Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.     

IL‐17A is not a treatment target in progressive vitiligo

Multiple reports confirm elevated circulating IL‐17 levels and increased numbers of Th17 lymphocytes in patients with non‐segmental vitiligo. Additionally, melanocyte damaging characteristics have been ascribed to IL‐17. A single‐arm pilot study using secukinumab in active non‐segmental vitiligo was conducted. The large majority of patients developed additional skin depigmentations limiting further enrollment. Overall, laboratory analysis revealed no change in secreted chemokines or Th subsets. Th17 lymphocytes correlated with Th2, Th9, and Th22 cells while an inverse link with Th1 cells and serum sCD25 levels was observed. In contrast, Th17.1 cells correlated positively with Th1 lymphocytes. Confirmatory results were found in an independent group of patients with vitiligo showing a significant increase in Th17.1 and Th1 lymphocytes in progressive vitiligo patients compared to healthy controls, which was not found for Th17 cells. These results do not support a direct pathogenic role of IL‐17 or Th17 cells in vitiligo. Nonetheless, a delicate Th17/Th17.1/Th1 balance seems evident which changes markedly according to disease activity. This may offer new treatment options by interfering with cytokines that drive differentiation of Th17 cells toward Th1.     

PDGF-B Is Required for Development of the Glymphatic System

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Toward an inordinate fondness for stars,beetles and Lobophora? Species diversity of the genus Lobophora (Dictyotales,Phaeophyceae) in New Caledonia

Until the recent use of molecular markers, species diversity of Lobophora, an ecologically important brown algal genus with a worldwide distribution in temperate and tropical seas, has been critically underestimated. Using a DNA‐based taxonomic approach, we re‐examined diversity of the genus from New Caledonia in the Southwest Pacific Ocean. First, species were delineated using general mixed Yule coalescent‐based and barcoding gap approaches applied to a mitochondrial cox3 data set. Results were subsequently confirmed using chloroplast psbA and rbcL data sets. Species delimitation analyses agreed well across markers and delimitation algorithms, with the barcoding gap approach being slightly more conservative. Analyses of the cox3 data set resulted in 31–39 molecular operational taxonomic units (MOTUs), four of which are previously described species (L. asiatica, L. crassa, L. nigrescens s.l., L. pachyventera). Of the remaining MOTUs for which we obtained a representative number of sequences and results are corroborated across analyses and genes, we described 10 species de novo: L. abaculusa, L. abscondita, L. densa, L. dimorpha, L. gibbera, L. hederacea, L. monticola, L. petila, L. rosacea, and L. undulata. Our study presents an excellent case of how a traditional morphology‐based taxonomy fails to provide accurate estimates of algal diversity. Furthermore, the level of Lobophora diversity unveiled from a single locality in the Pacific Ocean raises important questions with respect to the global diversity of the genus, the distributions and range sizes of the individual species, as well as the mechanisms facilitating coexistence.     

Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature’s adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543–555, 2007; Melief in Immunity 29:372–383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265–277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111–1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.     

Noninvasive Assessment of Pulse-Wave Velocity and Flow-Mediated Vasodilation in Anesthetized G?ttingen Minipigs

Few methods for noninvasive assessment of arterial stiffness and endothelial dysfunction in porcine models are available. The aim of this study was to evaluate methods for assessment of arterial stiffness and endothelial dysfunction in anesthetized Göttingen minipigs. Pulse-wave velocity (PWV) was assessed in male Göttingen minipigs (n = 8; age approximately 60 wk) by using applanation tonometry of the carotid and femoral arteries. In addition, flow-mediated vasodilation (FMD) was assessed by using vascular ultrasonography of the brachial artery to evaluate endothelial dysfunction. To evaluate the reproducibility of the methods, minipigs were anesthetized by intravenous infusion of ketamine and midazolam and examined every other day for a total of 3 trials. Neither examination day nor systolic, diastolic, or mean arterial blood pressure statistically influenced PWV or FMD. The median interexamination coefficient of variation was 17% for PWV and 59% for FMD. Measured values of PWV corresponded largely to those in clinically healthy humans, but FMD values were lower than expected for lean, young animals. Although the ketamine–midazolam anesthesia we used has been associated with minor hemodynamic effects in vivo, in vitro studies suggest that both drugs are vasodilatory. Therefore anesthesia might have influenced the endothelial response, contributing to the modest FMD response and the concurrent high coefficients of variation that we noted. We conclude that PWV—but not FMD—showed acceptable interexamination variation for its potential application in porcine models.Abbreviations: FMD, flow-mediated vasodilation; FVI, integrated flow velocity; GTN, glyceryl trinitrate; PWV, pulse-wave velocity; T, transit timeCardiovascular disease has become a global challenge in public health,⁴² and the development and characterization of comparative animal models are of increasing importance. Several animal models of atherosclerosis, including porcine, have been described.^11,12,34 Due to similarities to humans in the anatomy of the cardiovascular system and metabolic physiology, pigs represent a generally useful model in regard to preclinical evaluation and pharmacology.³⁶ Assessment of changes related to atherosclerosis in vivo would be valuable in for example longitudinal assessment of drug effect, but few noninvasive methods for evaluating structural and functional changes in the arteries of pigs are available. In humans, increased arterial stiffness, which occurs with advanced age, also is caused by the pathophysiologic changes associated with atherosclerosis,²⁶ and noninvasive methods for assessing arterial stiffness have been established. The evaluation of pulse-wave velocity (PWV) by using pressure transducers, such as applanation tonometry, is a method recognized as an independent predictor for cardiovascular events in epidemiologic studies.²¹ The method evaluates the velocity with which the pulse wave is propagated through the arterial tree, with arterial stiffness causing increased velocity.^{1,22,29,37,39} Flow-mediated vasodilation (FMD), assessed by vascular ultrasonography, represents a noninvasive evaluation of endothelial-dependent vasodilation. A decrease in vasodilation as a response to increased shear stress has been recognized as a marker of endothelial dysfunction, which precedes the development of atherosclerosis.^5,7 Recent studies have shown that the FMD method is applicable in large animals (that is, dogs and horses) and that a decreased FMD response occurs in dogs with valvular heart disease.^10,15,23,28The aim of this study was to evaluate the reproducibility of methods for assessing arterial stiffness (PWV) and endothelial function (FMD response) in anesthetized Göttingen minipigs, including the influences of arterial blood pressure, heart rate, and room and body temperatures on these methods.