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Summary: TFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. Using C. elegans and mammalian models, we report that the master metabolic modulator 5′-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK confers pathogen resistance via activation of TFEB/TFE3-dependent antimicrobial genes, whereas ablation of total AMPK activity abolishes this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages is observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status with innate immunity. : El-Houjeiri et al. show that loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression and phagocytosis in macrophages and confers pathogen resistance in C. elegans. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status to innate immunity. Keywords: TFEB, TFE3, FLCN, AMPK, innate immune response, pathogen resistance, autophagy, lysosomal biogenesis, phagocytosis

Reduction of mu activity within the EEG is an indicator of cognitive empathy and can be generated in response to visual depictions of others in pain. The current study tested whether this brain response can be modulated by an auditory and a chemosensory context. Participants observed pictures of painful and non-painful actions while pain associated and neutral exclamations were presented (Study 1, N = 30) or while chemosensory stimuli were presented via a constant flow olfactometer (Study 2, N = 22). Chemosensory stimuli were sampled on cotton pads while donors participated in a simulated job interview (stress condition) or cycled on a stationary bike (sport condition). Pure cotton was used as a control. The social chemosignals could not be detected as odors. Activity within the 8–13 Hz band at electrodes C3, C4 (mu activity) and electrodes O1, O2 (alpha-activity) was calculated using Fast-Fourier-Transformation (FFT). As expected, suppression of power in the 8–13 Hz band was stronger when painful as compared to non-painful actions were observed (Study 1, p = 0.020; Study 2, p = 0.005). In addition, as compared to the neutral auditory and chemosensory context, painful exclamations (Study 1, p = 0.039) and chemosensory stress signals (Study 2, p = 0.014) augmented mu-/alpha suppression also in response to non-painful pictures. The studies show that processing of social threat-related information is not dominated by visual information. Rather, cognitive appraisal related to empathy can be affected by painful exclamations and subthreshold chemosensory social information.

Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23+/− loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23+/−-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23+/− loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.

libRadtran is a widely used software package for radiative transfer calculations. It allows one to compute (polarized) radiances, irradiance, and actinic fluxes in the solar and thermal spectral regions. libRadtran has been used for various applications, including remote sensing of clouds, aerosols and trace gases in the Earth's atmosphere, climate studies, e.g., for the calculation of radiative forcing due to different atmospheric components, for UV forecasting, the calculation of photolysis frequencies, and for remote sensing of other planets in our solar system. The package has been described in Mayer and Kylling (2005). Since then several new features have been included, for example polarization, Raman scattering, a new molecular gas absorption parameterization, and several new parameterizations of cloud and aerosol optical properties. Furthermore, a graphical user interface is now available, which greatly simplifies the usage of the model, especially for new users. This paper gives an overview of libRadtran version 2.0.1 with a focus on new features. Applications including these new features are provided as examples of use. A complete description of libRadtran and all its input options is given in the user manual included in the libRadtran software package, which is freely available at http://www.libradtran.org.

Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed integrins are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to α5β1 integrin triggers ubiquitination and internalization of the receptor complex. Acidification facilitates FN dissociation from integrin α5β1 in vitro and in early endosomes, promoting receptor complex deubiquitination by the USP9x and recycling to the cell surface. Depending on residual ligand occupancy of receptors, some α5β1 integrins remain ubiquitinated and are captured by ESCRT-0/I, containing histidine domain-containing protein tyrosine phosphatase (HD-PTP) and ubiquitin-associated protein 1 (UBAP1), and are directed for lysosomal proteolysis, limiting receptor downstream signaling and cell migration. Thus, HD-PTP or UBAP1 depletion confers a pro-invasive phenotype. Thus, pH-dependent FN-integrin dissociation and deubiquitination of the activated integrin α5β1 are required for receptor resensitization and cell migration, representing potential targets to modulate tumor invasiveness.