Oncolytic Newcastle disease virus reduces growth of cervical cancer cell by inducing apoptosis

Although Oncolytic viruses have been regarded as a promising tool for targeted therapy of cancer, accomplishing high efficacy and specificity with this strategy is challenging. Oncolytic virotherapy is one of the novel therapeutic methods recently used for the therapy of human malignancies. Cervical cancer is on the major public health problem and the second most common cause of cancer death among females in less developed countries. The aim of this study was mainly to determine the apoptosis effect of oncolytic Newcastle disease virus (NDV) in TC-1 cell line.In the current study, the oncolytic NDV, vaccine strain LaSota, was used to infect murine TC-1 cells of human papillomavirus (HPV)-associated carcinoma which expressing human papillomavirus 16 (HPV-16) E6/E7 antigens in vitro. The effectiveness of NDV for cervical cancer cell line was investigated by evaluating the antitumor activity of oncolytic NDV and the involved mechanisms. Antitumor activities of oncolytic NDV were assessed by cell proliferation (MTT) and lactate dehydrogenase (LDH) release analysis. In addition, molecular changes of early stage of apoptosis and the role of reactive oxygen species (ROS) were analyzed by flow cytometry and Western Blot in NDV-treated TC-1 cells.The results showed that NDV treatment significantly decreased the viability of a TC-1 cell line and suppressed the growth by inducing apoptotic cell death. In addition, we demonstrated that NDV-induced apoptosis of TC-1 cells is mediated by ROS production. In summary, our findings suggest that oncolytic NDV is a possible therapeutic candidate as a selective antitumor agent for the treatment of cervical cancer.     

First report of leaf spot disease caused by Corynespora torulosa MCC-1368 on cotton plant from India

In present study, the leaf spot disease of cotton plant emerged in the North Maharashtra region of India was reported. The fungal phytopathogen associated with inducing the leaf spot disease symptoms was isolated and characterised. The isolated fungus was identified as Corynespora torulosa (Deposition accession number, MCC-1368; Genbank accession no. MF462072) based on morphological and cultural characteristics and molecular analysis of ITS region. The pathogenicity of fungal phytopathogen was verified by Koch’s postulates. To our knowledge, this is the first report of incidence of leaf spot disease caused by Corynespora torulosa on cotton plant.     

Anticipating white‐nose syndrome in the Southern Hemisphere: Widespread conditions favourable to Pseudogymnoascus destructans pose a serious risk to Australia's bat fauna

There is a serious concern that white‐nose syndrome (WNS), a fungal disease causing severe population declines in North American bats, could soon threaten bats on the Australian continent. Despite an ‘almost certain' risk of incursion within the next ten years, and high virulence in naïve bat populations, we remain uncertain about the vulnerability of Australian bats to WNS. In this study, we intersected occurrences for the 27 cave roosting bat species in Australia with interpolated data on mean annual surface temperature, which provides a proxy for thermal conditions within a cave and hence its suitability for growth by the fungal pathogen Pseudogymnoascus destructans. Our analysis identifies favourable roost thermal conditions within 30–100% of the ranges of eight bat species across south‐eastern Australia, including for seven species already listed as threatened with extinction. These results demonstrate the potential for widespread exposure to P. destructans and suggest that WNS could pose a serious risk to the conservation of Australia's bat fauna. The impacts of exposure to P. destructans will depend, however, on the sensitivity of bats to developing WNS, and a more comprehensive vulnerability assessment is currently prevented by a lack of information on the hibernation biology of Australian bats. Thus, given the clear potential for widespread exposure of Australia's bats to P. destructans demonstrated by our study, two specific policy actions seem justified: (i) urgent implementation of border controls that identify and decontaminate cave‐associated fomites and (ii) dedicated funding to enable research on key aspects of bat winter behaviour and hibernation physiology. Further, as accidental translocation of this fungus could also pose a risk to other naïve bat faunas in cooler regions of southern Africa and South America, we argue that a proactive, globally coordinated approach is required to understand and mitigate the potential impacts of WNS spreading to Southern Hemisphere bats.     

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf ^im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf ^im on motor function, suggesting that Dysf ^im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.     

Immune and genetic gardening of the intestinal microbiome

The mucosal immune system – consisting of adaptive and innate immune cells as well as the epithelium – is profoundly influenced by its microbial environment. There is now growing evidence that the converse is also true, that the immune system shapes the composition of the intestinal microbiome. During conditions of health, this bidirectional interaction achieves a homeostasis in which inappropriate immune responses to non-pathogenic microbes are averted and immune activity suppresses blooms of potentially pathogenic microbes (pathobionts). Genetic alteration in immune/epithelial function can affect host gardening of the intestinal microbiome, contributing to the diversity of intestinal microbiota within a population and in some cases allowing for unfavorable microbial ecologies (dysbiosis) that confer disease susceptibility.     

