The Heparan Sulfate Proteoglycans Dally-like and Syndecan Have Distinct Functions in Axon Guidance and Visual-System Assembly in Drosophila

SummaryHeparan sulfate proteoglycans (HSPGs), a class of glycosaminoglycan-modified proteins, control diverse patterning events via their regulation of growth-factor signaling and morphogen distribution [1]. In C. elegans, zebrafish, and the mouse, heparan sulfate (HS) biosynthesis is required for normal axon guidance [2–4], and mutations affecting Syndecan (Sdc), a transmembrane HSPG, disrupt axon guidance in Drosophila embryos [5, 6]. Glypicans, a family of glycosylphosphatidylinositol (GPI)-linked HSPGs, are expressed on axons and growth cones in vertebrates, but their role in axon guidance has not been determined [7, 8]. We demonstrate here that the Drosophila glypican Dally-like protein (Dlp) is required for proper axon guidance and visual-system function. Mosaic studies revealed that Dlp is necessary in both the retina and the brain for different aspects of visual-system assembly. Sdc mutants also showed axon guidance and visual-system defects, some that overlap with dlp and others that are unique. dlp+ transgenes were able to rescue some sdc visual-system phenotypes, but sdc+ transgenes were ineffective in rescuing dlp abnormalities. Together, these findings suggest that in some contexts HS chains provide the biologically critical component, whereas in others the structure of the protein core is also essential

A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-γ-activated human cells

ABSTRACT A core set of autophagy proteins is required for gamma interferon (IFN-γ)-mediated clearance of Toxoplasma gondii in the mouse because of their control of several downstream effectors, including immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). However, these effectors are absent (i.e., IRGs) from or nonessential (i.e., GBPs) in IFN-γ-activated human cells, raising the question of how these cells control parasite replication. Here, we define a novel role for ubiquitination and recruitment of autophagy adaptors in the strain-specific control of T. gondii replication in IFN-γ-activated human cells. Vacuoles containing susceptible strains of T. gondii became ubiquitinated, recruited the adaptors p62 and NDP52, and were decorated with LC3. Parasites within LC3-positive vacuoles became enclosed in multiple layers of host membranes, resulting in stunting of parasite replication. However, LC3-positive T. gondii-containing vacuoles did not fuse with endosomes and lysosomes, indicating that this process is fundamentally different from xenophagy, a form of autophagy involved in the control of intracellular bacterial pathogens. Genetic knockout of ATG16L or ATG7 reverted the membrane encapsulation and restored parasite replication, indicating that core autophagy proteins involved in LC3 conjugation are important in the control of parasite growth. Despite a role for the core autophagy machinery in this process, upstream activation through Beclin 1 was not sufficient to enhance the ubiquitination of T. gondii-containing vacuoles, suggesting a lack of reliance on canonical autophagy. These findings demonstrate a new mechanism for IFN-γ-dependent control of T. gondii in human cells that depends on ubiquitination and core autophagy proteins that mediate membrane engulfment and restricted growth

Bioinformatics

Motivation: Theoretical efforts to understand the regulation of gene expression are traditionally centered around the identification of transcription factor binding sites at specific DNA positions. More recently these efforts have been supplemented by experimental data for relative binding affinities of proteins to longer intergenic sequences. The question arises to what extent these two approaches converge. In this paper, we adopt a physical binding model to predict the relative binding affinity of a transcription factor for a given sequence. Results: We find that a significant fraction of genome-wide binding data in yeast can be accounted for by simple count matrices and a physical model with only two parameters. We demonstrate that our approach is both conceptually and practically more powerful than traditional methods, which require selection of a cutoff. Our analysis yields biologically meaningful parameters, suitable for predicting relative binding affinities in the absence of experimental binding data. Availability: The C source code for our TRAP program is freely available for non-commercial use at http://www.molgen.mpg.de/~manke/papers/TFaffinities

The MUMBA campaign: measurements of urban, marine and biogenic air

The Measurements of Urban, Marine and Biogenic Air (MUMBA) campaign took place in Wollongong, New South Wales (a small coastal city approximately 80 km south of Sydney, Australia) from 21 December 2012 to 15 February 2013. Like many Australian cities, Wollongong is surrounded by dense eucalyptus forest, so the urban airshed is heavily influenced by biogenic emissions. Instruments were deployed during MUMBA to measure the gaseous and aerosol composition of the atmosphere with the aim of providing a detailed characterisation of the complex environment of the ocean–forest–urban interface that could be used to test the skill of atmospheric models. The gases measured included ozone, oxides of nitrogen, carbon monoxide, carbon dioxide, methane and many of the most abundant volatile organic compounds. The aerosol characterisation included total particle counts above 3 nm, total cloud condensation nuclei counts, mass concentration, number concentration size distribution, aerosol chemical analyses and elemental analysis. The campaign captured varied meteorological conditions, including two extreme heat events, providing a potentially valuable test for models of future air quality in a warmer climate. There was also an episode when the site sampled clean marine air for many hours, providing a useful additional measure of the background concentrations of these trace gases within this poorly sampled region of the globe. In this paper we describe the campaign, the meteorology and the resulting observations of atmospheric composition in general terms in order to equip the reader with a sufficient understanding of the Wollongong regional influences to use the MUMBA datasets as a case study for testing a chemical transport model. © Author(s) 2017.The data are available from PANGAEA (http://doi.pangaea.de/10.1594/PANGAEA.871982)

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

The role of chick Ebf genes in the mediolateral patterning of the somites

This study was conducted to check whether the three chick Early B-cell Factor (Ebf) genes, particularly cEbf1, would be targets for Shh and Bmp signals during somites mediolateral (ML) patterning. Tissue manipulations and gain and loss of function experiments for Shh and Bmp4 were performed and the results revealed that cEbf1 expression was initiated in the cranial presomitic mesoderm by low dose of Bmp4 from the lateral mesoderm and maintained in the ventromedial part of the epithelial somite and the medial sclerotome by Shh from the notochord; while cEbf2/3 expression was induced and maintained by Bmp4 and inhibited by high dose of Shh. To determine whether Ebf1 plays a role in somite patterning, transfection of a dominant-negative construct was carried out; this showed suppression of cPax1 expression in the medial sclerotome and upregulation and medial expansion of cEbf3 and cPax3 expression in sclerotome and dermomyotome, respectively, suggesting that Ebf1 is important for ML patterning. Thus, it is possible that low doses of Bmp4 set up Ebf1 expression which, together with Shh from the notochord, leads to establishment of the medial sclerotome and suppression of lateral identities. These data also conclude that Bmp4 is required in both the medial and lateral domain of the somitic mesoderm to keep the ML identity of the sclerotome through maintenance of cEbf gene expression. These striking findings are novel and give a new insight on the role of Bmp4 on mediolateral patterning of somites

HSPG-Binding Peptide Corresponding to the Exon 6a-Encoded Domain of VEGF Inhibits Tumor Growth by Blocking Angiogenesis in Murine Model

Vascular endothelial growth factor VEGF165 is a critical element for development of the vascular system in physiological and pathological angiogenesis. VEGF isoforms have different affinities for heparan sulphate proteoglycan (HSPG) as well as for VEGF receptors; HSPGs are important regulators in vascular development. Therefore, inhibition of interactions between VEGF and HSPGs may prevent angiogenesis. Here, we demonstrate that an HSPG-binding synthetic peptide, corresponding to exon 6a-encoded domain of VEGF gene, has anti-angiogenic property. This 20 amino acids synthetic peptide prevents VEGF165 binding to several different cell types, mouse embryonic sections and inhibits endothelial cell migration, despite its absence in VEGF165 sequence. Our in vivo anti-tumor studies show that the peptide inhibits tumor growth in both mouse Lewis-Lung Carcinoma and human Liposarcoma tumor-bearing animal models. This is the first evidence that a synthetic VEGF fragment corresponding to exon 6a has functional antagonism both in vitro and in vivo. We conclude that the above HPSG binding peptide (6a-P) is a potent inhibitor of angiogenesis-dependent diseases

The Liberal Playground: Susan Isaacs, Psychoanalysis and Progressive Education in the Interwar Era

The Cambridge Malting House, an experimental school, serves here as a case study for investigating the tensions within 1920s liberal elites between their desire to abandon some Victorian and Edwardian sets of values in favour of more democratic ones, and at the same time their insistence on preserving themselves as an integral part of the English upper class. Susan Isaacs, the manager of the Malting House, provided the parents – some of whom were the most famous scientists and intellectuals of their age – with an opportunity to fulfil their ‘fantasy’ of bringing up children in total freedom. In retrospect, however, she deeply criticized those from their milieu for not fully understanding the real socio-cultural implications of their ideological decision to make independence and freedom the core values in their children’s education. Thus, 1920s progressive education is a paradigmatic case study of the cultural and ideological inner contradictions within liberal thought in the interwar era. The article also shows how psychoanalysis – which attracted many progressive educators – played a crucial role in providing liberals of all sorts with a new language to articulate their political visions, but, at the same time, explored the limits of the liberal discourse as a whole

The additional value of TGFβ1 and IL-7 to predict the course of prostate cancer progression

Background: Given the fact that prostate cancer incidence will increase in the coming years, new prognostic biomarkers are needed with regard to the biological aggressiveness of the prostate cancer diagnosed. Since cytokines have been associated with the biology of cancer and its prognosis, we determined whether transforming growth factor beta 1 (TGFβ1), interleukin-7 (IL-7) receptor and IL-7 levels add additional prognostic information with regard to prostate cancer