Role of neuronal and non-neuronal acetylcholine signaling in Drosophila humoral immunity

Acetylcholine (ACh) is one the major neurotransmitters in insects, whose role in mediating synaptic interactions between neurons in the central nervous system is well characterized. It also plays largely unexplored regulatory functions in non-neuronal tissues. Here we demonstrate that ACh signaling is involved in the modulation of the innate immune response of Drosophila melanogaster. Knockdown of ACh synthesis or ACh vesicular transport in neurons reduced the activation of drosomycin (drs), a gene encoding an antimicrobial peptide, in adult flies infected with a Gram-positive bacterium. drs transcription was similarly affected in Drosophila α7 nicotinic acetylcholine receptor, nAChRalpha7 (Dα7) mutants, as well as in flies expressing in the nervous system a dominant negative form (Dα7DN) of this specific receptor subunit. Interestingly, Dα7DN elicited a comparable response when it was expressed in non-neuronal tissues and even when it was specifically produced in the hemocytes. Consistently, full activation of the drs gene required Dα7 expression in these cells. Moreover, knockdown of ACh synthesis in non-neuronal cells affected drs expression. Overall, these findings uncover neural and non-neural cholinergic signals that modulate insect immune defenses and shed light on the role of hemocytes in the regulation of the humoral immune response

Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase

CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment

Measurement of 1323 and 1487 keV resonances in 15N({\alpha}, {\gamma})19F with the recoil separator ERNA

The origin of fluorine is a widely debated issue. Nevertheless, the ^{15}N({\alpha},{\gamma})^{19}F reaction is a common feature among the various production channels so far proposed. Its reaction rate at relevant temperatures is determined by a number of narrow resonances together with the DC component and the tails of the two broad resonances at E_{c.m.} = 1323 and 1487 keV. Measurement through the direct detection of the 19F recoil ions with the European Recoil separator for Nuclear Astrophysics (ERNA) were performed. The reaction was initiated by a 15N beam impinging onto a 4He windowless gas target. The observed yield of the resonances at Ec.m. = 1323 and 1487 keV is used to determine their widths in the {\alpha} and {\gamma} channels. We show that a direct measurement of the cross section of the ^{15}N({\alpha},{\gamma})^{19}F reaction can be successfully obtained with the Recoil Separator ERNA, and the widths {\Gamma}_{\gamma} and {\Gamma}_{\alpha} of the two broad resonances have been determined. While a fair agreement is found with earlier determination of the widths of the 1487 keV resonance, a significant difference is found for the 1323 keV resonance {\Gamma}_{\alpha} . The revision of the widths of the two more relevant broad resonances in the 15N({\alpha},{\gamma})19F reaction presented in this work is the first step toward a more firm determination of the reaction rate. At present, the residual uncertainty at the temperatures of the ^{19}F stellar nucleosynthesis is dominated by the uncertainties affecting the Direct Capture component and the 364 keV narrow resonance, both so far investigated only through indirect experiments.Comment: 8 pages, 11 figures. Accepted for publication in PR

Genetic Loss of miR-205 Causes Increased Mammary Gland Development

MiRNAs play crucial roles in a broad spectrum of biological processes, both physiological and pathological. Different reports implicate miR-205 in the control of breast stem cell properties. Differential miR-205 expression has been observed in different stages of mammary gland development and maturation. However, a functional role in this process has not been clearly demonstrated. We generated an miR-205 knockout in the FVB/N mouse strain, which is viable and characterized by enhanced mammary gland development. Indeed, mammary glands of miR-20

22Ne and 23Na ejecta from intermediate-mass stars: The impact of the new LUNA rate for 22Ne(p,gamma)23Na

We investigate the impact of the new LUNA rate for the nuclear reaction $^{22}$Ne$(p,\gamma)^{23}$Na on the chemical ejecta of intermediate-mass stars, with particular focus on the thermally-pulsing asymptotic giant branch (TP-AGB) stars that experience hot-bottom burning. To this aim we use the PARSEC and COLIBRI codes to compute the complete evolution, from the pre-main sequence up to the termination of the TP-AGB phase, of a set of stellar models with initial masses in the range $3.0\,M_{\odot} - 6.0\,M_{\odot}$, and metallicities $Z_{\rm i}=0.0005$, $Z_{\rm i}=0.006$, and $Z_{\rm i} = 0.014$. We find that the new LUNA measures have much reduced the nuclear uncertainties of the $^{22}$Ne and $^{23}$Na AGB ejecta, which drop from factors of $\simeq 10$ to only a factor of few for the lowest metallicity models. Relying on the most recent estimations for the destruction rate of $^{23}$Na, the uncertainties that still affect the $^{22}$Ne and $^{23}$Na AGB ejecta are mainly dominated by evolutionary aspects (efficiency of mass-loss, third dredge-up, convection). Finally, we discuss how the LUNA results impact on the hypothesis that invokes massive AGB stars as the main agents of the observed O-Na anti-correlation in Galactic globular clusters. We derive quantitative indications on the efficiencies of key physical processes (mass loss, third dredge-up, sodium destruction) in order to simultaneously reproduce both the Na-rich, O-poor extreme of the anti-correlation, and the observational constraints on the CNO abundance. Results for the corresponding chemical ejecta are made publicly available

Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition

A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors

Toward a reassessment of the 19F(p, α0)16O reaction rate at astrophysical temperatures

AbstractThe 19F(p, α0)16O reaction at low energies plays an important role in fundamental physics. In particular in nuclear astrophysics it represents, together with the 19F(p, γ)20Ne reaction, the crossing point between the CNO and the NeNa cycles in stars. Further, in hydrogen-rich stellar environments, it is the most important fluorine destruction channel. In this paper we report new measurements on the 19F(p, α0)16O reaction at deeply sub-Coulomb energies (0.2–0.6 MeV), a region where, despite the key role of this reaction, very few and old data are reported. The deduced astrophysical S-factor is ≈1.5–2 times larger than currently adopted extrapolations with possibly important astrophysical consequences

Telomerase inhibition, Telomere attrition and proliferation arrest of cancer cells induced by Phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT

Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells