Hypothesis and Theory: Evaluating the Co-Evolution of the Melanocortin-2 Receptor and the Accessory Protein MRAP1

The melanocortin receptors (MCRs) and the MRAP accessory proteins belong to distinct gene families that are unique to the chordates. During the radiation of the chordates, the melancortin-2 receptor paralog (MC2R) and the MRAP1 paralog (melanocortin-2 receptor accessory protein 1) have co-evolved to form a heterodimer interaction that can influence the ligand selectivity and trafficking properties of MC2R. This apparently spontaneous interaction may have begun with the ancestral gnathostomes and has persisted in both the cartilaginous fishes and the bony vertebrates. The ramifications of this interaction had profound effects on the hypothalamus/anterior pituitary/adrenal-interrenal axis of bony vertebrates resulting in MC2R orthologs that are exclusively selective for the anterior pituitary hormone, ACTH, and that are dependent on MRAP1 for trafficking to the plasma membrane. The functional motifs within the MRAP1 sequence and their potential contact sites with MC2R are discussed. The ramifications of the MC2R/MRAP1 interaction for cartilaginous fishes are also discussed, but currently the effects of this interaction on the hypothalamus/pituitary/interrenal axis is less clear. The cartilaginous fish MC2R orthologs have apparently retained the ability to be activated by either ACTH or MSH-sized ligands, and the effect of MRAP1 on trafficking varies by species. In this regard, the possible origin of the dichotomy between cartilaginous fish and bony vertebrate MC2R orthologs with respect to ligand selectivity and trafficking properties is discussed in light of the evolution of functional amino acid motifs within MRAP1.

Whey Protein Isolate, Tween 20 and Casein Hydrolysate Stabilized O/W Nano-Vesicular Emulsion Systems with Curcumin Cargo

Stable oil-in-water nanoemulsions were generated by ultra-high-pressure homogenization (UHPH) at 140 and 210 MPa for use as nano-vesicular vehicles (NVV) to carry hydrophobic generally recognized as safe (GRAS) curcumin (CU) by whey protein isolate (WPI) in aqueous nutraceutical systems. Curcumin was used for its antioxidant activity and participation in the Michael reaction with nucleophiles at pHs above 8.0. Two variables, (1) addition of casein hydrolysate (CH) (2%, w/w of WPI) and, (2) use of UHPH (140 and 210 MPa), were studied for their effect on the stabilization of monodispersed NVV and antioxidant capacity of the CU as cargo in the NVV throughout storage. CH and Tween 20 both were added to increase dispersibility and stability of the NVV. Addition of CH reduced nano-particle size (dvs) by 17% at 210 MPa when compared to140 MPa (P<0.05), and increased the stability with UHPH pressure as reflected by a 63% smaller dvs at 210 MPa as compared to 140 MPa (P<0.05). The nanoparticle distribution was not changed by the addition of CU, with dvs’s of 101 and 93 nm at 140 MPa and 73 and 92 at 210 MPa for NVV and CU-NVV, respectively. The NVV system was stable for 28 days as observed in zeta-potential, contact angle, and surface energy, and can be used to deliver CU and maintain its antioxidant activity.

Systematic analysis of membrane contact sites in Saccharomyces cerevisiae uncovers modulators of cellular lipid distribution

Actively maintained close appositions, or contact sites, between organelle membranes, enable the efficient transfer of biomolecules between the various cellular compartments. Several such sites have been described together with their tethering machinery. Despite these advances we are still far from a comprehensive understanding of the function and regulation of most contact sites. To systematically characterize the proteome of contact sites and support the discovery of new tethers and functional molecules, we established a high throughput screening approach in Saccharomyces cerevisiae based on co-localization imaging. We imaged split fluorescence reporters for six different contact sites, two of which have never been studied before, on the background of 1165 strains expressing a mCherry-tagged yeast protein that have a cellular punctate distribution (a hallmark of contact sites). By scoring both co-localization events and effects on reporter size and abundance, we discovered over 100 new potential contact site residents and effectors in yeast. Focusing on several of the newly identified residents, we identified one set of hits as previously unrecognized homologs to Vps13 and Atg2. These proteins share their lipid transport domain, thus expanding this family of lipid transporters. Analysis of another candidate, Ypr097w, which we now call Lec1 (Lipid-droplet Ergosterol Cortex 1), revealed that this previously uncharacterized protein dynamically shifts between lipid droplets and the cell cortex, and plays a role in regulation of ergosterol distribution in the cell.

