Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression

Remembering a past experience can, surprisingly, cause forgetting. Forgetting arises when other competing traces interfere with retrieval and inhibitory control mechanisms are engaged to suppress the distraction they cause. This form of forgetting is considered to be adaptive because it reduces future interference. The effect of this proposed inhibition process on competing memories has, however, never been observed, as behavioral methods are 'blind' to retrieval dynamics and neuroimaging methods have not isolated retrieval of individual memories. We developed a canonical template tracking method to quantify the activation state of individual target memories and competitors during retrieval. This method revealed that repeatedly retrieving target memories suppressed cortical patterns unique to competitors. Pattern suppression was related to engagement of prefrontal regions that have been implicated in resolving retrieval competition and, critically, predicted later forgetting. Thus, our findings demonstrate a cortical pattern suppression mechanism through which remembering adaptively shapes which aspects of our past remain accessible

E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer

The Mid-Infrared Instrument for the James Webb Space Telescope, III: MIRIM, The MIRI Imager

In this article, we describe the Mid-Infrared Imager Module (MIRIM), which provides broadband imaging in the 5-27 mum wavelength range for the James Webb Space Telescope. The imager has a 0.11" pixel scale and a total unobstructed view of 74" × 113". The remainder of its nominal 113" × 113" field is occupied by the coronagraphs and the low-resolution spectrometer. We present the instrument optical and mechanical design. We show that the test data, as measured during the test campaigns undertaken at CEA-Saclay, at the Rutherford Appleton Laboratory, and at the NASA Goddard Space Flight Center, indicate that the instrument complies with its design requirements and goals. We also discuss the operational requirements (multiple dithers and exposures) needed for optimal scientific utilization of the MIRIM.status: publishe

The Mid-Infrared Instrument for the James Webb Space Telescope, II: Design and Build

The Mid-InfraRed Instrument (MIRI) on the James Webb Space Telescope (JWST) provides measurements over the wavelength range 5 to 28.5 μm. MIRI has, within a single “package,” four key scientific functions: photometric imaging, coronagraphy, single-source low-spectral resolving power (R ∼ 100) spectroscopy, and medium-resolving power (R ∼ 1500 to 3500) integral field spectroscopy. An associated cooler system maintains MIRI at its operating temperature of < 6.7 K. This paper describes the driving principles behind the design of MIRI, the primary design parameters, and their realization in terms of the “as-built” instrument. It also describes the test program that led to delivery of the tested and calibrated Flight Model to NASA in 2012, and the confirmation after delivery of the key interface requirements