Nutritional Control of Nucleocytoplasmic Localization of cAMP-dependent Protein Kinase Catalytic and Regulatory Subunits in Saccharomyces cerevisiae

In budding yeast, cAMP-dependent protein kinase (PKA) plays a central role in the nutritional control of metabolism, cell cycle, and transcription. This study shows that both the regulatory subunit Bcy1p and the catalytic subunit Tpk1p associated with it are predominantly localized in the nucleus of rapidly growing cells. Activation of nuclear PKA by cAMP leads to fast entry of a significant part of Tpk1p into the cytoplasm, while the regulatory subunit remains nuclear. In contrast to rapidly proliferating cells, both Bcy1p and Tpk1p are distributed over nucleus and cytoplasm in cells growing on a nonfermentable carbon source or in stationary phase cells. These results demonstrate that at least two different mechanisms determine the subcellular localization of PKA; cAMP controls the localization of Tpk1p, and the carbon source determines that of Bcy1p. The N-terminal domain of Bcy1p serves to target it properly during logarithmic and stationary phase. Studies with Bcy1p mutant versions unable to concentrate in the nucleus revealed that cells producing them are less viable in stationary phase than wild type cells, display delayed reproliferation following transfer to fresh growth medium, and, as diploids, exhibit reduced efficiency of sporulation

Semi-Inclusive Pi(0) Target and Beam-Target Asymmetries from 6 GeV Electron Scattering with CLAS

We present precision measurements of the target and beam-target spin asymmetries from neutral pion electroproduction in deep-inelastic scattering (DIS) using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. We scattered 6-GeV, longitudinally polarized electrons off longitudinally polarized protons in a cryogenic 14NH3 target, and extracted double and single target spin asymmetries for ep→e′ π0 X in multidimensional bins in four-momentum transfer (1.0 2 \u3c 3.2 GeV2), Bjorken -x (0.12 \u3c x \u3c 0.48), hadron energy fraction (0.4 \u3c z 0.7), tranverse pion meomentum (0 \u3c PT \u3c 1.0 GeV), and azimuthal angle ϕh between the lepton scattering and hadron production planes. We extracted asymmetries as a function of both x and PT, which provides access to transverse-momentum distributions of longitudinally polarized quarks. The double spin asymmetries depend weakly on PT. The sin 2ϕh moments are zero within uncertainties, which is consistent with the expected suppression of the Collins fragmentation function. The observed sin ϕh moments suggest that quark gluon correlations are significant at large x

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease

Background: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology arid progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Methods: Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6 delta normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. Results: The newly identified inhibitors of the Rap1-Pde6 delta interaction counteract AD phenotypes, by reconfiguring Rapt signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or invivo. Thus, modulation of Rap1 by Pde6 delta accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. Conclusion: Targeting the Pde6 delta-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer’s Disease

Although a wide variety of genetic and nongenetic Alzheimer’s disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively

Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease

A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies.status: publishe