On the accuracy of solving confluent Prony systems

In this paper we consider several nonlinear systems of algebraic equations which can be called "Prony-type". These systems arise in various reconstruction problems in several branches of theoretical and applied mathematics, such as frequency estimation and nonlinear Fourier inversion. Consequently, the question of stability of solution with respect to errors in the right-hand side becomes critical for the success of any particular application. We investigate the question of "maximal possible accuracy" of solving Prony-type systems, putting stress on the "local" behavior which approximates situations with low absolute measurement error. The accuracy estimates are formulated in very simple geometric terms, shedding some light on the structure of the problem. Numerical tests suggest that "global" solution techniques such as Prony's algorithm and ESPRIT method are suboptimal when compared to this theoretical "best local" behavior

The Central Timna Valley Project: 5 Years of Ongoing Textile Research

In its initial five years of activity the Central Timna Valley Project has dedicated its efforts to the excavation of several Late Bronze and Iron Age sites (13th-9th centuries BC) in the southern Arabah Valley of Israel (fig. 1).1 The project, headed by Erez Ben-Yosef of Tel Aviv University, explores the ancient exploitation of copper ores at Timna; these were utilised for the production of copper ingots that were traded throughout the southern Levant and possibly the greater Mediterranean region. It is within the strata of several newly excavated sites that a few hundred individual textile, cordage and rope fragments were uncovered

Differential Proliferative Characteristics of Alveolar Fibroblasts in Interstitial Lung Diseases: Regulative Role of IL-1 and PGE2

Fibroblasts (Fb) from patients with sarcoidosis (SA) and hypersensitivity pneumonitis (HP) exhibited a lower proliferative capacity compared with Fb obtained from control (CO) and diffuse interstitial fibrosis patients (DIF). Proliferation of Fb from SA or lip patients was suppressed by autologous LPS-stimulated alveolar macrophages (AM) supernatants but not by those from CO patients. Similarly, alveolar macrophages (AM) derived supernatant, obtained from CO, did not suppress the proliferation of SA and HP Fb. AM from SA and HP patients secreted higher amounts of IL-1α and β compared with controls and compared with Fb from SA and HP patients. Steady levels of IL-1α and βmRNA were expressed in unstimulated and stimulated cultures. Fb from SA and HP patients could be stimulated by LPS to secrete significantly higher levels of PGE2 than those detected in supernatants from LPS stimulated Fb of DIF patients. Only the proliferation of Fb from SA and HP patients was sensitive to amounts of IL-1 equivalent to those detected in the lung of these diseases. As SA and HP are two diseases where irreversible deterioration occurs in only 20% of the patients, we hypothesize that mediators in the lung may modulate Fb proliferation. IL-1 of AM origin and PGE2 of Fb origin secreted at high levels, may be candidates for this suppression because it was abrogated by anti IL-1β and indomethacin

Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease

Background: Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. Methods: Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. Results: We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. Conclusion: This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease

Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease

Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn's disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

A genome-wide screen for essential yeast genes that affect telomere length maintenance

Telomeres are structures composed of repetitive DNA and proteins that protect the chromosomal ends in eukaryotic cells from fusion or degradation, thus contributing to genomic stability. Although telomere length varies between species, in all organisms studied telomere length appears to be controlled by a dynamic equilibrium between elongating mechanisms (mainly addition of repeats by the enzyme telomerase) and nucleases that shorten the telomeric sequences. Two previous studies have analyzed a collection of yeast deletion strains (deleted for nonessential genes) and found over 270 genes that affect telomere length (Telomere Length Maintenance or TLM genes). Here we complete the list of TLM by analyzing a collection of strains carrying hypomorphic alleles of most essential genes (DAmP collection). We identify 87 essential genes that affect telomere length in yeast. These genes interact with the nonessential TLM genes in a significant manner, and provide new insights on the mechanisms involved in telomere length maintenance. The newly identified genes span a variety of cellular processes, including protein degradation, pre-mRNA splicing and DNA replication

Hominin reactions to herbivore distribution in the Lower Palaeolithic of the Southern Levant

We explore the relationship between the edaphic potential of soils and the mineral properties of the underlying geology as a means of mapping the differential productivity of different areas of the Pleistocene landscape for large herbivores. These factors strongly control the health of grazing animals irrespective of the particular types of vegetation growing on them, but they have generally been neglected in palaeoanthropological studies in favour of a more general emphasis on water and vegetation, which provide an incomplete picture. Taking the Carmel-Galilee-Golan region as an example, we show how an understanding of edaphic potential provides insight into how animals might have exploited the environment. In order to simplify the analysis, we concentrate on the Lower Palaeolithic period and the very large animals that dominate the archaeofaunal assemblages of this period. Topography and the ability of soils to retain water also contribute to the differential productivity and accessibility of different regions and to patterns of seasonal movements of the animals, which are essential to ensure a supply of healthy fodder throughout the year, especially for large animals such as elephants, which require substantial regions of good grazing and browsing. Other animals migrating in groups have similar needs. The complex topography of the Southern Levant with frequent sudden and severe changes in gradient, and a wide variety of landforms including rocky outcrops, cliffs, gorges, and ridges, places major limits on these patterns of seasonal movements. We develop methods of mapping these variables, based on the geology and our substantial field experience, in order to create a framework of landscape variation that can be compared with the locations and contents of archaeological sites to suggest ways in which early hominins used the variable features of the landscape to target animal prey, and we extend the analysis to the consideration of smaller mammals that were exploited more intensively after the disappearance of the elephants. We consider some of the ways in which this regional-scale approach can be further tested and refined, and advocate the development of such studies as an essential contribution to understanding the wider pattern of hominin dispersal