TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ～5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.     

Nucleotide sequence of the yeast plasmid

The nucleotide sequence of the yeast DNA plasmid (2 mu circle) from Saccharomyces cerevisiae strain A364A D5 has been determined. The plasmid contains 6,318 base pairs, including two identical inverted repeats of 599 base pairs. Possible functions are suggested, and attributes of an improved vector for cloning foreign DNAs in yeast are discussed.     

Sexual conflict reduces offspring fitness in zebra finches

Parental care is often costly; hence, in sexually reproducing species where both male and female parents rear their offspring (biparental care), sexual conflict over parental investment can arise. Such conflict occurs because each care-giver would benefit from withholding parental investment for use with another partner, leading to a reduction in the amount of care given by one parent at the expense of the other. Here we report experiments to explore the prediction from theory that parents rearing offspring alone may provide greater parental investment than when rearing offspring together with a partner. We found that when the number of offspring per parent, and hence the potential workload, were kept constant, offspring received a greater per capita parental investment from single females than from both parents working together, and that males reared by single mothers were more sexually attractive as adults than their biparentally reared siblings. This difference between single- and two-parent families is due to a reduction in care provided by females when they care together with a male, rather than laziness by males or differences in the begging behaviour of chicks, supporting the claim that sexual conflict in biparental care can reduce the quality of offspring raised.     

To Attract or to Inform： What Are Titles For？

This paper critiques some titles in journal articles for being misleading and it argues that titles need to be informative. Examples are given of work on measuring the effectiveness of titles in two areas-sentence structure and reader comprehension - and the paper concludes with brief comments on the effectiveness of book titles.     

Open-reading-frame sequence tags (OSTs) support the existence of at least 17,300 genes in C. elegans

The genome sequences of Caenorhabditis elegans, Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively. Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. First, the gene number estimates obtained in silico and not yet supported by any experimental data need to be verified. For example, it seems biologically paradoxical that C. elegans would have 50% more genes than Drosophilia. Second, intron/exon predictions need to be tested experimentally. Third, complete sets of open reading frames (ORFs), or "ORFeomes," need to be cloned into various expression vectors. To address these issues simultaneously, we have designed and applied to C. elegans the following strategy. Predicted ORFs are amplified by PCR from a highly representative cDNA library using ORF-specific primers, cloned by Gateway recombination cloning and then sequenced to generate ORF sequence tags (OSTs) as a way to verify identity and splicing. In a sample (n=1,222) of the nearly 10,000 genes predicted ab initio (that is, for which no expressed sequence tag (EST) is available so far), at least 70% were verified by OSTs. We also observed that 27% of these experimentally confirmed genes have a structure different from that predicted by GeneFinder. We now have experimental evidence that supports the existence of at least 17,300 genes in C. elegans. Hence we suggest that gene counts based primarily on ESTs may underestimate the number of genes in human and in other organisms.     

Totally synthetic (±)-13-Alkyl-3-hydroxy and methoxy-gona-1,3,5(10)-trien-17-ones and related compounds

Zusammenfassung Von mehreren (±) 3-Oxy- und (±) 3-Methoxy-13-alkylgona-1,3,5(10)trien-17-onen und verwandten Verbindungen, einschliesslich von Vertretern der (±) 13-Alkylgon-4-en-3-on-Reihe, werden Totalsynthese und biologische Wirksamkeit beschrieben.     

Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination

Dendritic cells have a unique function in the immune response owing to their ability to stimulate immunologically naive T lymphocytes. In response to microbial and inflammatory stimuli, dendritic cells enhance their capacity for antigen presentation by a process of terminal differentiation, termed maturation. The conversion of immature to mature dendritic cells is accompanied by a marked cellular reorganization, including the redistribution of major histocompatibility complex class II molecules (MHC II) from late endosomal and lysosomal compartments to the plasma membrane and the downregulation of some forms of endocytosis, which has been thought to slow the clearance of MHC II from the surface. The relative extent to which these or other mechanisms contribute to the regulation of surface MHC II remains unclear, however. Here we find that the MHC II beta-chain cytoplasmic tail is ubiquitinated in mouse immature dendritic cells. Although only partly required for the sequestration of MHC II in multivesicular bodies, this modification is essential for endocytosis. Notably, ubiquitination of MHC II ceased upon maturation, resulting in the accumulation of MHC II at the cell surface. Dendritic cells thus exhibit a unique ability to regulate MHC II surface expression by selectively controlling MHC II ubiquitination.     

Neurodegenerative disease: amyloid pores from pathogenic mutations

Alzheimer's and Parkinson's diseases are associated with the formation in the brain of amyloid fibrils from beta-amyloid and alpha-synuclein proteins, respectively. It is likely that oligomeric fibrillization intermediates (protofibrils), rather than the fibrils themselves, are pathogenic, but the mechanism by which they cause neuronal death remains a mystery. We show here that mutant amyloid proteins associated with familial Alzheimer's and Parkinson's diseases form morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases.     

Logarithmic rate dependence of force networks in sheared granular materials

Many models of slow, dense granular flows assume that the internal stresses are independent of the shearing rate. In contrast, logarithmic rate dependence is found in solid-on-solid friction, geological settings and elsewhere. Here we investigate the rate dependence of stress in a slowly sheared two-dimensional system of photoelastic disks, in which we are able to determine forces on the granular scale. We find that the mean (time-averaged) stress displays a logarithmic dependence on the shear rate for plastic (irreversible) deformations. However, there is no perceivable dependence on the driving rate for elastic (reversible) deformations, such as those that occur under moderate repetitive compression. Increasing the shearing rate leads to an increase in the strength of the force network and stress fluctuations. Qualitatively, this behaviour resembles the changes associated with an increase in density. Increases in the shearing rate also lead to qualitative changes in the distributions of stress build-up and relaxation events. If shearing is suddenly stopped, stress relaxations occur with a logarithmic functional form over long timescales. This slow collective relaxation of the stress network provides a mechanism for rate-dependent strengthening.