A controversial role of neutrophils in tuberculosis infection pathogenesis

Tuberculosis (TB) continues to be an important and unresolved medical problem. About a quarter of mankind is infected with Mycobacterium tuberculosis, and about 5–10% of these people eventually develop TB. Macrophages and CD4+ T cells are considered the key cells providing defense against TB infection. The role of neutrophils in TB is less well defined. Neutrophils are short-lived granulocytes among first migrate into the infectious lung tissue and phagocy tose mycobacteria. On the one hand, there is evidence for protective role of neutrophils in TB released via anti-microbial peptides inhibiting mycobacterial growth, up-regulation of CD4+ T-cell activation, and dendritic cell migration in the lymph nodes. On the other hand, infection of genetically TB susceptible animals leads to an overwhelming lung neutrophil inflammation, development of necrotic granulomata, and a rapid death. Neutrophils act directly or indirectly on mycobacteria by different oxidative or other reactions including neutrophil extracellular traps (NETs) formation. Phagocytosis of mycobacteria by neutrophils is accompanied by the production of pro-inflammatory factors, thus making neutrophils active participants of inflammation in all stages of the infectious process. Finally, neutrophils die by apoptosis or necrosis. Necrosis of neutrophils, which is activated by reactive oxygen species, also prolongs the inflammation. In this way, there is strong evidence that neutrophils are the cells involved in the transition of infection to the terminal stage, participating in lung tissue destruction. Although neutrophils evolutionary developed many ways to resist pathogens, it is likely, that neutrophils do not possess sufficient anti-mycobactericidal capacities due to the development of many adaptations allowing mycobacteria to survive inside the neutrophils. Neutrophils effectively phagocytose but poorly kill mycobacteria, thus hiding bacilli from more efficient killers, macrophages, and playing the role of the “Trojan Horse”. In this review, we summarize the data on the involvement of neutrophils in TB inflammation. We discuss their ambiguous role in pathogenesis which depends upon mycobacterial virulence, host genetics, dynamics of migration to inflammatory foci, and persistence during initial and chronic stages of the infectious process

B-lymphocyte aggregation in the lung tissue is a pathogenic factor in experimental infection caused by Mycobacterium avium

When infecting the lungs with Mycobacterium avium of B6 line mice genetically susceptible to this infection the compact aggregates (follicles) of B-lymphocytes are formed with the peak at the 11-13th week after the infection. Physiological role of these cellular accumulations remained unclear. Having applied segregative genetic analysis to allele conglutination of Slc11a1 gene with two signs – quantity of mycobacteria and accumulation of B-cellular follicles to the F2 mice from crossing (В6 × I/St), one managed to find out that the quantity and size of follicles directly correlate with M. avium replication in the lungs. Thus this type of the lung tissue infiltration does not protect the host from infection and it is a pathogenic factor

Deletion of the miR172 target site in a TOE-type gene is a strong candidate variant for dominant double-flower trait in Rosaceae

Double flowers with supernumerary petals have been selected by humans for their attractive appearance and commercial value in several ornamental plants, including Prunus persica (peach), a recognized model for Rosaceae genetics and genomics. Despite the relevance of this trait, knowledge of the underlying genes is limited. Of two distinct loci controlling the double-flower phenotype in peach, we focused on the dominant Di2 locus. High-resolution linkage mapping in five segregating progenies delimited Di2 to an interval spanning 150858bp and 22 genes, including Prupe.6G242400 encoding an euAP2 transcription factor. Analyzing genomic resequencing data from single- and double-flower accessions, we identified a deletion spanning the binding site for miR172 in Prupe.6G242400 as a candidate variant for the double-flower trait, and we showed transcript expression for both wild-type and deleted alleles. Consistent with the proposed role in controlling petal number, Prupe.6G242400 is expressed in buds at critical times for floral development. The indelDi2 molecular marker designed on this sequence variant co-segregated with the phenotype in 621 progenies, accounting for the dominant inheritance of the Di2 locus. Further corroborating the results in peach, we identified a distinct but similar mutation in the ortholog of Prupe.6G242400 in double-flower roses. Phylogenetic analysis showed that these two genes belong to a TARGET OF EAT (TOE)-type clade not represented in Arabidopsis, indicating a divergence of gene functions between AP2-type and TOE-type factors in Arabidopsis and other species. The identification of orthologous candidate genes for the double-flower phenotype in two important Rosaceae species provides valuable information to understand the genetic control of this trait in other major ornamental plants. Significance Statement We used peach as a model to gain insight into the molecular basis of double flowers, an important trait in many ornamental plants. We propose that a deletion causes a TOE-type transcription factor to escape miR172-mediated repression, in turn resulting in an increased number of petals, as corroborated by results on the orthologous gene in rose

