Toxicity of statins on rat skeletal muscle mitochondria

We investigated mitochondrial toxicity of four lipophilic stains (cerivastatin, fluvastatin, atorvastatin, simvastatin) and one hydrophilic statin (pravastatin). In L6 cells (rat skeletal muscle cell line), the four lipophilic statins (100 micromol/l) induced death in 27-49% of the cells. Pravastatin was not toxic up to 1 mmol/l. Cerivastatin, fluvastatin and atorvastatin (100 micromol/l) decreased the mitochondrial membrane potential by 49-65%, whereas simvastatin and pravastatin were less toxic. In isolated rat skeletal muscle mitochondria, all statins, except pravastatin, decreased glutamate-driven state 3 respiration and respiratory control ratio. Beta-oxidation was decreased by 88-96% in the presence of 100 micromol/l of the lipophilic statins, but only at higher concentrations by pravastatin. Mitochondrial swelling, cytochrome c release and DNA fragmentation was induced in L6 cells by the four lipophilic statins, but not by pravastatin. Lipophilic statins impair the function of skeletal muscle mitochondria, whereas the hydrophilic pravastatin is significantly less toxic.     

The origin of diversity: studying the evolution of multi-faceted CD8<Superscript>+</Superscript> T cell responses

During the past two decades of research in T cell biology, an increasing number of distinct T cell subsets arising during the transition from naïve to antigen-experienced T cells have been identified. Recently, it has been appreciated that, in different experimental settings, distinct T cell subsets can be generated in parallel within the same immune response. While signals driving a single “lineage” path of T cell differentiation are becoming increasingly clear, it remains largely enigmatic how the phenotypic and functional diversification creating a multi-faceted T cell response is achieved. Here, we review current literature indicating that diversification is a stable trait of CD8⁺ T cell responses. We showcase novel technologies providing deeper insights into the process of diversification among the descendants of individual T cells, and introduce two models that emphasize either intrinsic noise or extrinsic signals as driving forces behind the diversification of single cell-derived T cell progeny populations in vivo.     

Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.     

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).     

Geometric division problems, quadratic equations, and recursive geometric algorithms in Mesopotamian mathematics

Most of what is told in this paper has been told before by the same author, in a number of publications of various kinds, but this is the first time that all this material has been brought together and treated in a uniform way. Smaller errors in the earlier publications are corrected here without comment. It has been known since the 1920s that quadratic equations played a prominent role in Babylonian mathematics. See, most recently, Høyrup (Hist Sci 34:1–32, 1996, and Lengths, widths, surfaces: a portrait of old Babylonian algebra and its kin. Springer, New York, 2002). What has not been known, however, is how quadratic equations came to play that role, since it is difficult to think of any practical use for quadratic equations in the life and work of a Babylonian scribe. One goal of the present paper is to show how the need to find solutions to quadratic equations actually arose in Mesopotamia not later than in the second half of the third millennium BC, and probably before that in connection with certain geometric division of property problems. This issue was brought up for the first time in Friberg (Cuneiform Digit Lib J 2009:3, 2009). In this connection, it is argued that the tool used for the first exact solution of a quadratic equation was either a clever use of the “conjugate rule” or a “completion of the square,” but that both methods ultimately depend on a certain division of a square, the same in both cases. Another, closely related goal of the paper is to discuss briefly certain of the most impressive achievements of anonymous Babylonian mathematicians in the first half of the second millennium BC, namely recursive geometric algorithms for the solution of various problems related to division of figures, more specifically trapezoidal fields. For an earlier, comprehensive (but less accessible) treatment of these issues, see Friberg (Amazing traces of a Babylonian origin in Greek mathematics. WorldScientific, Singapore 2007b, Ch. 11 and App. 1).     

Galanin – 25 years with a multitalented neuropeptide

Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics.     

Galanin – 25 years with a multitalented neuropeptide

The pathophysiology of depression remains unclear, but involves disturbances in brain monoaminergic transmission. Current antidepressant drugs, which act by enhancing this type of transmission, have limited therapeutic efficacy in a number of patients, and not rarely serious side-effects. Increasing evidence suggests that neuropeptides, including galanin, can be of relevance in mood disorders. Galanin is coexpressed with and modulates noradrenaline and serotonin systems, both implicated in depression. Pharmacological and genetic studies have suggested a role for galanin in depression-like behaviour in rodents, whereby the receptor subtype involved appears to play an important role. Thus, stimulation of GalR1 and/or GalR3 receptors results in depression-like phenotype, while activation of the GalR2 receptor attenuates depression-like behaviour. These findings suggest that galanin receptor subtypes represent targets for development of novel antidepressant drugs.     

α-Actinin structure and regulation

Alpha-actinin is a cytoskeletal actin-binding protein and a member of the spectrin superfamily, which comprises spectrin, dystrophin and their homologues and isoforms. It forms an anti-parallel rod-shaped dimer with one actin-binding domain at each end of the rod and bundles actin filaments in multiple cell-type and cytoskeleton frameworks. In non-muscle cells, alpha-actinin is found along the actin filaments and in adhesion sites. In striated, cardiac and smooth muscle cells, it is localized at the Z-disk and analogous dense bodies, where it forms a lattice-like structure and stabilizes the muscle contractile apparatus. Besides binding to actin filaments alpha-actinin associates with a number of cytoskeletal and signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, rendering it important structural and regulatory roles in cytoskeleton organization and muscle contraction. This review reports on the current knowledge on structure and regulation of alpha-actinin.     

Medium- and short-chain dehydrogenase/reductase gene and protein families

The MDR superfamily with ~350-residue subunits contains the classical liver alcohol dehydrogenase (ADH), quinone reductase, leukotriene B4 dehydrogenase and many more forms. ADH is a dimeric zinc metalloprotein and occurs as five different classes in humans, resulting from gene duplications during vertebrate evolution, the first one traced to ~500 MYA (million years ago) from an ancestral formaldehyde dehydrogenase line. Like many duplications at that time, it correlates with enzymogenesis of new activities, contributing to conditions for emergence of vertebrate land life from osseous fish. The speed of changes correlates with function, as do differential evolutionary patterns in separate segments. Subsequent recognitions now define at least 40 human MDR members in the Uniprot database (corresponding to 25 genes when excluding close homologues), and in all species at least 10888 entries. Overall, variability is large, but like for many dehydrogenases, subdivided into constant and variable forms, corresponding to household and emerging enzyme activities, respectively. This review covers basic facts and describes eight large MDR families and nine smaller families. Combined, they have specific substrates in metabolic pathways, some with wide substrate specificity, and several with little known functions.