The DNA sequence and comparative analysis of human chromosome 5

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.     

Western diamondback rattlesnake in southern Nevada: a correction and comments

Reports of the occurrence of Crotalus atrox Baird & Girard from Nevada are reviewed. There is no evidence to support the occurrence of this species in Nevada.     

Chromosome instability and deregulated proliferation: an unavoidable duo

The concept that aneuploidy is a characteristic of malignant cells has long been known; however, the idea that aneuploidy is an active contributor to tumorigenesis, as opposed to being an associated phenotype, is more recent in its evolution. At the same time, we are seeing the emergence of novel roles for tumor suppressor genes and oncogenes in genome stability. These include the adenomatous polyposis coli gene (APC), p53, the retinoblastoma susceptibility gene (RB1), and Ras. Originally, many of these genes were thought to be tumor suppressive or oncogenic solely because of their role in proliferative control. Because of the frequency with which they are disrupted in cancer, chromosome instability caused by their dysfunction may be more central to tumorigenesis than previously thought. Therefore, this review will highlight how the proper function of cell cycle regulatory genes contributes to the maintenance of genome stability, and how their mutation in cancer obligatorily connects proliferation and chromosome instability.     

Astrocytes in multiple sclerosis: A product of their environment

It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity.     

Optically healable supramolecular polymers

Polymers with the ability to repair themselves after sustaining damage could extend the lifetimes of materials used in many applications. Most approaches to healable materials require heating the damaged area. Here we present metallosupramolecular polymers that can be mended through exposure to light. They consist of telechelic, rubbery, low-molecular-mass polymers with ligand end groups that are non-covalently linked through metal-ion binding. On exposure to ultraviolet light, the metal-ligand motifs are electronically excited and the absorbed energy is converted into heat. This causes temporary disengagement of the metal-ligand motifs and a concomitant reversible decrease in the polymers' molecular mass and viscosity, thereby allowing quick and efficient defect healing. Light can be applied locally to a damage site, so objects can in principle be healed under load. We anticipate that this approach to healable materials, based on supramolecular polymers and a light-heat conversion step, can be applied to a wide range of supramolecular materials that use different chemistries.     

Solution structure of a minor and transiently formed state of a T4 lysozyme mutant

Proteins are inherently plastic molecules, whose function often critically depends on excursions between different molecular conformations (conformers). However, a rigorous understanding of the relation between a protein's structure, dynamics and function remains elusive. This is because many of the conformers on its energy landscape are only transiently formed and marginally populated (less than a few per cent of the total number of molecules), so that they cannot be individually characterized by most biophysical tools. Here we study a lysozyme mutant from phage T4 that binds hydrophobic molecules and populates an excited state transiently (about 1?ms) to about 3% at 25?°C (ref. 5). We show that such binding occurs only via the ground state, and present the atomic-level model of the 'invisible', excited state obtained using a combined strategy of relaxation-dispersion NMR (ref. 6) and CS-Rosetta model building that rationalizes this observation. The model was tested using structure-based design calculations identifying point mutants predicted to stabilize the excited state relative to the ground state. In this way a pair of mutations were introduced, inverting the relative populations of the ground and excited states and altering function. Our results suggest a mechanism for the evolution of a protein's function by changing the delicate balance between the states on its energy landscape. More generally, they show that our approach can generate and validate models of excited protein states.     

Adherens junction protein nectin-4 is the epithelial receptor for measles virus

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.     

Density, distribution, and habitat of Flammulated Owls in Idaho

From 1990 to 1992 we surveyed for Flammulated Owls ( Otus flammeolus ) in 3 areas in Idaho: Salmon National Forest (SNF), Payette National Forest and adjacent Hells Canyon National Recreation Area (PNF-HCNRA), and Nez Perce National Forest (NPNF). We also collected and summarized information on all historic and modern records of Flammulated Owls in Idaho. Flammulated Owls were detected on 65% of 68 routes (2-16 km in length) surveyed at densities ranging from 0.04 to 1.25 singing males/40 ha. Owls were detected on survey routes as early as 10 May and as late as 23 July. Mean percent canopy cover estimated at owl locations on the PNF-HCNRA and NPNF study sites ranged from 52% to 64%, while shrub cover ranged from 16% to 21% and ground cover was 39% to 49%. Our surveys and summary of distributional records indicated that Flammulated Owls occur throughout the montane forests of Idaho in old or mature stands of open ponderosa pine ( Pinus ponderosa ), Douglas-fir ( Pseudotsuga menziesii ), and stands co-dominated by those 2 species. Fire suppression and timber harvest activity in ponderosa pine forests represent 2 main threats to the species' future security in Idaho. More research on the effects of various silvicultural treatments on Flammulated Owl populations is warranted.     

Lime in the Early Bleaching Industry of Britain 1633-1828: Its Prohibition and Repeal

This essay describes the background and possible reasons for legal intervention in the use of lime in the early bleaching industry and draws on the Statutes at Large and other Acts of Parliament as primary sources. The developing chemical knowledge that may have contributed to the later Acts of repeal is also considered in some detail. The earliest noted prohibition was in 1633 and the years 1823, 1825, and 1828 were important repeal dates. No related legislation later than 1828 has been found. During the period from 1633 to 1828 there were many renewals and modifications to existing laws concerning linen and hempen manufacture; several of these contained subsections regarding bleaching. The considerable number of such Acts may account for the apparent confusion shown by earlier authors on this subject. Furthermore, the various Acts passed by the Irish House of Commons over its lifetime from 1400 to 1800, with its many interruptions, were published in a limited number of editions and are consequently held by few libraries. Ireland instituted its own laws and it was only after the Act of Union in 1800 that matters were dealt with by Westminster. Indeed, earlier historians have not always appreciated that, at certain periods of the history of the United Kingdom, Ireland and Scotland (as well as England) had their own separate parliaments.