Development and Evaluation of a 9K SNP Addition to the Peach Ipsc 9K SNP Array v1

The IPSC 9K peach SNP array released by the international community has been a valuable tool in research and application. Even though majority of SNPs (84%) were polymorphic in the evaluation panels there were many genomic regions with low coverage, including those important for breeding. The existing peach array has been updated with 9K additional SNPs covering previously identified gaps and including recently identified SNPs important for breeding. SNPs (1,808,996) identified by sequencing 49 genomes of additional peach accessions were used as the main source of additional SNPs. Focal point strategy was used to select 8,971 SNPs within 40kb window from the 2,821 focal points distributed across the genome. Additional 129 SNPs were chosen to saturate either regions important for breeding or close the gaps larger than 100kb. The array was validated with 1,770 peach and 26 Prunus accessions (almond, plum, apricot, wild relatives). The add-on contained 7,862 SNPs evenly spread across 8 peach pseudo-molecules with only one SNP positioned on scaffold 13 covering 224.99Mbp of peach genome. The 9K add-on improved the 9K peach array by increasing the total number of usable SNPs by 7,206. The number of SNPs per chromosome increased on average by 50% with only on average 0.18% increase in total physical coverage. Number of gaps larger than 0.3 Mbp was reduced to 2 one on each chromosome 3 and 8. Overall genotyping efficiency in all material was >90% except in almond, 82%. Number of informative markers, assessed by ASSIsT software, were highest in peach 64% and lowest in almond 10%, with 61% of markers being informative in wild Prunus (12) and 35% in apricot (4) and 2 - 33% in Japanese and European plum, respectively. Among 36.2% discarded markers 33% were monomorphic and 30% shifted homozygous in material used. Those markers could be informative in different background raising total number of informative markers. Ann addition of new SNPs to array improved the density and usefulness of the array in Prunus species. The practical applications of new 16K Illumina SNP peach array will be discussed. Specified Source(s) of Funding: USDA-NIFA-SCRI-Ros- BREED (2014-51181-22378

Molecular basis of FIR-mediated c-myc transcriptional control

The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.MRC Grant-in-aid U11757455

Ядерные аварии: последствия для человека, общества и энергетики

The article examines radiation and hygienic regulations with regard to the elimination of consequences of the Chernobyl NPP accident in the context of relationships with other aspects, primarily socio-economic and political factors. This experience is reasonable to take into account when defining criteria in other regulatory fields, for example, in radioactive waste classification and remediation of areas. The article presents an analysis of joint features and peculiarities of nuclear accidents in the industry and energy sectors. It is noted that the scale of global consequences of the Chernobyl NPP accident is defined by the large-scale release of radioactivity into the environment, as well as an affiliation of the nuclear installation with the energy sector. Large-scale radiation accidents affect the most diverse spheres of human activities, what, in its turn, evokes the reverse reaction from the society and its institutions, including involvement of political means of settlement. If the latter is seeing for criteria that are scientifically justified and feasible, then the preconditions for minimizing socio-economic impacts are created. In other cases, political decisions, such as nuclear units’ shutdown and phasing out of nuclear energy, appear to be an economic price which society, as a whole and a single industry sector, pay to compensate the negative public response. The article describes fundamental changes in approaches to ensure nuclear and radiation safety that occurred after the Chernobyl NPP accident. Multiple and negative consequences of the Chernobyl accident for human and society are balanced to some extent by a higher level of operational safety, emergency preparedness, and life-cycle safety. The article indicates that harmonization and ensuring consistency of regulations that involve different aspects of nuclear and radiation safety are important to implement practical solutions to the nuclear legacy problems. The development of regulations on criteria for the classification of radioactive waste and the issues of remediation of radioactively contaminated areas are discussed as the examples.Статья рассматривает вопросы радиационно-гигиенического нормирования при ликвидации последствий аварии на Чернобыльской АЭС в контексте взаимосвязи с другими аспектами, прежде всего, социально-экономическими и политическими факторами. Этот опыт целесообразно учитывать при установлении критериев в других областях нормирования, например, при классификации радиоактивных отходов и реабилитации территорий. В статье представлен анализ общих черт и отличий ядерных аварий в промышленности и энергетике. Отмечается, что масштаб глобальных последствий аварии на Чернобыльской АЭС определяется как масштабным выходом радиоактивности в окружающую среду, так и принадлежностью установки к энергетическому сектору. При крупных радиационных авариях затрагиваются самые разнообразные сферы жизнедеятельности человека, что, в свою очередь, обусловливает ответную волну реагирования со стороны общества и его институтов, включая вовлечение политических механизмов урегулирования. Если последние нацелены на использование научно обоснованных и практически реализуемых критериев, это создает предпосылки для минимизации социально-экономических последствий. В других случаях такие политические решения, как останов энергоблоков, свертывание атомной энергетики, являются экономической ценой, которую общество в целом и отдельная отрасль платят в качестве компенсации негативной общественной реакции. В статье показаны принципиальные изменения подходов к обеспечению ядерной и радиационной безопасности, которые произошли за прошедший после аварии на Чернобыльской АЭС период. Многоплановые и негативные последствия чернобыльской аварии для человека и общества в определенной степени компенсируются более высоким уровнем безопасной эксплуатации, аварийной готовности и безопасности жизненного цикла. В статье отмечается, что для практического решения проблем наследия важными являются гармонизация и приведение во взаимное соответствие нормативных документов, затрагивающих различные аспекты ядерной и радиационной безопасности. В качестве примеров рассмотрены вопросы разработки нормативных документов по критериям отнесения к радиоактивным отходам и вопросы реабилитации радиационно загрязненных территорий

