Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2

Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries. About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache. Although the mode of transmission is controversial, population-based and twin studies have implicated genetic factors, especially in migraine with aura. Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23 (OMIM 602481). Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2. This is the first report associating mutations of Na+K+ pump subunits to genetic diseases.     

Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity

Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated cellular cytotoxicity in humans.     

A New Dimension Reduction Method: Factor Discriminant K-means

Reduced K-means (RKM) and Factorial K-means (FKM) are two data reduction techniques incorporating principal component analysis and K-means into a unified methodology to obtain a reduced set of components for variables and an optimal partition for objects. RKM finds clusters in a reduced space by maximizing the between-clusters deviance without imposing any condition on the within-clusters deviance, so that clusters are isolated but they might be heterogeneous. On the other hand, FKM identifies clusters in a reduced space by minimizing the within-clusters deviance without imposing any condition on the between-clusters deviance. Thus, clusters are homogeneous, but they might not be isolated. The two techniques give different results because the total deviance in the reduced space for the two methodologies is not constant; hence the minimization of the within-clusters deviance is not equivalent to the maximization of the between-clusters deviance. In this paper a modification of the two techniques is introduced to avoid the afore mentioned weaknesses. It is shown that the two modified methods give the same results, thus merging RKM and FKM into a new methodology. It is called Factor Discriminant K-means (FDKM), because it combines Linear Discriminant Analysis and K-means. The paper examines several theoretical properties of FDKM and its performances with a simulation study. An application on real-world data is presented to show the features of FDKM.     

The politics of environments before the environment: Biopolitics in the longue durée

Our understanding of body–world relations is caught in a curious contradiction. On one side, it is well established that many concepts that describe interaction with the outer world – ‘plasticity’ or ‘metabolism’- or external influences on the body - ‘environment’ or ‘milieu’ – appeared with rise of modern science. On the other side, although premodern science lacked a unifying term for it, an anxious attentiveness to the power of ‘environmental factors’ in shaping physical and moral traits held sway in nearly all medical systems before and alongside modern Europe. In this article, I build on a new historiography on the policing of bodies and environments in medieval times and at the urban scale to problematize Foucault's claim about biopolitics as a modern phenomenon born in the European eighteenth-century. I look in particular at the collective usage of ancient medicine and manipulation of the milieu based on humoralist notions of corporeal permeability (Hippocrates, Galen, Ibn Sīnā) in the Islamicate and Latin Christendom between the 12th and the 15th century. This longer history has implications also for a richer genealogy of contemporary tropes of plasticity, permeability and environmental determinism beyond usual genealogies that take as a starting point the making of the modern body and EuroAmerican biomedicine.     

Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint

In both yeast and mammals, uncapped telomeres activate the DNA damage response (DDR) and undergo end-to-end fusion. Previous work has shown that the Drosophila HOAP protein, encoded by the caravaggio (cav) gene, is required to prevent telomeric fusions. Here we show that HOAP-depleted telomeres activate both the DDR and the spindle assembly checkpoint (SAC). The cell cycle arrest elicited by the DDR was alleviated by mutations in mei-41 (encoding ATR), mus304 (ATRIP), grp (Chk1) and rad50 but not by mutations in tefu (ATM). The SAC was partially overridden by mutations in zw10 (also known as mit(1)15) and bubR1, and also by mutations in mei-41, mus304, rad50, grp and tefu. As expected from SAC activation, the SAC proteins Zw10, Zwilch, BubR1 and Cenp-meta (Cenp-E) accumulated at the kinetochores of cav mutant cells. Notably, BubR1 also accumulated at cav mutant telomeres in a mei-41-, mus304-, rad50-, grp- and tefu-dependent manner. Our results collectively suggest that recruitment of BubR1 by dysfunctional telomeres inhibits Cdc20-APC function, preventing the metaphase-to-anaphase transition.     

Reynolds应力模型在热分层流场中的应用及优化

对Reynolds应力模型(RSM)在数值模拟热分层流场方面进行了优化,即在Reynolds应力方程和湍动能耗散方程的基础上加入标量通量方程和温度扰动方程,使原来的7方程成为了11方程。优化后的模型可以通过精确计算湍流通量输运方程来求解加热湍流中重要的热浮力项。采用7方程RSM、11方程RSM,并用k-ε湍流模型作为参考,对平板间非稳定热分层流动和模拟池式快堆堆心上方的腔室内受迫对流和热分层之间的混合流动进行数值模拟和比较分析,并将计算结果与现有实验数据相比较。结论是:优化后的11方程RSM比其他的湍流模型更适合于计算各向异性的热分层流动。     

Robertsonian chromosomal polymorphism in the mouse (M. musculus domesticus)

Zusammenfassung Hausmäuse (M. m. domesticus) aus dem Bergell/GR zeigen einen intraspezifischen Chromosomenpolymorphismus vomRobertson'schen Typ mit wenigstens zwei verschiedenen metazentrischen Chromosomen. Für eines dieser beiden Chromosomen konnte gezeigt werden, dass es von den sieben bei der Tabakmaus (M. poschiavinus) vorhandenen metazentrischen Chromosomen unabhängig ist. Ein für dieses Chromosom (T8Bnr) homozygoter Stamm auf dem Hintergrund der Laboratoriumsmaus wird für experimentelle Verwendung herausgezüchtet.

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Work supported by Landesamt für Forschung, Nordrehein-Westfalen.     

Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease

Among the dementias, Alzheimer’s disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn₇MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.