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When exposed to low oxygen or hypoxia, animals must alter their metabolism and physiology to ensure proper cell-, tissue-, and whole-body level adaptations to their hypoxic environment. These alterations often involve changes in gene expression. While extensive work has emphasized the importance of the HIF-1 alpha transcription factor on controlling hypoxia gene expression, less is known about other transcriptional mechanisms. We previously identified the transcription factor FOXO as a regulator of hypoxia tolerance in Drosophila larvae and adults. Here, we use an RNA-sequencing approach to identify FOXO-dependent changes in gene expression that are associated with these tolerance effects. We found that hypoxia altered the expression of over 2,000 genes and that ∼40% of these gene expression changes required FOXO. We discovered that hypoxia exposure led to a FOXO-dependent increase in genes involved in cell signaling, such as kinases, GTPase regulators, and regulators of the Hippo/Yorkie pathway. Among these, we identified homeodomain-interacting protein kinase as being required for hypoxia survival. We also found that hypoxia suppresses the expression of genes involved in ribosome synthesis and egg production, and we showed that hypoxia suppresses tRNA synthesis and mRNA translation and reduces female fecundity. Among the downregulated genes, we discovered that FOXO was required for the suppression of many ribosomal protein genes and genes involved in oxidative phosphorylation, pointing to a role for FOXO in limiting energetically costly processes such as protein synthesis and mitochondrial activity upon hypoxic stress. This work uncovers a widespread role for FOXO in mediating hypoxia changes in gene expression.

BACKGROUND: Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. METHODS: To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. RESULTS: Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions. CONCLUSIONS: We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.

In this paper we investigate some qualitative properties of the solutions to the following doubly nonlocal equation \begin{equation}\label{eq_abstract} (- \Delta)^s u + \mu u = (I_\alpha*F(u))F'(u) \quad \hbox{in $\mathbb{R}^N$} \tag{P} \end{equation} where $N \geq 2$, $s\in (0,1)$, $\alpha \in (0,N)$, $\mu>0$ is fixed, $(-\Delta)^s$ denotes the fractional Laplacian and $I_{\alpha}$ is the Riesz potential. Here $F \in C^1(\mathbb{R})$ stands for a general nonlinearity of Berestycki-Lions type. We obtain first some regularity result for the solutions of \eqref{eq_abstract}. Then, by assuming $F$ odd or even and positive on the half-line, we get constant sign and radial symmetry of the Pohozaev ground state solutions related to equation \eqref{eq_abstract}. In particular, we extend some results contained in \cite{DSS1}. Similar qualitative properties of the ground states are obtained in the limiting case $s=1$, generalizing some results by Moroz and Van Schaftingen in \cite{MS2} when $F$ is odd.

Goal of this paper is to study the following doubly nonlocal equation \begin{equation}\label{eq_abstract} (- \Delta)^s u + \mu u = (I_\alpha*F(u))F'(u) \quad \hbox{in $\mathbb{R}^N$} \tag{P} \end{equation} in the case of general nonlinearities $F \in C^1(\R)$ of Berestycki-Lions type, when $N \geq 2$ and $\mu>0$ is fixed. Here $(-\Delta)^s$, $s \in (0,1)$, denotes the fractional Laplacian, while the Hartree-type term is given by convolution with the Riesz potential $I_{\alpha}$, $\alpha \in (0,N)$. We prove existence of ground states of \eqref{eq_abstract}. Furthermore we obtain regularity and asymptotic decay of general solutions, extending some results contained in \cite{DSS1, MS2}.

Saggio introduttivo a A. Moro, Lezioni di Istituzioni di diritto e procedura penale, Cacucci, Bari, 2005

Skin reactions after transarterial chemoembolization (TACE) with anthracyclines are rare and mostly limited to small areas. We describe a 56-year-old male with hepatocellular carcinoma treated with epirubicin chemoembolization. Immediately the procedure, pain on the right side and an extended livedo reticularis-like skin reaction appeared. Since dexrazoxane, a topoisomerase-II catalytic-cycle inhibitor, has been shown to be effective in preventing or reducing skin necrosis and ulceration following anthracycline extravasation, the drug was administered 8 h after TACE and repeated in the following 2 days. Due to marked extrahepatic diffusion of epirubicin as evidenced by computed tomography imaging, the patient showed signs of systemic organ involvement. The critically ill patient required close follow-up and intensified treatment including blood supply and pulmonary drainage of a pleural effusion. The patient presented a significant clinical improvement of the skin lesions and resolution of organ involvement with normalization of laboratory parameters after dexrazoxane. In conclusion, adverse extended skin reactions and severe systemic effects related to anthracyclines diffusion could be properly treated with dexrazoxane infusion.

We prove existence of infinitely many solutions $u \in H^1_r(\mathbb{R}^N)$ for the nonlinear Choquard equation $$ - \Delta u + \mu u =(I_\alpha*F(u)) f(u) \quad \hbox{in}\ \mathbb{R}^N, $$ where $N\geq 3$, $\alpha\in (0,N)$, $I_\alpha(x) := \frac{\Gamma(\frac{N-\alpha}{2})}{\Gamma(\frac{\alpha}{2}) \pi^{N/2} 2^\alpha } \frac{1}{|x|^{N- \alpha}}$, $x \in \mathbb{R}^N \setminus\{0\}$ is the Riesz potential, and $F$ is an almost optimal subcritical nonlinearity, assumed odd or even. We analyze the two cases: $\mu$ is a fixed positive constant or $\mu$ is unknown and the $L^2$-norm of the solution is prescribed, i.e. $\int_{\mathbb{R}^N} |u|^2 =m>0$. Since the presence of the nonlocality prevents to apply the classical approach, introduced by Berestycki and Lions in \cite{BL2}, we implement a new construction of multidimensional odd paths, where some estimates for the Riesz potential play an essential role, and we find a nonlocal counterpart of their multiplicity results. In particular we extend the existence results in \cite{MS2}, due to Moroz and Van Schaftingen.