Dihydrotestosterone treatment delays the conversion from mild cognitive impairment to Alzheimer's disease in SAMP8 mice

The senescence-accelerated-prone mouse 8 (SAMP8) has been proposed as a suitable, naturally derived animal model for Alzheimer's disease (AD). In the current study, we focus on the problem whether SAMP8 mice show abnormal behavioral and neuropathological signs before they present the characteristic of AD. Our results demonstrated that given the presence of the senescent, behavioral and neuropathological characteristics, the “middle-aged” SAMP8 mice appear to be a suitable and naturally derived animal model for MCI basic research. There is relatively less evidence that androgen may be involved in the pathogenesis of AD. We determined testosterone (T) levels of SAMR1 and SAMP8 mice and found that the marked age-related decrease in serum androgen levels may be one of the risk factors for Alzheimer's dementia. We also evaluated the interventional effect on MCI phase by dihydrotestosterone (DHT) in male SAMP8 mice and found that timely and appropriate androgen intervention can postpone the onset and improve the symptoms of dementia.     

Stable DNA Methylation Boundaries and Expanded Trinucleotide Repeats: Role of DNA Insertions

The human genome segment upstream of the FMR1 (fragile X mental retardation 1) gene (Xq27.3) contains several genetic signals, among them is a DNA methylation boundary that is located 65–70 CpGs upstream of the CGG repeat. In fragile X syndrome (FXS), the boundary is lost, and the promoter is inactivated by methylation spreading. Here we document boundary stability in spite of critical expansions of the CGG trinucleotide repeat in male or female premutation carriers and in high functioning males (HFMs). HFMs carry a full CGG repeat expansion but exhibit an unmethylated promoter and lack the FXS phenotype. The boundary is also stable in Turner (45, X) females. A CTCF-binding site is located slightly upstream of the methylation boundary and carries a unique G-to-A polymorphism (single nucleotide polymorphism), which occurs 3.6 times more frequently in genomes with CGG expansions. The increased frequency of this single nucleotide polymorphism might have functional significance. In CGG expansions, the CTCF region does not harbor additional mutations. In FXS individuals and often in cells transgenomic for EBV (Epstein Barr Virus) DNA or for the telomerase gene, the large number of normally methylated CpGs in the far-upstream region of the boundary is decreased about 4-fold. A methylation boundary is also present in the human genome segment upstream of the HTT (huntingtin) promoter (4p16.3) and is stable both in normal and Huntington disease chromosomes. Hence, the vicinity of an expanded repeat does not per se compromise methylation boundaries. Methylation boundaries exert an important function as promoter safeguards.     

Factors Influencing Compact–Extended Structure Equilibrium in Oligomers of Aβ1–40 Peptide—An Ion Mobility Mass Spectrometry Study

Oligomers formed by amyloid β (Aβ) peptide are widely believed to be the main neurotoxic agent in Alzheimer's disease. Studies discovered a broad variety of oligomeric forms, which display different levels of toxicity. Some of these forms may further assemble into mature fibrils, while other might be off-pathway from conversion to fibrils and assemble into alternative forms. To better understand a relationship between the structure and toxicity of Aβ oligomers, we require systematic characterization and classification of all possible forms, facilitating rational design of the beneficial modifiers of their activity. In previous ion mobility analysis of Aβ1–40 oligomers, we have detected the coexistence of two alternative structural forms (compact and extended) in a pool of low-order Aβ1–40 oligomers. These forms may represent two pathways of the oligomer evolution, leading either to fibrils or to off-pathway oligomers, which are potential candidates for the neurotoxic species. Here, we have analyzed the impact of incubation time, the presence of selected metal ions and the effect of a series of point mutations on mutual population of alternative forms. We have shown that a salt bridge D23K28 provides stabilization of the compact form whereas G25 is required for the existence of the extended form. We have found that binding of metal ions also stabilizes the compact form. These results improve our understanding of the possible molecular mechanism of the bifurcation of structural evolution of non-monomeric Aβ species into an off-fibril pathway, ultimately leading to the formation of potentially neurotoxic species.     

Create and preserve: Proteostasis in development and aging is governed by Cdc48/p97/VCP

The AAA-ATPase Cdc48 (also called p97 or VCP) acts as a key regulator in proteolytic pathways, coordinating recruitment and targeting of substrate proteins to the 26S proteasome or lysosomal degradation. However, in contrast to the well-known function in ubiquitin-dependent cellular processes, the physiological relevance of Cdc48 in organismic development and maintenance of protein homeostasis is less understood. Therefore, studies on multicellular model organisms help to decipher how Cdc48-dependent proteolysis is regulated in time and space to meet developmental requirements. Given the importance of developmental regulation and tissue maintenance, defects in Cdc48 activity have been linked to several human pathologies including protein aggregation diseases. Thus, addressing the underlying disease mechanisms not only contributes to our understanding on the organism-wide function of Cdc48 but also facilitates the design of specific medical therapies. In this review, we will portray the role of Cdc48 in the context of multicellular organisms, pointing out its importance for developmental processes, tissue surveillance, and disease prevention. This article is part of a Special Issue entitled: Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.