Leptomeningeal disease and tumor dissemination in a murine diffuse intrinsic pontine glioma model: Implications for the study of the tumor-cerebrospinal fluid-ependymal microenvironment

BACKGROUND: Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. METHODS: A Nestin-Tva model of DIPG utilizing the 3 most common DIPG genetic alterations (H3.3K27M, PDGF-B, and p53) was used for this study. All mice underwent MR imaging and a subset underwent histopathologic analysis with H&E and immunostaining. RESULTS: Tumor dissemination within the CSF pathways (ventricles, leptomeninges) from the subependyma was present in 76% (25/33) of mice, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region-specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. CONCLUSIONS: This is the first study to report CSF pathway tumor dissemination associated with subependymal tumor in an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus

Smoking‐induced genetic and epigenetic alterations in infertile men

Male fertility rates have shown a progressive decrease in both developing and industrialised countries in the past 50 years. Clinical and epidemiological studies have demonstrated controversial results about the harmful effects of cigarette smoking on seminal parameters. Some studies could not establish a negative effect by tobacco smoking on sperm quality and function, whereas others have found a significant reduction in sperm quality and function. This study reviews the components in cigarette smoke and discusses the effects of smoking on male fertility by focusing extensively on smoking‐induced genetic and epigenetic alterations in infertile men. Chromosomal aneuploidies, sperm DNA fragmentation and gene mutations are discussed in the first section, while changes in DNA methylation, chromatin remodelling and noncoding RNAs are discussed in the second section as part of epigenetic alterations

Suspicious Actions Detection System Using Enhanced CNN and Surveillance Video

Suspicious pre- and post-activity detection in crowded places is essential as many suspicious activities may be carried out by culprits. Usually, there will be installations of surveillance cameras. These surveillance cameras capture videos or images later investigated by authorities and post-event such suspicious activity would be detected. This leads to high human intervention to detect suspicious activity. However, there are no systems available to protect valuable things from such suspicious incidents. Nowadays machine learning (ML)- and deep learning (DL)-based pre-incident warning alarm systems could be adapted to monitor suspicious activity. Suspicious activity prediction would be based on human gestures and unusual activity detection. Even though some methods based on ML or DL have been proposed, the need for a highly accurate, highly precise, low-false-positive and low-false-negative prediction system can be enhanced by hybrid or enhanced ML- or DL-based systems. This proposed research work has introduced an enhanced convolutional neural network (ECNN)-based suspicious activity detection system. The experiment was carried out and the results were claimed. The results are analyzed with the Statistical Package for the Social Sciences (SPSS) tool. The results showed that the mean accuracy, mean precision, mean false-positive rate, and mean false-negative rate of suspicious activity detections were 97.050%, 96.743%, 2.957%, and 2.927% respectively. This result was also compared with the convolutional neural network (CNN) algorithm. This research work can be applied to enhance the pre-suspicious activity alert security system to avoid risky situations

Suspicious Actions Detection System Using Enhanced CNN and Surveillance Video

Suspicious pre- and post-activity detection in crowded places is essential as many suspicious activities may be carried out by culprits. Usually, there will be installations of surveillance cameras. These surveillance cameras capture videos or images later investigated by authorities and post-event such suspicious activity would be detected. This leads to high human intervention to detect suspicious activity. However, there are no systems available to protect valuable things from such suspicious incidents. Nowadays machine learning (ML)- and deep learning (DL)-based pre-incident warning alarm systems could be adapted to monitor suspicious activity. Suspicious activity prediction would be based on human gestures and unusual activity detection. Even though some methods based on ML or DL have been proposed, the need for a highly accurate, highly precise, low-false-positive and low-false-negative prediction system can be enhanced by hybrid or enhanced ML- or DL-based systems. This proposed research work has introduced an enhanced convolutional neural network (ECNN)-based suspicious activity detection system. The experiment was carried out and the results were claimed. The results are analyzed with the Statistical Package for the Social Sciences (SPSS) tool. The results showed that the mean accuracy, mean precision, mean false-positive rate, and mean false-negative rate of suspicious activity detections were 97.050%, 96.743%, 2.957%, and 2.927% respectively. This result was also compared with the convolutional neural network (CNN) algorithm. This research work can be applied to enhance the pre-suspicious activity alert security system to avoid risky situations

Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection

The Zika virus (ZIKV) epidemic has resulted in congenital abnormalities in fetuses and neonates. Although some cross-reactive dengue virus (DENV)-specific antibodies can enhance ZIKV infection in mice, those recognizing the DENV E-dimer epitope (EDE) can neutralize ZIKV infection in cell culture. We evaluated the therapeutic activity of human monoclonal antibodies to DENV EDE for their ability to control ZIKV infection in the brains, testes, placentas, and fetuses of mice. A single dose of the EDE1-B10 antibody given 3 d after ZIKV infection protected against lethality, reduced ZIKV levels in brains and testes, and preserved sperm counts. In pregnant mice, wild-type or engineered LALA variants of EDE1-B10, which cannot engage Fcg receptors, diminished ZIKV burden in maternal and fetal tissues, and protected against fetal demise. Because neutralizing antibodies to EDE have therapeutic potential against ZIKV, in addition to their established inhibitory effects against DENV, it may be possible to develop therapies that control disease caused by both viruses

Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.Farrah El-Saafin, Maria I. Bergamasco, Yunshun Chen, Rose E. May, Prabagaran Esakky, Soroor Hediyeh-zadeh, Mathew Dixon, Stephen Wilcox, Melissa J. Davis, Andreas Strasser, Gordon K. Smyth, Tim Thomas, and Anne K. Vos