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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.
Treatment with the common diuretic bumetanide during a susceptible developmental window prevents epileptogenesis in a mouse model of a genetic epileptic encephalopathy.
The authors uncover a therapeutic vulnerability to PARP inhibition of acute myeloid leukemias driven by certain oncogenic fusions, and they unravel the mechanisms by which these cancers rely on DNA damage and repair pathways for growth.
An inhibitor of Aurora kinase promotes megakaryocytic differentiation of cells from patients with primary myelofibrosis and shows antifibrotic effects in mouse models of this disease.
Michael Diamond and colleagues report that TAM receptor deficiency exacerbated West Nile Virus infection in mice and increased the permeability of the blood-brain barrier.
In human FMCD tissue, a small fraction of pS6+ neurons are enriched for somatic activating mutations of the PI3K-AKT-mTOR pathway. Sparse electroporation of the AKT3 mutation into the developing mouse brain causes a reelin-dependent, non–cell autonomous disruption of neuronal migration, leading to impaired cortical lamination and seizure-like epileptiform EEG activity.
From a systematic analysis of genome-wide association studies of blood lipid levels, Wagschal et al. identify several miRNAs that target key proteins involved in cholesterol and lipid metabolism, including the LDL receptor and the ABCA1 cholesterol transporter.
Induction of cardiac contractility, although desirable for restoring heart function, often has long-term detrimental effects. From studies on RKIP, an upstream regulator of β-adrenergic receptor signaling, Schmid et al. show that cardiac contractility in mice can be increased in a well-tolerated manner through the balanced activation of the β1 and β2 subtypes of the adrenergic receptor.
Factors traditionally associated with coagulation and inflammation, such as thrombin, PAR1, aPC and EPCR, also independently control the nitric oxide production switch in hematopoietic stem cells, thereby regulating EPCR-expressing stem cell adhesion and retention in the bone marrow or recruitment to the blood.
MicroRNA-148a, whose expression is regulated by the transcription factor SREBP1c, controls LDL and HDL metabolism through direct targeting of the genes encoding the LDL receptor and the cholesterol transporter ABCA1.
CD4+ T cell responses are classically induced by presentation of exogenous antigens by antigen-presenting cells. Miller et al. now report that endogenous presentation drives most CD4+ T cell responses in influenza-infected mice.
The bromodomain and extraterminal (BET) inhibitor JQ1 synergizes with the histone deacetylase inhibitor SAHA to suppress tumor growth in mouse models of pancreatic cancer.
Upregulation of the ATP-dependent ACF chromatin-remodeling complex in the NAc is a necessary and causal component for susceptibility to stress-induced depressive behaviors in mice, and this complex is also shown to be upregulated in the NAc of depressed humans.