Brownian motion: absolute negative particle mobility

Noise effects in technological applications, far from being a nuisance, can be exploited with advantage - for example, unavoidable thermal fluctuations have found application in the transport and sorting of colloidal particles and biomolecules. Here we use a microfluidic system to demonstrate a paradoxical migration mechanism in which particles always move in a direction opposite to the net acting force ('absolute negative mobility') as a result of an interplay between thermal noise, a periodic and symmetric microstructure, and a biased alternating-current electric field. This counterintuitive phenomenon could be used for bioanalytical purposes, for example in the separation and fractionation of colloids, biological molecules and cells.     

A contractile nuclear actin network drives chromosome congression in oocytes

Chromosome capture by microtubules is widely accepted as the universal mechanism of spindle assembly in dividing cells. However, the observed length of spindle microtubules and computer simulations of spindle assembly predict that chromosome capture is efficient in small cells, but may fail in cells with large nuclear volumes such as animal oocytes. Here we investigate chromosome congression during the first meiotic division in starfish oocytes. We show that microtubules are not sufficient for capturing chromosomes. Instead, chromosome congression requires actin polymerization. After nuclear envelope breakdown, we observe the formation of a filamentous actin mesh in the nuclear region, and find that contraction of this network delivers chromosomes to the microtubule spindle. We show that this mechanism is essential for preventing chromosome loss and aneuploidy of the egg--a leading cause of pregnancy loss and birth defects in humans.     

Silencing of microRNAs in vivo with 'antagomirs'

MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are believed to be important in many biological processes through regulation of gene expression. The precise molecular function of miRNAs in mammals is largely unknown and a better understanding will require loss-of-function studies in vivo. Here we show that a novel class of chemically engineered oligonucleotides, termed 'antagomirs', are efficient and specific silencers of endogenous miRNAs in mice. Intravenous administration of antagomirs against miR-16, miR-122, miR-192 and miR-194 resulted in a marked reduction of corresponding miRNA levels in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries and adrenals. The silencing of endogenous miRNAs by this novel method is specific, efficient and long-lasting. The biological significance of silencing miRNAs with the use of antagomirs was studied for miR-122, an abundant liver-specific miRNA. Gene expression and bioinformatic analysis of messenger RNA from antagomir-treated animals revealed that the 3' untranslated regions of upregulated genes are strongly enriched in miR-122 recognition motifs, whereas downregulated genes are depleted in these motifs. Analysis of the functional annotation of downregulated genes specifically predicted that cholesterol biosynthesis genes would be affected by miR-122, and plasma cholesterol measurements showed reduced levels in antagomir-122-treated mice. Our findings show that antagomirs are powerful tools to silence specific miRNAs in vivo and may represent a therapeutic strategy for silencing miRNAs in disease.     

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.     

Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy

SIL1 (also called BAP) acts as a nucleotide exchange factor for the Hsp70 chaperone BiP (also called GRP78), which is a key regulator of the main functions of the endoplasmic reticulum. We found nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sj?gren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. Identification of SIL1 mutations implicates Marinesco-Sj?gren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders.     

Communication at millimetre-submillimetre wavelengths using a ceramic ribbon

Following the discovery by Kao and Hockman that ultra-low-loss optical fibres could be made from pure silica through the elimination of impurities, the ability to guide signals effectively at optical wavelengths has been assured. But there remains an important region of the spectrum--from 30 to 3,000 GHz (the millimetre-submillimetre band)--where low-loss waveguides are unknown. The main problem here in finding low-loss solids is no longer one of eliminating impurities, but is due to the presence of intrinsic vibration absorption bands. And the use of highly conducting materials is also precluded owing to high skin-depth losses in this part of the spectrum. Here we show that a combination of material and waveguide geometry can circumvent these difficulties. We adopt a ribbon-like structure with an aspect ratio of 10:1, fabricated from ceramic alumina (Coors' 998 Alumina), and the resulting waveguide has an attenuation factor of less than 10 dB km(-1) in the millimetre-submillimetre band. This attenuation is more than 100 times smaller than that of a typical ceramic (or other dielectric) circular rod waveguide and is sufficient for immediate application.     

Interactions between amphetamine and reserpine in vitro

Resumen Se estudia en el conducto deferente aislado de rata la respuesta a la reserpina después de la estimulación del preparado con anfetamina. En estas condiciones, la reserpina produce una contracción que es proporcional a las concentraciones de anfetamina y reserpina utilizadas, y es máxima para una concentración de reserpina de 2,5×10^–5 g/ml, para ser luego decreciente cualquiera que sea la concentración de anfetamina que se haya empleado previamente. Se discuten los posibles mecanismos que regulan la respuesta a la reserpina después de la anfetamina.