ER morphology and endo-lysosomal crosstalk: Functions and disease implications.

The endoplasmic reticulum (ER) is a continuous endomembrane system comprising the nuclear envelope, ribosome-studded sheets, dense peripheral matrices, and an extensive polygonal network of interconnected tubules. In addition to performing numerous critical cellular functions, the ER makes extensive contacts with other organelles, including endosomes and lysosomes. The molecular and functional characterization of these contacts has advanced significantly over the past several years. These contacts participate in key functions such as cholesterol transfer, endosome tubule fission, and Ca2+ exchange. Disruption of key proteins at these sites can result in often severe diseases, particularly those affecting the nervous system.

From clinical assistant to clinical associate professor: Examination of a sample of promotion guidelines.

INTRODUCTION: As accreditation standards for doctor of pharmacy programs have placed a greater emphasis on practice experiences, programs have a need for more clinical faculty. While clinical faculty are expected to achieve success in teaching, scholarly activity, and service, they tend to hold lower academic ranks and take more time to achieve promotion. This may be especially true when promotion guidelines lack clarity. METHODS: Guidelines for promotion of clinical faculty from assistant to associate rank for 10, research-intensive pharmacy programs were reviewed for predetermined factors in the areas of teaching, scholarly activity, and service using the following scale: required, desired, considered, not considered, or not specified. Some factors reviewed included: classroom teaching hours, number of clerkship students, types of scholarly activity considered, grantsmanship, and patient care services. RESULTS: There is significant variation in criteria utilized when considering promotion of clinical faculty from assistant to associate rank; few programs provide quantifiable requirements. All programs expect clinical faculty to participate in teaching. Only one program quantifies the amount of teaching expected. One program does not describe types of scholarly activity considered for promotion. No programs expect salary support from grants for clinical faculty. All programs consider direct patient care activities. CONCLUSIONS: A wide variety of criteria are considered when evaluating a clinical faculty member for promotion to the rank of associate professor. Clearly defined promotion criteria may help faculty direct their efforts toward activities that are recognized to ensure timely promotion.

Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion.

Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson's disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trak1 that causes hypertonia in mice. Moreover, elevated Trak1 protein expression is associated with several types of cancers and variants in Trak1 are linked to childhood absence epilepsy in humans. Despite the importance of Trak1 in health and disease, the mechanisms of Trak1 action remain unclear and the pathogenic effects of Trak1 mutation are unknown. Here we report that Trak1 has a crucial function in regulation of mitochondrial fusion. Depletion of Trak1 inhibits mitochondrial fusion, resulting in mitochondrial fragmentation, whereas overexpression of Trak1 elongates and enlarges mitochondria. Our analyses revealed that Trak1 interacts and colocalizes with mitofusins on the outer mitochondrial membrane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trak1 is required for stress-induced mitochondrial hyperfusion and pro-survival response. We found that hypertonia-associated mutation impairs Trak1 mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trak1 as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochondrial dynamics to hypertonia pathogenesis.

Evidence for transgenerational transmission of epigenetic tumor susceptibility in Drosophila.

Transgenerational epigenetic inheritance results from incomplete erasure of parental epigenetic marks during epigenetic reprogramming at fertilization. The significance of this phenomenon, and the mechanism by which it occurs, remains obscure. Here, we show that genetic mutations in Drosophila may cause epigenetic alterations that, when inherited, influence tumor susceptibility of the offspring. We found that many of the mutations that affected tumorigenesis induced by a hyperactive JAK kinase, Hop(Tum-l), also modified the tumor phenotype epigenetically, such that the modification persisted even in the offspring that did not inherit the modifier mutation. We analyzed mutations of the transcription repressor Krüppel (Kr), which is one of the hop(Tum-l) enhancers known to affect ftz transcription. We demonstrate that the Kr mutation causes increased DNA methylation in the ftz promoter region, and that the aberrant ftz transcription and promoter methylation are both transgenerationally heritable if Hop(Tum-l) is present in the oocyte. These results suggest that genetic mutations may alter epigenetic markings in the form of DNA methylation, which are normally erased early in the next generation, and that JAK overactivation disrupts epigenetic reprogramming and allows inheritance of epimutations that influence tumorigenesis in future generations.