Metaspin and dirishonic dark matter

The antisymmetry requirement of rishon bound state wave functions suggests a new rishon quantum number called M spin. From M spin conservation and the Nussinov-Weingarten-Witten theorem we predict the existence of a stable pseudoscalar dirishonic meson, called zeta, that is lighter than the lightest neutrino. Its mass is estimated as m(zeta) = 10^{-9} eV. This particle could make up the major part of cold dark matter in the Universe.Comment: 8 pages, 1 figur

Analytical Rebridging Monte Carlo: Application to cis/trans Isomerization in Proline-Containing, Cyclic Peptides

We present a new method, the analytical rebridging scheme, for Monte Carlo simulation of proline-containing, cyclic peptides. The cis/trans isomerization is accommodated by allowing for two states of the amide bond. We apply our method to five peptides that have been previously characterized by NMR methods. Our simulations achieve effective equilibration and agree well with experimental data in all cases. We discuss the importance of effective equilibration and the role of bond flexibility and solvent effects on the predicted equilibrium properties.Comment: 29 pages, 8 PostScript figures, LaTeX source. to appear in J. Chem. Phys., 199

Electron Cryomicroscopy of Biological Machines at Subnanometer Resolution

Advances in electron cryomicroscopy (cryo-EM) have made possible the structural determination of large biological machines in the resolution range of 6–9 Å. Rice dwarf virus and the acrosomal bundle represent two distinct types of machines amenable to cryo-EM investigations at subnanometer resolutions. However, calculating the density map is only the first step, and much analysis remains to extract structural insights and the mechanism of action in these machines. This paper will review the computational and visualization methodologies necessary for analysis (structure mining) of the computed cryo-EM maps of these machines. These steps include component segmentation, averaging based on local symmetry among components, density connectivity trace, incorporation of bioinformatics analysis, and fitting of high-resolution component data, if available. The consequences of these analyses can not only identify accurately some of the secondary structure elements of the molecular components in machines but also suggest structural mechanisms related to their biological functions

Hsc70 is required for endocytosis and clathrin function in Drosophila

By screening for Drosophila mutants exhibiting aberrant bride of sevenless (Boss) staining patterns on eye imaginal disc epithelia, we have recovered a point mutation in Hsc70-4, the closest homologue to bovine clathrin uncoating ATPase. Although the mutant allele was lethal, analysis of mutant clones generated by FLP/FRT recombination demonstrated that the Sevenless-mediated internalization of Boss was blocked in mutant Hsc70-4 eye disc epithelial cells. Endocytosis of other probes was also greatly inhibited in larval Garland cells. Immunostaining and EM analysis of the mutant cells revealed disruptions in the organization of endosomal/lysosomal compartments, including a substantial reduction in the number of clathrin-coated structures in Garland cells. The Hsc70-4 mutation also interacted genetically with a dominant-negative mutant of dynamin, a gene required for the budding of clathrin-coated vesicles (CCVs). Consistent with these phenotypes, recombinant mutant Hsc70 proteins exhibited diminished clathrin uncoating activity in vitro. Together, these data provide genetic support for the long-suspected role of Hsc70 in clathrin-mediated endocytosis, at least in part by inhibiting the uncoating of CCVs

Impact of Genetic Background on Allele Selection in a Highly Mutable Candida albicans Gene, PNG2

In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8×10−5 (confidence interval 3.3×10−6−9. 9×10−5) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term

Protection by immunoglobulin dual-affinity retargeting antibodies against dengue virus

Dengue viruses are the most common arthropod-transmitted viral infection, with an estimated 390 million human infections annually and ∼3.6 billion people at risk. Currently, there are no approved vaccines or therapeutics available to control the global dengue virus disease burden. In this study, we demonstrate the binding, neutralizing activity, and therapeutic capacity of a novel bispecific dual-affinity retargeting molecule (DART) that limits infection of all four serotypes of dengue virus

Walking and running with non-specific chronic low back pain: what about the lumbar lordosis angle?

Non-specific chronic low back pain (NSCLBP) is a major health problem, affecting about one fifth of the population worldwide. To avoid further pain or injury, patients with NSCLBP seem to adopt a stiffer movement pattern during everyday living activities. However, it remains unknown how NSCLBP affects the lumbar lordosis angle (LLA) during repetitive activities such as walking or running. This pilot study therefore aimed at exploring possible NSCLBP-related alterations in LLAs during walking and running by focusing on discrete parameters as well as continuous data. Thirteen patients with NSCLBP and 20 healthy pain-free controls were enrolled and underwent a full-body movement analysis involving various everyday living activities such as standing, walking and running. LLAs were derived from markers placed on the spinous processes of the vertebrae L1-L5 and S1. Possible group differences in discrete (average and range of motion (ROM)) and continuous LLAs were analyzed descriptively using mean differences with confidence intervals ranging from 95% to 75%. Patients with NSCLBP indicated reduced average LLAs during standing, walking and running and a tendency for lower LLA-ROM during walking. Analyses of continuous data indicated the largest group differences occurring around 25% and 70% of the walking and 25% and 75% of the running cycle. Furthermore, patients indicated a reversed movement pattern during running, with increasing instead of a decreasing LLAs after foot strike. This study provides preliminary evidence that NSCLBP might affect LLAs during walking and running. These results can be used as a basis for future large-scale investigations involving hypothesis testing.Comment: This is the accepted manuscript version of an article published in the Journal of Biomechanics (https://doi.org/10.1016/j.jbiomech.2020.109883