Underground Research Laboratory in “the Yenisei” Section of the Nizhnekansky Massif of the Krasnoyarsk Region

Рассмотрены вопросы сооружения и эксплуатации подземной исследовательской лаборатории для обоснования долговременной безопасности пункта глубинного захоронения радиоактивных отходов в Российской Федерации с позиции научного сопровождения. Изложены основные принципы и ключевые направления долговременной программы научных исследований, в том числе в подземной лаборатории, для оценки и обоснования безопасности объекта на всех этапах его жизненного циклаThe issues of the construction and operation of an underground research laboratory for the purpose of substantiating the long-term safety of the deep radioactive waste disposal facility in the Russian Federation from the perspective of scientific support are considered. The basic principles are stated and the key directions of a long-term program of scientific research, including in an underground laboratory, are justified for assessing and substantiating the safety of an object at all stages of its life cycl

Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

Intellectual activism: the path to change in policy and practice through critical research. The work of the Global Hospitality Research Alliance (GHRA)

This presentation will focus on the role of intellectual activism as a driver and outcome of critical research in the area of hospitality employment. A criticism of much academic research in tourism and hospitality is that our impact is limited and our goals, in terms of output, are framed in terms of high-quality journal papers. Hospitality employment is a domain where our collective endeavours, as academic researchers, has been singularly unsuccessful in real impact terms. This conference presentation will explore the experience of an international group of critical scholars, sharing a common interest in hospitality employment, in engaging with intellectual activism to translate academic research into vehicles for stakeholder advocacy

SpeB of Streptococcus pyogenes Differentially Modulates Antibacterial and Receptor Activating Properties of Human Chemokines

BACKGROUND: CXC chemokines are induced by inflammatory stimuli in epithelial cells and some, like MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, are antibacterial for Streptococcus pyogenes. METHODOLOGY/PRINCIPAL FINDINGS: SpeB from S. pyogenes degrades a wide range of chemokines (i.e. IP10/CXCL10, I-TAC/CXCL11, PF4/CXCL4, GROalpha/CXCL1, GRObeta/CXCL2, GROgamma/CXCL3, ENA78/CXCL5, GCP-2/CXCL6, NAP-2/CXCL7, SDF-1/CXCL12, BCA-1/CXCL13, BRAK/CXCL14, SRPSOX/CXCL16, MIP-3alpha/CCL20, Lymphotactin/XCL1, and Fractalkine/CX3CL1), has no activity on IL-8/CXCL8 and RANTES/CCL5, partly degrades SRPSOX/CXCL16 and MIP-3alpha/CCL20, and releases a 6 kDa CXCL9 fragment. CXCL10 and CXCL11 loose receptor activating and antibacterial activities, while the CXCL9 fragment does not activate the receptor CXCR3 but retains its antibacterial activity. CONCLUSIONS/SIGNIFICANCE: SpeB destroys most of the signaling and antibacterial properties of chemokines expressed by an inflamed epithelium. The exception is CXCL9 that preserves its antibacterial activity after hydrolysis, emphasizing its role as a major antimicrobial on inflamed epithelium