Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway

Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes. DOI: http://dx.doi.org/10.7554/eLife.02809.00

Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease

The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients. Furthermore, cells with low SMN are more susceptible to cell death. These findings raise the important clinical implication that some SMN-elevating therapeutics might be effective in MN diseases besides SMA. Supporting this, we found that increasing SMN across all MN populations using an Nedd8-activating enzyme inhibitor promotes survival in both SMA and ALS-derived MNs. Altogether, our work demonstrates that examination of human neurons at the single-cell level can reveal alternative strategies to be explored in the treatment of degenerative diseases

A taxonomic and biostratigraphic re-evaluation of the Post Quarry vertebrate assemblage from the Cooper Canyon Formation (Dockum Group, Upper Triassic) of southern Garza County, western Texas

The Post Quarry, within the lower part of the type section of the Upper Triassic Cooper Canyon Formation in southern Garza County, western Texas, contains a remarkably diverse vertebrate assemblage. The Post Quarry has produced: the small temnospondyl Rileymillerus cosgriffi; the metoposaurid Apachesaurus gregorii; possible dicynodonts and eucynodonts; a clevosaurid sphenodontian; non-archosauriform archosauromorphs (Trilophosaurus dornorum, simiosaurians, and possibly Malerisaurus); the phytosaur Leptosuchus; several aetosaurs (Calyptosuchus wellesi, Typothorax coccinarum, Paratypothorax, and Desmatosuchus smalli); the poposauroid Shuvosaurus inexpectatus (“Chatterjeea elegans”); the rauisuchid Postosuchus kirkpatricki; an early crocodylomorph; several dinosauromorphs (the lagerpetid Dromomeron gregorii, the silesaurid Technosaurus smalli, a herrerasaurid, and an early neotheropod); and several enigmatic small diapsids. Revised lithostratigraphic correlations of the lower Cooper Canyon Formation with the Tecovas Formation, the occurrence of Leptosuchus, and the overall composition of the assemblage indicate that the Post Quarry falls within the Adamanian biozone, and not the Revueltian biozone. Stratigraphic subdivision of the Adamanian biozone may be possible, and the Post Quarry may be correlative with the upper part of the Adamanian biozone in Arizona. The age of the Post Quarry assemblage is possibly late Lacian or earliest Alaunian (late early Norian or earliest middle Norian), between 220 and 215 Ma

Looking Backward, Looking Forward: MLA Members Speak

In 1997 I was asked to organize humanities outreach activities at the University of California, Irvine. The result was the formation of Humanities Out There (HOT). In our workshops, faculty members and graduate students supervise teams of undergraduates in order to take the methods and materials of the university into the larger community.I believe that programs like these will  become increasingly important in the next century, as economic, cultural, and educational divisions deepen in the wake of the demise of affirmative action and as the humanities fight to define their missions in a world driven by technology and its discontents. In this brave new world, what I call the new outreach may have a role to play in responding to social crises as they are visited on the life of the university. The new outreach will be driven by intellectual content, not public relations.It will take its orientation from the faculty rather than administrators. It will engage all the research disciplines rather than remain the purview of education departments. It will be integrated into the professional lives of its participants rather than rely on the spirit of volunteerism alone

Looking Backward, Looking Forward: MLA Members Speak

In 1997 I was asked to organize humanities outreach activities at the University of California, Irvine. The result was the formation of Humanities Out There (HOT). In our workshops, faculty members and graduate students supervise teams of undergraduates in order to take the methods and materials of the university into the larger community.I believe that programs like these will  become increasingly important in the next century, as economic, cultural, and educational divisions deepen in the wake of the demise of affirmative action and as the humanities fight to define their missions in a world driven by technology and its discontents. In this brave new world, what I call the new outreach may have a role to play in responding to social crises as they are visited on the life of the university. The new outreach will be driven by intellectual content, not public relations.It will take its orientation from the faculty rather than administrators. It will engage all the research disciplines rather than remain the purview of education departments. It will be integrated into the professional lives of its participants rather than rely on the spirit of volunteerism alone