Using Gene Expression Arrays to Elucidate Transcriptional Profiles Underlying Prolactin Function

Prolactin is an ancient hormone, with different functions in many species. The binding of prolactin to its receptor, a member of the cytokine receptor superfamily, results in the activation of different intracellular signaling pathways, such as JAK2/STAT5, MAP kinase, and PI3K/AKT. How prolactin elicits so many different biological responses remains unclear. Recently, microarray technology has been applied to identify prolactin target genes in different systems. Here, we attempt to summarize and compare the available data. Our comparison of the genes reported to be transcriptionally regulated by prolactin indicates that there are few genes in common between the different tissues. Among the organs studied, mammary and prostate glands displayed the largest number of overlaps in putative prolactin target genes. Some of the candidates have been implicated in tumorigenesis. The relevance and validation of microarray data, as well as comparison of the results obtained by different groups, will be discusse

HENMT1 and piRNA Stability Are Required for Adult Male Germ Cell Transposon Repression and to Define the Spermatogenic Program in the Mouse

piRNAs are critical for transposable element (TE) repression and germ cell survival during the early phases of spermatogenesis, however, their role in adult germ cells and the relative importance of piRNA methylation is poorly defined in mammals. Using a mouse model of HEN methyltransferase 1 (HENMT1) loss-of-function, RNA-Seq and a range of RNA assays we show that HENMT1 is required for the 2’ O-methylation of mammalian piRNAs. HENMT1 loss leads to piRNA instability, reduced piRNA bulk and length, and ultimately male sterility characterized by a germ cell arrest at the elongating germ cell phase of spermatogenesis. HENMT1 loss-of-function, and the concomitant loss of piRNAs, resulted in TE de-repression in adult meiotic and haploid germ cells, and the precocious, and selective, expression of many haploid-transcripts in meiotic cells. Precocious expression was associated with a more active chromatin state in meiotic cells, elevated levels of DNA damage and a catastrophic deregulation of the haploid germ cell gene expression. Collectively these results define a critical role for HENMT1 and piRNAs in the maintenance of TE repression in adult germ cells and setting the spermatogenic program

A game of “Cut and Mouse”:bypassing antivirus by simulating user inputs

To protect their digital assets from malware attacks, most users and companies rely on anti-virus (AV) software. But AVs' protection is a full-time task and AVs are engaged in a cat-and-mouse game where malware, e.g., through obfuscation and polymorphism, denial of service attacks and malformed packets and parameters, try to circumvent AV defences or make them crash. On the other hand, AVs react by complementing signature-based with anomaly or behavioral detection, and by using OS protection, standard code, and binary protection techniques. Further, malware counter-act, for instance by using adversarial inputs to avoid detection, et cetera. This paper investigates two novel moves for the malware side. The first one consists in simulating mouse events to control AVs, namely to send them mouse "clicks" to deactivate their protection. We prove that many AVs can be disabled in this way, and we call this class of attacks Ghost Control. The second one consists in controlling high-integrity white-listed applications, such as Notepad, by sending them keyboard events (such as "copy-and-paste") to perform malicious operations on behalf of the malware. We prove that the anti-ransomware protection feature of some AVs can be bypassed if we use Notepad as a "puppet" to rewrite the content of protected files as a ransomware would do. Playing with the words, and recalling the cat-and-mouse game, we call this class of attacks Cut-and-Mouse

Developing a collaborative agenda for humanities and social scientific research on laboratory animal science and welfare.

Improving laboratory animal science and welfare requires both new scientific research and insights from enquiry in the humanities and social sciences. Whilst scientific research provides evidence to replace, reduce and refine procedures involving laboratory animals (the ‘3Rs’), work in the humanities and social sciences can help understand the social, economic and cultural processes that enhance or impede humane ways of knowing and working with laboratory animals. However, communication across these disciplinary perspectives is currently limited, and they frame questions, generate results, engage users, and seek to influence policy in different ways. To facilitate dialogue and future research at this interface, we convened an interdisciplinary group of 45 life scientists, social scientists, humanities scholars, non-governmental organisations and policy-makers to generate a collaborative research agenda. This drew on other agenda-setting exercises in science policy, using a collaborative and deliberative approach for the identification of research priorities. Participants were recruited from across the community, invited to submit research questions and vote on their priorities. They then met at an interactive workshop in the UK, discussed all 136 questions submitted, and collectively defined the 30 most important issues for the group. The output is a collaborative future agenda for research in the humanities and social sciences on laboratory animal science and welfare. The questions indicate a demand for new research in the humanities and social sciences to inform emerging discussions and priorities on the governance and practice of laboratory animal research, including around: international harmonisation, openness and public engagement, ‘cultures of care’, harm-benefit analysis and the future of the 3Rs. The process underlines the value of interdisciplinary exchange for improving mutual understanding of different research cultures and identifies ways of enhancing the effectiveness of future research at the interface between the humanities, social sciences, science and science policy

