Relict occurrence of three "American" Scolytidae (Coleoptera) in Asia

The first non-American representatives of the bark beetle genus Pseudopityophthorus , of the subtribe Corthylina (Corthylini), and of the Ips concinnus species group are named. All are apparently relicts of an early faunal exchange with North America. The new taxa include: Gnatharus , new genus, and its type-species Gnatharus tibetensis , new species (Tibet); Xenophthorus , new subgenus, and its type-species Pseudopityophthorus (Xenophthorus) peregrinus , new species (Tibet), and Ips orientalis , new species (Tibet, China). The intercontinental exchange of other taxa in Scolytidae are also mentioned.     

Cicuta bulbifera L. (Umbelliferae) in Alaska

Cited are distribution records for Alaska of Cicuta bulbifera L. It was discovered growing in the Nowitna National Wildlife Refuge in north central Alaska in 1984 and again in 1987. An earlier record is also known from near Fairbanks.     

A new combination in Penstemon (Scrophulariaceae)

Field and herbarium studies of Penstemon cyananthus Hook. ssp. longiflorus Pennell suggest that this taxon be elevated to species rank.       

The goal of explanation

I defend the claim that understanding is the goal of explanation against various persistent criticisms, especially the criticism that understanding is not truth-connected in the appropriate way, and hence is a merely psychological (rather than epistemic) state. Part of the reason why understanding has been dismissed as the goal of explanation, I suggest, is because the psychological dimension of the goal of explanation has itself been almost entirely neglected. In turn, the psychological dimension of understanding—the Aha! experience, the sense that a certain explanation “feels right”, and so on—has been conspicuously overemphasized. I try to correct for both of these exaggerations. Just as the goal of explanation includes a richer psychological—including phenomenological—dimension than is generally acknowledged, so too understanding has a stronger truth connection than is generally acknowledged.     

The Advantages of Obscurity: Charles Darwin's Negative Inference from the Histories of Domestic Breeds

In The Origin of Species, Charles Darwin famously accounted for the lack of fossil evidence in support of species evolution on the grounds that the fossil record is naturally incomplete. This essay examines a similar argument that Darwin applied to his analogy between natural and artificial selection: the scarcity of data about the historical backgrounds of domestic breeds was the natural by-product of an extremely gradual change process. The point was to enhance the ability of the artificial selection analogy to suggest that nature's species had undergone a similar transformation. Darwin did not depend on this negative inference alone, however, for in his writings he included whatever information he could find about the actual histories of particular breeds. A comparison with Darwin's treatment of the fossil record suggests the reasonableness of this combined use of opposite kinds of evidence to establish a single point. The comparison also suggests the unique qualities of negative inference as applied to the breeding analogy.     

The unique features of follicular T cell subsets

The germinal center (GC) reaction is critical for humoral immunity, but also contributes adversely to a variety of autoimmune diseases. While the major protective function of GCs is mediated by plasma cells and memory B cells, follicular helper T (TFH) cells represent a specialized T cell subset that provides essential help to the antigen-specific B cells in the form of membrane-bound ligands and secreted factors such as IL-21. Recent studies have revealed that TFH cells are capable of considerable functional diversity as well as possessing the ability to form memory cells. The molecular basis of this plasticity and heterogeneity is only now emerging. It has also become apparent that several other populations of follicular T cells exist, including natural killer T cells and regulatory T cells. In this review we will discuss the function of follicular T cells and interaction of these populations within the GC response.     

Human CtIP promotes DNA end resection

In the S and G2 phases of the cell cycle, DNA double-strand breaks (DSBs) are processed into single-stranded DNA, triggering ATR-dependent checkpoint signalling and DSB repair by homologous recombination. Previous work has implicated the MRE11 complex in such DSB-processing events. Here, we show that the human CtIP (RBBP8) protein confers resistance to DSB-inducing agents and is recruited to DSBs exclusively in the S and G2 cell-cycle phases. Moreover, we reveal that CtIP is required for DSB resection, and thereby for recruitment of replication protein A (RPA) and the protein kinase ATR to DSBs, and for the ensuing ATR activation. Furthermore, we establish that CtIP physically and functionally interacts with the MRE11 complex, and that both CtIP and MRE11 are required for efficient homologous recombination. Finally, we reveal that CtIP has sequence homology with Sae2, which is involved in MRE11-dependent DSB processing in yeast. These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.