What Remains to Be Discovered?

What major scientific breakthroughs will occur in the rest of the 21st century? We can hardly imagine what discoveries await us in the fields of physics, biology, human health, or artificial intelligence. Every time people think that everything has already been discovered, there occurs another breakthrough. However, it is impossible to predict specifically when and what it will be. Among the most promising challenges on the border between science and our imaginations, is an exploration of our universe, and potential contact with an extra-terrestrial civilisation, better understanding of space, time, matter, and energy (including “dark matter” and “dark energy”) and, of course, the “unthinkable” potential of the human brain. It seems that what may never be discovered is scientific evidence of life after death. This is not found on the border between science and our fantasy (imagination), but on the border between science and faith.

Tetraploids expanded beyond the mountain niche of their diploid ancestors in the mixed-ploidy grass Festuca amethystina L.

One promising area in understanding the responses of plants to ongoing global climate change is the adaptative effect of polyploidy. This work examines whether there is a coupling between the distribution of cytotypes and their biogeographical niche, and how different niches will affect their potential range. The study uses a range of techniques including flow cytometry, gradient and niche analysis, as well as distribution modelling. In addition, climatic, edaphic and habitat data was used to analyse environmental patterns and potential ranges of cytotypes in the first wide-range study of Festuca amethystina—a mixed-ploidy mountain grass. The populations were found to be ploidy homogeneous and demonstrate a parapatric pattern of cytotype distribution. Potential contact zones have been identified. The tetraploids have a geographically broader distribution than diploids; they also tend to occur at lower altitudes and grow in more diverse climates, geological units and habitats. Moreover, tetraploids have a more extensive potential range, being six-fold larger than diploids. Montane pine forests were found to be a focal environment suitable for both cytotypes, which has a central place in the environmental space of the whole species. Our findings present polyploidy as a visible driver of geographical, ecological and adaptive variation within the species.

English and the use of the simple past in Dutch

The global dominance of English has resulted in contact-induced change in many of the world’s languages. While lexical influence is perhaps the most widespread and the most visible form of change, there are indications that English may also be influencing languages on a structural level. In this article, we investigate a case of potential contact-induced structural change in the verb tense system of Dutch. Non-standard use of the simple past (instead of the standard present perfect) has been noticed for some time, and often linked to English influence. Based on an acceptability judgment questionnaire, we show that there is little evidence for language change in this feature in apparent time, but that judgments do depend on raters’ exposure to English, with higher exposure correlating with more positive judgments. This suggests that contact-induced change through diffusion may be a factor in the use of this construction.

Climatic windows for human migration out of Africa in the past 300,000 years

Whilst an African origin of modern humans is well established, the timings and routes of their expansions into Eurasia are the subject of heated debate, due to the scarcity of fossils and the lack of suitably old ancient DNA. Here, we use high-resolution palaeoclimate reconstructions to estimate how difficult it would have been for humans in terms of rainfall availability to leave the African continent in the past 300k years. We then combine these results with an anthropologically and ecologically motivated estimate of the minimum level of rainfall required by hunter-gatherers to survive, allowing us to reconstruct when, and along which geographic paths, expansions out of Africa would have been climatically feasible. The estimated timings and routes of potential contact with Eurasia are compatible with archaeological and genetic evidence of human expansions out of Africa, highlighting the key role of palaeoclimate variability for modern human dispersals.

A Hybrid Method to Obtain the Wheel–Rail Contact Point at Extreme Positions

When conducting a numerical simulation of a train’s derailment and post-derailment, it is necessary to continuously observe the relative position of the wheel and rail, which is of great significance for the correct evaluation of train safety. In this paper, a non-analytic method is proposed to extend the search range and improve the accuracy of the classical semi-analytical method, i.e. the contact locus method. Based on the point cloud convex hull, a high-density wheel contact locus vertical profile is obtained by projecting the chamfer and internal zone of the flange onto the rail cutting plane. To obtain maximum compression in the normal direction and avoid singularities on both rail head sides in the Cartesian coordinate system the rail surface is interpolated with the polar spline curve. Compared with the classical method used to describe the wheel contact locus, in the proposed hybrid method, potential contact points are provided. Finally, the proposed hybrid method and the classical methods are applied to the wheel track coupling simulation. Numerical results demonstrate the high reliability and effectiveness of the proposed method.