Localized Intravascular Coagulopathy of Venous Malformation Involving the Labia as a Mimic of Child Sexual Abuse: A Case Report

Given location and relative rarity, ano-genital injuries in children often prompt concern for maltreatment. We present a case of localized intravascular coagulopathy as a complication of venous malformation, which mimicked abusive trauma leading to an evaluation for maltreatment. Comprehensive assessment identified the underlying medical cause. This case represents an example of the importance of objective assessment in unusual case presentations to ensure diagnostic accuracy, and appropriate direction of medical and child protection resources

Evolution of Cooperation and Coordination in a Dynamically Networked Society

Situations of conflict giving rise to social dilemmas are widespread in society and game theory is one major way in which they can be investigated. Starting from the observation that individuals in society interact through networks of acquaintances, we model the co-evolution of the agents' strategies and of the social network itself using two prototypical games, the Prisoner's Dilemma and the Stag Hunt. Allowing agents to dismiss ties and establish new ones, we find that cooperation and coordination can be achieved through the self-organization of the social network, a result that is non-trivial, especially in the Prisoner's Dilemma case. The evolution and stability of cooperation implies the condensation of agents exploiting particular game strategies into strong and stable clusters which are more densely connected, even in the more difficult case of the Prisoner's Dilemma.Comment: 18 pages, 14 figures. to appea

Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface.

Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino-acid Loop Extension (TALE) homeodomain-containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2- or Pbx3-deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)-derived mesenchyme on a Pbx2-deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in-depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC-specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC-specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro-caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue-specific Pbx loss-of-function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology

Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)–induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11^+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

In silico characterization and expression profiling of the diacylglycerol acyltransferase gene family (DGAT1, DGAT2, DGAT3 and WS/DGAT) from oil palm, Elaeis guineensis

The diacylglycerol acyltransferases (DGAT) (diacylglycerol:acyl-CoA acyltransferase, EC 2.3.1.20) are a key group of enzymes that catalyse the final and usually the most important rate-limiting step of triacylglycerol biosynthesis in plants and other organisms. Genes encoding four distinct functional families of DGAT enzymes have been characterised in the genome of the African oil palm, Elaeis guineensis. The contrasting features of the various isoforms within the four families of DGAT genes, namely DGAT1, DGAT2, DGAT3 and WS/DGAT are presented both in the oil palm itself and, for comparative purposes, in 12 other oil crop or model/related plants, namely Arabidopsis thaliana, Brachypodium distachyon, Brassica napus, Elaeis oleifera, Glycine max, Gossypium hirsutum, Helianthus annuus, Musa acuminata, Oryza sativa, Phoenix dactylifera, Sorghum bicolor, and Zea mays. The oil palm genome contains respectively three, two, two and two distinctly expressed functional copies of the DGAT1, DGAT2, DGAT3 and WS/DGAT genes. Phylogenetic analyses of the four DGAT families showed that the E. guineensis genes tend to cluster with sequences from P. dactylifera and M. acuminata rather than with other members of the Commelinid monocots group, such as the Poales which include the major cereal crops such as rice and maize. Comparison of the predicted DGAT protein sequences with other animal and plant DGATs was consistent with the E. guineensis DGAT1 being ER located with its active site facing the lumen while DGAT2, although also ER located, had a predicted cytosol-facing active site. In contrast, DGAT3 and some (but not all) WS/DGAT in E. guineensis are predicted to be soluble, cytosolic enzymes. Evaluation of E. guineensis DGAT gene expression in different tissues and developmental stages suggests that the four DGAT groups have distinctive physiological roles and are particularly prominent in developmental processes relating to reproduction, such as flowering, and in fruit/seed formation especially in the mesocarp and endosperm tissues

MetaPalette: a k-mer Painting Approach for Metagenomic Taxonomic Profiling and Quantification of Novel Strain Variation

Metagenomic profiling is challenging in part because of the highly uneven sampling of the tree of life by genome sequencing projects and the limitations imposed by performing phylogenetic inference at fixed taxonomic ranks. We present the algorithm MetaPalette, which uses long k-mer sizes (k = 30, 50) to fit a k-mer “palette” of a given sample to the k-mer palette of reference organisms. By modeling the k-mer palettes of unknown organisms, the method also gives an indication of the presence, abundance, and evolutionary relatedness of novel organisms present in the sample. The method returns a traditional, fixed-rank taxonomic profile which is shown on independently simulated data to be one of the most accurate to date. Tree figures are also returned that quantify the relatedness of novel organisms to reference sequences, and the accuracy of such figures is demonstrated on simulated spike-ins and a metagenomic soil sample. The software implementing MetaPalette is available at: https://github.com/dkoslicki/MetaPalette. Pretrained databases are included for Archaea, Bacteria, Eukaryota, and viruses

Contributions of lean mass and fat mass to bone mineral density: a study in postmenopausal women

<p>Abstract</p> <p>Background</p> <p>The relative contribution of lean and fat to the determination of bone mineral density (BMD) in postmenopausal women is a contentious issue. The present study was undertaken to test the hypothesis that lean mass is a better determinant of BMD than fat mass.</p> <p>Methods</p> <p>This cross-sectional study involved 210 postmenopausal women of Vietnamese background, aged between 50 and 85 years, who were randomly sampled from various districts in Ho Chi Minh City (Vietnam). Whole body scans, femoral neck, and lumbar spine BMD were measured by DXA (QDR 4500, Hologic Inc., Waltham, MA). Lean mass (LM) and fat mass (FM) were derived from the whole body scan. Furthermore, lean mass index (LMi) and fat mass index (FMi) were calculated as ratio of LM or FM to body height in metre squared (m²).</p> <p>Results</p> <p>In multiple linear regression analysis, both LM and FM were independent and significant predictors of BMD at the spine and femoral neck. Age, lean mass and fat mass collectively explained 33% variance of lumbar spine and 38% variance of femoral neck BMD. Replacing LM and FM by LMi and LMi did not alter the result. In both analyses, the influence of LM or LMi was greater than FM and FMi. Simulation analysis suggested that a study with 1000 individuals has a 78% chance of finding the significant effects of both LM and FM, and a 22% chance of finding LM alone significant, and zero chance of finding the effect of fat mass alone.</p> <p>Conclusions</p> <p>These data suggest that both lean mass and fat mass are important determinants of BMD. For a given body size -- measured either by lean mass or height --women with greater fat mass have greater BMD.</p