An Essential Role for Katanin p80 and Microtubule Severing in Male Gamete Production

Katanin is an evolutionarily conserved microtubule-severing complex implicated in multiple aspects of microtubule dynamics. Katanin consists of a p60 severing enzyme and a p80 regulatory subunit. The p80 subunit is thought to regulate complex targeting and severing activity, but its precise role remains elusive. In lower-order species, the katanin complex has been shown to modulate mitotic and female meiotic spindle dynamics and flagella development. The in vivo function of katanin p80 in mammals is unknown. Here we show that katanin p80 is essential for male fertility. Specifically, through an analysis of a mouse loss-of-function allele (the Taily line), we demonstrate that katanin p80, most likely in association with p60, has an essential role in male meiotic spindle assembly and dissolution and the removal of midbody microtubules and, thus, cytokinesis. Katanin p80 also controls the formation, function, and dissolution of a microtubule structure intimately involved in defining sperm head shaping and sperm tail formation, the manchette, and plays a role in the formation of axoneme microtubules. Perturbed katanin p80 function, as evidenced in the Taily mouse, results in male sterility characterized by decreased sperm production, sperm with abnormal head shape, and a virtual absence of progressive motility. Collectively these data demonstrate that katanin p80 serves an essential and evolutionarily conserved role in several aspects of male germ cell development

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity

HENMT1 and piRNA stability are required for adult male germ cell transposon repression and to define the spermatogenic program in the mouse

piRNAs are critical for transposable element (TE) repression and germ cell survival during the early phases of spermatogenesis, however, their role in adult germ cells and the relative importance of piRNA methylation is poorly defined in mammals. Using a mouse model of HEN methyltransferase 1 (HENMT1) loss-of-function, RNA-Seq and a range of RNA assays we show that HENMT1 is required for the 2' O-methylation of mammalian piRNAs. HENMT1 loss leads to piRNA instability, reduced piRNA bulk and length, and ultimately male sterility characterized by a germ cell arrest at the elongating germ cell phase of spermatogenesis. HENMT1 loss-of-function, and the concomitant loss of piRNAs, resulted in TE de-repression in adult meiotic and haploid germ cells, and the precocious, and selective, expression of many haploid-transcripts in meiotic cells. Precocious expression was associated with a more active chromatin state in meiotic cells, elevated levels of DNA damage and a catastrophic deregulation of the haploid germ cell gene expression. Collectively these results define a critical role for HENMT1 and piRNAs in the maintenance of TE repression in adult germ cells and setting the spermatogenic program.Shu Ly Lim, Zhi Peng Qu, R. Daniel Kortschak, David M. Lawrence, Joel Geoghegan, Anna-Lena Hempfling, Martin Bergmann, Christopher C. Goodnow, Christopher J. Ormandy, Lee Wong, Jeff Mann, Hamish S. Scott, Duangporn Jamsai, David L. Adelson, Moira K. O, Brya

Manchette structure in wild-type and <i>Katnb1^Taily/Taily</i> spermatids.

<p>A. α-Tubulin staining (green) of manchette microtubules in isolated spermatids from WT mice. Elongating spermatids are shown in progressive steps of manchette development from left to right. Arrows indicate the distance between perinuclear ring of the manchette and the posterior portion of the nucleus. B. α-Tubulin staining (green) of manchette microtubules in isolated spermatids from <i>Katnb1^Taily/Taily</i> mice. Arrows indicate the distance of the peri-nuclear ring to the posterior portion of the nucleus. In all images, blue staining = DNA (TOPRO). The scale bar in each micrograph = 5 µm.</p