Nucleon resonances in the constituent quark model with chiral symmetry

The mass spectra of nucleon resonances with spin 1/2, 3/2, and 5/2 are systematically studied in the constituent quark model with meson-quark coupling, which is inspired by the spontaneous breaking of chiral symmetry of QCD. The meson-quark coupling gives rise not only to the one-meson-exchange potential between quarks but also to the self-energy of baryon resonances due to the existence of meson-baryon decay channels. The two contributions are consistently taken into account in the calculation. The gross properties of the nucleon resonance spectra are reproduced fairly well although the predicted mass of N(1440) is too high.Comment: 14 pages, 6 figures, Late

Natural Voltage‐Gated Sodium Channel Ligands: Biosynthesis and Biology

Natural product biosynthetic pathways are composed of enzymes that use powerful chemistry to assemble complex molecules. Small molecule neurotoxins are examples of natural products with intricate scaffolds which often have high affinities for their biological targets. The focus of this Minireview is small molecule neurotoxins targeting voltage‐gated sodium channels (VGSCs) and the state of knowledge on their associated biosynthetic pathways. There are three small molecule neurotoxin receptor sites on VGSCs associated with three different classes of molecules: guanidinium toxins, alkaloid toxins, and ladder polyethers. Each of these types of toxins have unique structural features which are assembled by biosynthetic enzymes and the extent of information known about these enzymes varies among each class. The biosynthetic enzymes involved in the formation of these toxins have the potential to become useful tools in the efficient synthesis of VGSC probes.Terrific toxins: Living organisms produce highly potent small molecule neurotoxins as forms of self‐defense. A subset of these toxins target voltage‐gated sodium channels, a potential target for non‐opioid pain management in humans. The biosynthetic pathways of these channel‐disrupting ligands are discussed in the context of biocatalytic applications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/1/cbic201800754.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/2/cbic201800754-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/3/cbic201800754_am.pd

Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26 S proteasome

hHR23B is one of two human homologs of the Saccharomyces cerevisiae nucleotide excision repair (NER) gene product RAD23 and a component of a protein complex that specifically complements the NER defect of xeroderma pigmentosum group C (XP-C) cell extracts in vitro. Although a small proportion of hHR23B is tightly complexed with the XP-C responsible gene product, XPC protein, a vast majority exists as an XPC-free form, indicating that hHR23B has additional functions other than NER in vivo. Here we demonstrate that the human NER factor hHR23B as well as another human homolog of RAD23, hHR23A, interact specifically with S5a, a subunit of the human 26 S proteasome using the yeast two-hybrid system. Furthermore, hHR23 proteins were detected with S5a at the position where 26 S proteasome sediments in glycerol gradient centrifugation of HeLa S100 extracts. Intriguingly, hHR23B showed the inhibitory effect on the degradation of (125)I-lysozyme in the rabbit reticulocyte lysate. hHR23 proteins thus appear to associate with 26 S proteasome in vivo. From co-precipitation experiments using several series of deletion mutants, we defined the domains in hHR23B and S5a that mediate this interaction. From these results, we propose that part of hHR23 proteins are involved in the proteolytic pathway in cells

A Study of Degenerate Four-quark states in SU(2) Lattice Monte Carlo

The energies of four-quark states are calculated for geometries in which the quarks are situated on the corners of a series of tetrahedra and also for geometries that correspond to gradually distorting these tetrahedra into a plane. The interest in tetrahedra arises because they are composed of {\bf three } degenerate partitions of the four quarks into two two-quark colour singlets. This is an extension of earlier work showing that geometries with {\bf two} degenerate partitions (e.g.\ squares) experience a large binding energy. It is now found that even larger binding energies do not result, but that for the tetrahedra the ground and first excited states become degenerate in energy. The calculation is carried out using SU(2) for static quarks in the quenched approximation with $\beta=2.4$ on a $16^3\times 32$ lattice. The results are analysed using the correlation matrix between different euclidean times and the implications of these results are discussed for a model based on two-quark potentials.Comment: Original Raw PS file replace by a tarred, compressed and uuencoded PS fil

Simultaneous disruption of two DNA polymerases, Polη and Polζ, in Avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions

Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase η, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ζ by generating POLη−/−/POLζ−/− cells from the chicken DT40 cell line. POLζ−/− cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Polη plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLη−/−/POLζ−/− cells shows that, unexpectedly, the loss of Polη significantly rescued all mutant phenotypes of POLζ−/− cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Polη contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells

Temporal Progression Patterns of Brain Atrophy in Corticobasal Syndrome and Progressive Supranuclear Palsy Revealed by Subtype and Stage Inference (SuStaIn)

Differentiating corticobasal degeneration presenting with corticobasal syndrome (CBD-CBS) from progressive supranuclear palsy with Richardson's syndrome (PSP-RS), particularly in early stages, is often challenging because the neurodegenerative conditions closely overlap in terms of clinical presentation and pathology. Although volumetry using brain magnetic resonance imaging (MRI) has been studied in patients with CBS and PSP-RS, studies assessing the progression of brain atrophy are limited. Therefore, we aimed to reveal the difference in the temporal progression patterns of brain atrophy between patients with CBS and those with PSP-RS purely based on cross-sectional data using Subtype and Stage Inference (SuStaIn)—a novel, unsupervised machine learning technique that integrates clustering and disease progression modeling. We applied SuStaIn to the cross-sectional regional brain volumes of 25 patients with CBS, 39 patients with typical PSP-RS, and 50 healthy controls to estimate the two disease subtypes and trajectories of CBS and PSP-RS, which have distinct atrophy patterns. The progression model and classification accuracy of CBS and PSP-RS were compared with those of previous studies to evaluate the performance of SuStaIn. SuStaIn identified distinct temporal progression patterns of brain atrophy for CBS and PSP-RS, which were largely consistent with previous evidence, with high reproducibility (99.7%) under cross-validation. We classified these diseases with high accuracy (0.875) and sensitivity (0.680 and 1.000, respectively) based on cross-sectional structural brain MRI data; the accuracy was higher than that reported in previous studies. Moreover, SuStaIn stage correctly reflected disease severity without the label of disease stage, such as disease duration. Furthermore, SuStaIn also showed the genialized performance of differentiation and reflection for CBS and PSP-RS. Thus, SuStaIn has potential for improving our understanding of disease mechanisms, accurately stratifying patients, and providing prognoses for patients with CBS and PSP-RS

Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites

Molecular dissection of the domain architecture and catalytic activities of human PrimPol

PrimPol is a primase–polymerase involved in nuclear and mitochondrial DNA replication in eukaryotic cells. Although PrimPol is predicted to possess an archaeo-eukaryotic primase and a UL52-like zinc finger domain, the role of these domains has not been established. Here, we report that the proposed zinc finger domain of human PrimPol binds zinc ions and is essential for maintaining primase activity. Although apparently dispensable for its polymerase activity, the zinc finger also regulates the processivity and fidelity of PrimPol's extension activities. When the zinc finger is disrupted, PrimPol becomes more promutagenic, has an altered translesion synthesis spectrum and is capable of faithfully bypassing cyclobutane pyrimidine dimer photolesions. PrimPol's polymerase domain binds to both single- and double-stranded DNA, whilst the zinc finger domain binds only to single-stranded DNA. We additionally report that although PrimPol's primase activity is required to restore wild-type replication fork rates in irradiated PrimPol−/− cells, polymerase activity is sufficient to maintain regular replisome progression in unperturbed cells. Together, these findings provide the first analysis of the molecular architecture of PrimPol, describing the activities associated with, and interplay between, its functional domains and defining the requirement for its primase and polymerase activities during nuclear DNA replication

Branching ratio change in K- absorption at rest and the nature of the Lambda(1405)

We investigate in-medium corrections to the branching ratio in K- absorption at rest and their effect on the (positively and negatively) charged pion spectrum. The in-medium corrections are due to Pauli blocking, which arises if the Lambda(1405) is assumed to be a $\bar{K}$-nucleon bound state and leads to a density and momentum dependent mass shift of the Lambda(1405). Requiring that the optical potential as well as the branching ratio are derived from the same elementary T-matrix, we find that the in-medium corrected, density dependent T-matrix gives a better description of the K- absorption reaction than the free, density-independent one. This result suggests that the dominant component of the Lambda(1405) wave function is the $\bar{K}N$ bound state.Comment: 8 Pages, Revtex with epsf, and embedded 8 ps figure