Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV

Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 × 10⁻¹¹), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 × 10⁻²). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 × 10⁻³). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV.     

A revision of the genus <Emphasis Type="Italic">Talbotiella</Emphasis> Baker f. (Caesalpinioideae: Leguminosae)

A revision of the genus Talbotiella Baker f. (Caesalpinioideae: Leguminosae) is presented. Four species from Cameroon are described as new and a species of Hymenostegia, also from Cameroon, is transferred to Talbotiella bringing the number of species in Talbotiella to eight: T. bakossiensis Cheek, T. batesii Baker f., T. breteleri (Aubrév.) Mackinder & Wieringa, T. ebo Mackinder & Wieringa, T. eketensis Baker f., T. gentii Hutch. & Greenway, T. korupensis Mackinder & Wieringa and T. velutina Burgt & Wieringa. The centre of diversity is Cameroon where six of the eight species occur, five of which are country endemics. Vegetative characters that can be used to distinguish the species are provided in tabular form. Species distributions are mapped and all species are assessed for conservation status.     

Community-acquired MRSA and pig-farming

Background

Female genital tuberculosis is an uncommon disease that is rarely diagnosed in developed countries.

Case presentation

A 61-year-old postmenopausal woman who had undergone surgery and treated with adjuvant chemotherapy for infiltrating ductal carcinoma of the breast five years ago, presented with bloody vaginal discharge, fatigue, weight loss, and low grade fevers at night for two months. Histological examination of the endometrium, done based on the suspicion of a second primary cancer due to the tamoxifen therapy, revealed a granulomatous reaction. Liquid and solid mycobacterial cultures of the tissues were performed. Although the acid fast staining was negative, the liquid culture was positive for Mycobacterium tuberculosis. Involvement of other systems was not detected. The patient was treated with a three-drug antituberculosis regimen for 9 months and recovered fully.

Conclusion

Female genital tuberculosis is a rare but curable disease that should be included in the differential diagnosis of women with menstrual problems. Early diagnosis is important and may prevent unnecessary invasive procedures for the patient.     

Granuloma formation in vitro requires B-1 cells and is modulated by Paracoccidioides brasiliensis gp43 antigen

The mechanisms that determine granuloma formation and the significance of this type of inflammatory response in the pathogenesis of fungal diseases such as paracoccidioidomycosis are far from fully understood. We developed a granuloma model in vitro using beads to evaluate the role of isolated mouse peritoneal macrophages and B-1 cells. We also investigated granuloma formation in the presence of gp43, the main antigenic component of Paracoccidioides brasiliensis, which is secreted exocellularly. To determine whether B-1 cells, macrophages, or both, participate in granuloma formation, peritoneal cells from Xid mice, which lack B-1 cells, were used. Granuloma-like structures were not formed with Xid peritoneal cells or with cells from wild type mice that had their peritoneal and pleural cavities irradiated before the cultures were established. Granulomas were observed either when total adherent peritoneal cells or when isolated B-1 cells were added to macrophage cultures. The data strongly suggest that an interaction of B-1 cells and macrophages plays an important role in granuloma-like formation in this experimental model and that the presence of gp43 strongly stimulates this response.     

Transthoracic Echocardiography in Mice

In recent years, murine models have become the primary avenue for studying the molecular mechanisms of cardiac dysfunction resulting from changes in gene expression. Transgenic and gene targeting methods can be used to generate mice with altered cardiac size and function,^1-3 and as a result, in vivo techniques are needed to evaluate their cardiac phenotype. Transthoracic echocardiography, pulse wave Doppler (PWD), and tissue Doppler imaging (TDI) can be used to provide dimensional measurements of the mouse heart and to quantify the degree of cardiac systolic and diastolic performance. Two-dimensional imaging is used to detect abnormal anatomy or movements of the left ventricle, whereas M-mode echo is used for quantification of cardiac dimensions and contractility.^4,5 In addition, PWD is used to quantify localized velocity of turbulent flow,⁶ whereas TDI is used to measure the velocity of myocardial motion.⁷ Thus, transthoracic echocardiography offers a comprehensive method for the noninvasive evaluation of cardiac function in mice.     

A 4-deoxy analogue of N-acetyl-d-glucosamine inhibits heparan sulphate expression and growth factor binding in vitro

Heparan sulphate (HS) is a long, linear polysaccharide, which has a basic backbone of -β1-4GlcA-α1-4GlcNAc- units. The involvement of HS in many steps of tumourigenesis, including growth and angiogenesis, makes it an appealing target for cancer therapy. To target the biosynthesis of HS by interfering with its chain elongation, a 4-deoxy analogue of N-acetyl-d-glucosamine (4-deoxy-GlcNAc) was synthesized. Using immunocytochemistry and agarose gel electrophoresis it was shown that incubation with the 4-deoxysugar resulted in a dose dependent reduction of HS expression of MV3 melanoma cells, 1 mM resulting in an almost nullified HS expression. The parent sugar GlcNAc had no effect. 4-deoxysugar treated cells were viable and proliferated at the same rate as control cells. Other glycan structures appeared to be only mildly affected, as staining by various lectins was generally not or only modestly inhibited. At 1 mM of the 4-deoxysugar, the capacity of cells to bind the HS-dependent pro-angiogenic growth factors FGF-2 and VEGF was greatly compromised. Using an in vitro angiogenesis assay, 4-deoxysugar treated endothelial cells showed a sharp reduction of FGF-2-induced sprout formation. Combined, these data indicate that an inexpensive, easily synthesized, water-soluble monosaccharide analogue can interfere with HS expression and pro-angiogenic growth factor binding.     

Phylogeny and systematics of the tribe Sonerileae (Melastomataceae) in Africa: A revised taxonomic classification

The tribe Sonerileae in tropical Africa and Madagascar is a morphologically diverse lineage that consists of 239 species in 10 genera. In this study, we present the first in-depth phylogenetic analysis of African Sonerileae to test monophyly of the currently recognized genera. Phylogenetic analyses were performed using sequence data from two nuclear (nrITS and nrETS) and three plastid loci (accD-psaI, ndhF and psbK-psbL). Sampling consisted of 140 accessions including 64 African, 27 Malagasy, 46 Asian, and three neotropical Sonerileae together with a broad outgroup sampling (105 spp.). Phylogenetic relationships were inferred using maximum likelihood and Bayesian inference approaches, and a careful reassessment of morphological characters was carried out. Our results neither support the monophyly of the Old World nor African Sonerileae. The monospecific African genus Benna is partially supported as sister to Phainantha, one of the basal neotropical lineages, while African and Malagasy Medinilla are nested among the SE Asian genera. Gravesia (116 spp.), the most species-rich and morphologically diverse genus in Madagascar, is recovered as monophyletic. The African genera of Sonerileae Calvoa, Dicellandra, and Preussiella form well-supported clades. In contrast, Amphiblemma (including Amphiblemma molle) and Cincinnobotrys s.l. (including Cincinnobotrys felicis) are not monophyletic. To accommodate the caulescent C. felicis we propose reinstatement of the monospecific genus Bourdaria. For the distinctive A. molle a new genus Mendelia is described. Calvoa hirsuta is designated here as the type of genus Calvoa, lectotypes are designated for Medinilla engleri and Veprecella lutea, and a neotype is designated for Preussiella kamerunensis.     

The Polybasic Insertion in Autotaxin α Confers Specific Binding to Heparin and Cell Surface Heparan Sulfate Proteoglycans

Autotaxin (ATX) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), playing a key role in diverse physiological and pathological processes. ATX exists in distinct splice variants, but isoform-specific functions remain elusive. Here we characterize the ATXα isoform, which differs from the canonical form (ATXβ) in having a 52-residue polybasic insertion of unknown function in the catalytic domain. We find that the ATXα insertion is susceptible to cleavage by extracellular furin-like endoproteases, but cleaved ATXα remains structurally and functionally intact due to strong interactions within the catalytic domain. Through ELISA and surface plasmon resonance assays, we show that ATXα binds specifically to heparin with high affinity (K_d ∼10⁻⁸ m), whereas ATXβ does not; furthermore, heparin moderately enhanced the lysophospholipase D activity of ATXα. We further show that ATXα, but not ATXβ, binds abundantly to SKOV3 carcinoma cells. ATXα binding was abolished after treating the cells with heparinase III, but not after chondroitinase treatment. Thus, the ATXα insertion constitutes a cleavable heparin-binding domain that mediates interaction with heparan sulfate proteoglycans, thereby targeting LPA production to the plasma membrane.