Impact of Maternal Air Pollution exposure on children's lung health: An Indian perspective

© 2018 by the authors. Air pollution has become an emerging invisible killer in recent years and is a major cause of morbidity and mortality globally. More than 90% of the world's children breathe toxic air every day. India is among the top ten most highly polluted countries with an average PM 10 level of 134 μg/m 3 per year. It is reported that 99% of India's population encounters air pollution levels that exceed the World Health Organization Air Quality Guideline, advising a PM 2.5 permissible level of 10 μg/m 3 . Maternal exposure to air pollution has serious health outcomes in offspring because it can affect embryonic phases of development during the gestation period. A fetus is more prone to effects from air pollution during embryonic developmental phases due to resulting oxidative stress as antioxidant mechanisms are lacking at that stage. Any injury during this vulnerable period (embryonic phase) will have a long-term impact on offspring health, both early and later in life. Epidemiological studies have revealed that maternal exposure to air pollution increases the risk of development of airway disease in the offspring due to impaired lung development in utero. In this review, we discuss cellular mechanisms involved in maternal exposure to air pollution and how it can impact airway disease development in offspring. A better understanding of these mechanisms in the context of maternal exposure to air pollution can offer a new avenue to prevent the development of airway disease in offspring

Differential Effect of Contrast Polarity Reversals in Closed Squares and Open L-Junctions

Scene segmentation depends on interaction between geometrical and photometric factors. It has been shown that reversals in contrast polarity at points of highest orientation discontinuity along closed contours significantly impair shape discrimination performance, while changes in contrast polarity at straight(er) contour segments do not have such deleterious effects (Spehar, 2002). Here we employ (semi) high resolution fMRI (1.5 mm × 1.5 mm × 1.5 mm) to investigate the neuronal substrate underlying these perception effects. Stimuli consisted of simple elements (a) squares with contrast reversals along straight segments; (b) squares with contrast reversals in the corner (highest orientation discontinuity); (c) L-Junctions with contrast reversals along the straight ends; (d) L-Junctions with contrast reversals in the corner. Element with contrast polarity reversals are easy to distinguish though appear geometrically equivalent. For squares with contrast polarity reversals only along straight lines we find significantly lower BOLD modulation compared to any of the control conditions, which show similar responses to each other. In the light of previous psychophysical work (Elder and Zucker, 1993; Spehar, 2002) we speculate that this effect is due to closure perception. We observe this across a wide range of areas on occipital cortex

Fuzzy modelling of acid mine drainage environments using geochemical, ecological and mineralogical indicators

Fuzzy logic was applied to model acid mine drainage (AMD) and to obtain a classification index of the environmental impact in a contaminated riverine system. The data set used to develop this fuzzy model (a fuzzy classifier) concerns an abandoned mine in Northern Portugal— Valdarcas mining site. Here, distinctive drainage environments (spatial patterns) can be observed based on the AMD formed in the sulphide-rich waste-dumps. Such environments were established, as the effluent flows through the mining area, using several kinds of indicators. These are physical–chemical, ecological and mineralogical parameters, being expressed in a quantitative or qualitative basis. The fuzzy classifier proposed in this paper is a min– max fuzzy inference system, representing the spatial behaviour of those indicators, using the AMD environments as patterns. As they represent different levels (classes) of contamination, the fuzzy classifier can be used as a tool, allowing a more reasonable approach, compared with classical models, to characterize the environmental impact caused by AMD. In a general way it can be applied to other sites where sulphide-rich waste-dumps are promoting the pollution of superficial water through the generation of AMD

HARPS3 for a roboticized Isaac Newton telescope

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We present a description of a new instrument development, HARPS3, planned to be installed on an upgraded and roboticized Isaac Newton Telescope by end-2018. HARPS3 will be a high resolution (R = 115,000) echelle spectrograph with a wavelength range from 380-690 nm. It is being built as part of the Terra Hunting Experiment - a future 10 year radial velocity measurement programme to discover Earth-like exoplanets. The instrument design is based on the successful HARPS spectrograph on the 3.6m ESO telescope and HARPS-N on the TNG telescope. The main changes to the design in HARPS3 will be: a customised fibre adapter at the Cassegrain focus providing a stabilised beam feed and on-sky fibre diameter ~ 1.4 arcsec, the implementation of a new continuous flow cryostat to keep the CCD temperature very stable, detailed characterisation of the HARPS3 CCD to map the effective pixel positions and thus provide an improved accuracy wavelength solution, an optimised integrated polarimeter and the instrument integrated into a robotic operation. The robotic operation will optimise our programme which requires our target stars to be measured on a nightly basis. We present an overview of the entire project, including a description of our anticipated robotic operation.R.H. acknowledges the Science and Technologies Facilities Council (STFC) for his PhD studentship award (2015).J.I.G.H. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO) under the 2013 Ram´on y Cajal program MINECO RYC-2013-14875.J.I.G.H., R.R., and S.S.T. also acknowledge the Spanish ministry project MINECO AYA2014-56359-P.NP and ES are grateful to Knut and Alice Wallenberg Foundation for a generous support of the Swedish contribution to the THE project.AD acknowledges the support from Russian Foundation for Basic Research as part of research grant 15-52-12371

Silencing Early Viral Replication in Macrophages and Dendritic Cells Effectively Suppresses Flavivirus Encephalitis

