophore model was developed which justifies the importance of the main pharmacophoric groups as well as of their relative distances. The substitution pattern and spatial considerations of the π-systems in regard to the quinazoline nucleus proved critical for biological activity.     

Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype

Background

A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM.

Methods

To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility.

Results

Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction.

Conclusions

Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.     

Effect of slice thickness on brain magnetic resonance image texture analysis

Background  

The accuracy of texture analysis in clinical evaluation of magnetic resonance images depends considerably on imaging arrangements and various image quality parameters. In this paper, we study the effect of slice thickness on brain tissue texture analysis using a statistical approach and classification of T1-weighted images of clinically confirmed multiple sclerosis patients.