Volume 22 Issue 1, January 2016

A new study demonstrates that dysregulation of proteostasis can be a transforming event in hematopoiesis that could prove to be therapeutically actionable for treatment of myeloproliferative neoplasms.

Sentinel macrophages in the lymph node provide a first line of defense against invading viruses. A new study visualizes inflammasome activation in virally infected nodal macrophages in mice and shows that this activation augments both innate and adaptive immunity.

A new study in mice suggests that pharmacologically targeting the apoptosis proteins BCL-2 and BCL-xL can clear senescent cells from bone marrow and ameliorate stem cell function during aging, bringing us a step closer to preventing senescence-associated tissue attrition in the clinic.

A new study shows that aggregated forms of tau that cause frontotemporal dementia impair proteasome activity. Furthermore, proteasome inhibition can be alleviated by a small molecule that leads to proteasome phosphorylation and activation, thereby reducing tau accumulation.

Prospects for engineered T cell therapy of solid tumors.

PPAR-δ activity is impaired by mutant huntingtin, and a PPAR-δ agonist attenuates disease in a mouse model of Huntington's disease.

In a model of tauopathy, tau directly inhibits proteasome activity, and cognitive impairment can be prevented by activation of cAMP-PKA signaling.

Mutations in VPS35 that are associated with Parkinson's disease increase the interaction of VPS35 with mitochondrial DLP1, leading to removal of the DLP1 complexes and mitochondrial fragmentation. Structural and functional mitochondrial impairments caused by mutant VPS35 are observed in vitro using cultured neurons and fibroblasts from individuals with PD and in vivo in mouse substantia nigra neurons, where they induce neurodegeneration.

Visualization and tracking of inflammasome activity and ASC speck formation in vivo following viral infection.

Early life differentiation and regulatory function of human T cells is confined to particular anatomical sites.

A small-molecule inducer of apoptosis is able to kill senescent cells in the bone marrow of irradiated or aged mice, thereby improving hematopoietic stem cell function.

The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity.

The authors uncover a role for the proteostasis modulator AIRAPL as a tumor suppressor in myeloproliferative malignancies, through its regulation of IGFR stability. The results ascribe a biological function to AIRAPL, and they implicate prosteostatic deregulation as an oncogenic mechanism in myeloid transformation, thus suggesting potential novel therapeutic strategies.

The authors develop a new method to mine genomic cancer data to uncover complex indels. These simultaneous deletions and insertions have been over-looked by previous sequencing data analysis methods, and the Pindel-C algorithm uncovers new information about their potential contribution to tumorigenesis.

The authors analyze the extent of intratumor heterogeneity across 12 tumor types to reveal that increased heterogeneity is a general phenomenon and has a biphasic contribution to tumor progression.