West Nile (WN) and St. Louis encephalitis (SLE) viruses can cause fatal neurological infection and currently there is neither a specific treatment nor an approved vaccine for these infections. In our earlier studies, we have reported that siRNAs can be developed as broad-spectrum antivirals for the treatment of infection caused by related viruses and that a small peptide called RVG-9R can deliver siRNA to neuronal cells as well as macrophages. To increase the repertoire of broad-spectrum antiflaviviral siRNAs, we screened 25 siRNAs targeting conserved regions in the viral genome. Five siRNAs were found to inhibit both WNV and SLE replication in vitro reflecting broad-spectrum antiviral activity and one of these was also validated in vivo. In addition, we also show that RVG-9R delivers siRNA to macrophages and dendritic cells, resulting in effective suppression of virus replication. Mice were challenged intraperitoneally (i.p.) with West Nile virus (WNV) and treated i.v. with siRNA/peptide complex. The peritoneal macrophages isolated on day 3 post infection were isolated and transferred to new hosts. Mice receiving macrophages from the anti-viral siRNA treated mice failed to develop any disease while the control mice transferred with irrelevant siRNA treated mice all died of encephalitis. These studies suggest that early suppression of viral replication in macrophages and dendritic cells by RVG-9R-mediated siRNA delivery is key to preventing the development of a fatal neurological disease

Immunoregulation of bovine macrophages by factors in the salivary glands of Rhipicephalus microplus

<p>Abstract</p> <p>Background</p> <p>Alternative strategies are required to control the southern cattle tick, <it>Rhipicephalus microplus</it>, due to evolving resistance to commercially available acaricides. This invasive ectoparasite is a vector of economically important diseases of cattle such as bovine babesiosis and anaplasmosis. An understanding of the biological intricacies underlying vector-host-pathogen interactions is required to innovate sustainable tick management strategies that can ultimately mitigate the impact of animal and zoonotic tick-borne diseases. Tick saliva contains molecules evolved to impair host innate and adaptive immune responses, which facilitates blood feeding and pathogen transmission. Antigen presenting cells are central to the development of robust T cell responses including Th1 and Th2 determination. In this study we examined changes in co-stimulatory molecule expression and cytokine response of bovine macrophages exposed to salivary gland extracts (SGE) obtained from 2-3 day fed, pathogen-free adult <it>R. microplus</it>.</p> <p>Methods</p> <p>Peripheral blood-derived macrophages were treated for 1 hr with 1, 5, or 10 μg/mL of SGE followed by 1, 6, 24 hr of 1 μg/mL of lipopolysaccharide (LPS). Real-time PCR and cytokine ELISA were used to measure changes in co-stimulatory molecule expression and cytokine response.</p> <p>Results</p> <p>Changes were observed in co-stimulatory molecule expression of bovine macrophages in response to <it>R</it>. <it>microplus </it>SGE exposure. After 6 hrs, CD86, but not CD80, was preferentially up-regulated on bovine macrophages when treated with 1 μg/ml SGE and then LPS, but not SGE alone. At 24 hrs CD80, CD86, and CD69 expression was increased with LPS, but was inhibited by the addition of SGE. SGE also inhibited LPS induced upregulation of TNFα, IFNγ and IL-12 cytokines, but did not alter IL-4 or CD40 mRNA expression.</p> <p>Conclusions</p> <p>Molecules from the salivary glands of adult <it>R. microplus </it>showed bimodal concentration-, and time-dependent effects on differential up-regulation of CD86 in bovine macrophages activated by the TLR4-ligand, LPS. Up regulation of proinflammatory cytokines and IL-12, a Th1 promoting cytokine, were inhibited in a dose-dependent manner. The co-stimulatory molecules CD80, as well as the cell activation marker, CD69, were also suppressed in macrophages exposed to SGE. Continued investigation of the immunomodulatory factors will provide the knowledge base to research and develop therapeutic or prophylactic interventions targeting <it>R. microplus</it>-cattle interactions at the blood-feeding interface.</p

RNAi Targeting of West Nile Virus in Mosquito Midguts Promotes Virus Diversification

West Nile virus (WNV) exists in nature as a genetically diverse population of competing genomes. This high genetic diversity and concomitant adaptive plasticity has facilitated the rapid adaptation of WNV to North American transmission cycles and contributed to its explosive spread throughout the New World. WNV is maintained in nature in a transmission cycle between mosquitoes and birds, with intrahost genetic diversity highest in mosquitoes. The mechanistic basis for this increase in genetic diversity in mosquitoes is poorly understood. To determine whether the high mutational diversity of WNV in mosquitoes is driven by RNA interference (RNAi), we characterized the RNAi response to WNV in the midguts of orally exposed Culex pipiens quinquefasciatus using high-throughput, massively parallel sequencing and estimated viral genetic diversity. Our data demonstrate that WNV infection in orally exposed vector mosquitoes induces the RNAi pathway and that regions of the WNV genome that are more intensely targeted by RNAi are more likely to contain point mutations compared to weakly targeted regions. These results suggest that, under natural conditions, positive selection of WNV within mosquitoes is stronger in regions highly targeted by the host RNAi response. Further, they provide a mechanistic basis for the relative importance of mosquitoes in driving WNV diversification

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL

RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery

The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies