Testing the Inverse Born Procedure for Spheroidal Voids

Previously we have shown that the inverse Born approximation allows an accurate determination of the radius of spherical flaws in Ti. Here we report the results of extending that analysis to spheroidal voids. Both oblate and prolate spheroids are considered. Using scattering amplitude generated by the T-matrix method, we find that both the major and minor axes of 2-1 spheroids are accurately determined. Inversion results using experimental data will be presented for the 2-1 oblate spheroid: a comparison of the experimental and theoretical results will be given

Tunability of the dielectric response of epitaxially strained SrTiO3 from first principles

The effect of in-plane strain on the nonlinear dielectric properties of SrTiO3 epitaxial thin films is calculated using density-functional theory within the local-density approximation. Motivated by recent experiments, the structure, zone-center phonons, and dielectric properties with and without an external electric field are evaluated for several misfit strains within +-3% of the calculated cubic lattice parameter. In these calculations, the in-plane lattice parameters are fixed, and all remaining structural parameters are permitted to relax. The presence of an external bias is treated approximately by applying a force to each ion proportional to the electric field. After obtaining zero-field ground state structures for various strains, the zone-center phonon frequencies and Born effective charges are computed, yielding the zero-field dielectric response. The dielectric response at finite electric field bias is obtained by computing the field dependence of the structure and polarization using an approximate technique. The results are compared with recent experiments and a previous phenomenological theory. The tunability is found to be strongly dependent on the in-plane lattice parameter, showing markedly different behavior for tensile and compressive strains. Our results are expected to be of use for isolating the role of strain in the tunability of real ultrathin epitaxial films.Comment: 11 pages, with postscript figures embedded. Uses REVTEX and epsf macros. Also available at http://www.physics.rutgers.edu/~dhv/preprints/ant_srti/index.htm

Technology, infrastructure and enterprise trade-off: Strengthening smallholder farming systems in Tamil Nadu State of India for sustainable income and food security

The complexities of smallholder farming systems pose a challenge in demonstrating the potential benefits or risks of new technologies and policies. Using Integrated Analysis Tool, a rule-based dynamic simulation model, this study tried to improve the performance of major farming systems in the Tamil Nadu State of India. Amongst the four major farming systems viz. Black gram-based (BFS), Paddy-based (PFS), and Integrated Farming Systems (IFS) in Villupuram district and Dryland Farming System (DFS) in Virudhunagar district, IFS was found to be the most profitable and resilient based on their performance simulated for a 3-year rotation. Setting IFS as a benchmark, potential interventions were evaluated under other farming systems to improve their relative performance. The analysis allowed understanding the interactions in smallholder farming systems and the potential impact of interventions in a whole farm way considering the cash flows, cost intensity, and input-output trade-offs. While multi-bloom technology in black gram increased the net profit of BFS without much stress on input and labour, area expansion under rainfed groundnut incurred high expenditure. Trading-off paddy with maize and groundnut significantly increased the net profit of PFS but replacing sugarcane with tapioca and turmeric was not remunerative. Improved livestock management practices have substantially increased the net profit of DFS wherein crop yield could not be enhanced substantially without the prospects of good irrigation infrastructure. The irrigation endowed PFS has achieved 90% performance, whereas the water-starved BFS and DFS could achieve only 65% performance of IFS. We conclude that agricultural policy must not only focus on potential interventions that are profitable but also consider what is acceptable to the farmer, considering synergies and trade-offs between competing resources at the farm level

Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain

To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked cell cycle progression by inhibiting cyclin B proteolysis and inhibited degradation of ubiquitinated Sic1 by purified proteasomes. Ubistatins blocked the binding of ubiquitinated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of Lys^(48)-linked chains. The same interface is recognized by ubiquitin-chain receptors of the proteasome, indicating that ubistatins act by disrupting a critical protein-protein interaction in the ubiquitin-proteasome system

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

The small ubiquitin-like modifier (SUMO) can form polymeric chains that are important signals in cellular processes such as meiosis, genome maintenance and stress response. The SUMO-targeted ubiquitin ligase RNF4 engages with SUMO chains on linked substrates and catalyses their ubiquitination, which targets substrates for proteasomal degradation. Here we use a segmental labelling approach combined with solution nuclear magnetic resonance (NMR) spectroscopy and biochemical characterization to reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer

Novel Insights Into Breast Cancer Copy Number Genetic Heterogeneity Revealed by Single-Cell Genome Sequencing

Copy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse

Understanding the Role of the Josephin Domain in the PolyUb Binding and Cleavage Properties of Ataxin-3

Ataxin-3, the disease protein in the neurodegenerative disorder Spinocerebellar Ataxia Type 3 or Machado Joseph disease, is a cysteine protease implicated in the ubiquitin proteasome pathway. It contains multiple ubiquitin binding sites through which it anchors polyubiquitin chains of different linkages that are then cleaved by the N-terminal catalytic (Josephin) domain. The properties of the ubiquitin interacting motifs (UIMs) in the C-terminus of ataxin-3 are well established. Very little is known, however, about how two recently identified ubiquitin-binding sites in the Josephin domain contribute to ubiquitin chain binding and cleavage. In the current study, we sought to define the specific contribution of the Josephin domain to the catalytic properties of ataxin-3 and assess how the topology and affinity of these binding sites modulate ataxin-3 activity. Using NMR we modeled the structure of diUb/Josephin complexes and showed that linkage preferences are imposed by the topology of the two binding sites. Enzymatic studies further helped us to determine a precise hierarchy between the sites. We establish that the structure of Josephin dictates specificity for K48-linked chains. Site 1, which is close to the active site, is indispensable for cleavage. Our studies open the way to understand better the cellular function of ataxin-3 and its link to pathology

Structural Analysis of the UBA Domain of X-linked Inhibitor of Apoptosis Protein Reveals Different Surfaces for Ubiquitin-Binding and Self-Association

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. PRINCIPAL FINDINGS: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha1 and helix alpha2, separate from the ubiquitin-binding surface. CONCLUSION: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.published_or_final_versio

Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p