Pleasure, arousal, dominance, and judgments about music in everyday life

The aim of the present research was to consider what particular features are significant predictors of whether music is present in a given situation, as well as what factors influence a person’s judgments about the music. Applying Mehrabian and Russell’s (1974) Pleasure-Arousal-Dominance model to everyday experiences of music, 569 people reported on their activity for the previous day via the Day Reconstruction Method (Kahneman, Krueger, Schkade, Schwarz, & Stone, 2004). Data concerning each event included the activity and location, and characterization of the experience using the Pleasure–Arousal–Dominance measure. Moreover, for those events where music was present, participants also indicated how they heard the music and made four judgments about the music. Results indicated that the location, activity, and the person’s perception of dominance were significant predictors of the presence of music during everyday activities and that person’s judgments about the music. Contrary to prior research that has considered predominantly situational pleasure and arousal variables, the present results demonstrate that dominance is arguably the important variable in contextualized music listening

An ideal journey: Making bus travel desirable

© 2016 Informa UK Limited, trading as Taylor & Francis Group. This paper explores the ways in which people use their travel-time on local buses, and explains how this knowledge can assist with efforts in many ‘auto-centric’ societies to make bus travel more attractive and encourage a shift away from excessive private car use. Framing the discussion around the concept of an ‘ideal bus journey’, this paper examines whether travel-time activities on-board the bus give subjective value to the journey experience. Particular attention is given to emergent mobile Information and Communications Technologies, which are rapidly reconfiguring the ways in which we can inhabit and use mobile spaces such as the bus. This paper reports a novel mixed-methodology, creating a synthesised analysis of online discussions, focus groups, and a large-scale questionnaire survey of 840 bus users in Bristol, UK. The findings demonstrate that the bus is a very active space, with high levels of travel-time activity. The most popular activities on the bus are those related to relaxation and personal benefit, such as reading, listening to music, and browsing the internet. It is the passengers themselves that are largely in control of their in-vehicle experience, being able to craft a range of different positive journey experiences through travel-time activity. However, negative experiences are very common, and there is a need to challenge unfavourable public perception and media representations of bus travel to create a more positive cultural construction of the bus which would allow for the concept of an ‘ideal journey’ to be more easily realised. Passengers are the main creators of their travel-time experience, however there is much that can be done by bus operators to facilitate different types of activity and encourage a desirable public space. The overarching message is that there is a distinct opportunity to unlock travel-time activity as a ‘Unique Selling Point’ of the bus. Creating a perception of the bus journey as a desirable piece of time will allow local bus services to compete with the car on their own terms, and assist with international efforts to encourage people out of their cars and onto public transport for some trips

Ribosome Binding of a Single Copy of the SecY Complex: Implications for Protein Translocation

The SecY complex associates with the ribosome to form a protein translocation channel in the bacterial plasma membrane. We have used cryo-electron microscopy and quantitative mass spectrometry to show that a nontranslating E. coli ribosome binds to a single SecY complex. The crystal structure of an archaeal SecY complex was then docked into the electron density maps. In the resulting model, two cytoplasmic loops of SecY extend into the exit tunnel near proteins L23, L29, and L24. The loop between transmembrane helices 8 and 9 interacts with helices H59 and H50 in the large subunit RNA, while the 6/7 loop interacts with H7. We also show that point mutations of basic residues within either loop abolish ribosome binding. We suggest that SecY binds to this primary site on the ribosome and subsequently captures and translocates the nascent chain

Ribosome Binding of a Single Copy of the SecY Complex: Implications for Protein Translocation

The SecY complex associates with the ribosome to form a protein translocation channel in the bacterial plasma membrane. We have used cryo-electron microscopy and quantitative mass spectrometry to show that a nontranslating E. coli ribosome binds to a single SecY complex. The crystal structure of an archaeal SecY complex was then docked into the electron density maps. In the resulting model, two cytoplasmic loops of SecY extend into the exit tunnel near proteins L23, L29, and L24. The loop between transmembrane helices 8 and 9 interacts with helices H59 and H50 in the large subunit RNA, while the 6/7 loop interacts with H7. We also show that point mutations of basic residues within either loop abolish ribosome binding. We suggest that SecY binds to this primary site on the ribosome and subsequently captures and translocates the nascent chain

ATG24 represses autophagy and differentiation and is essential for homeostasy of the flagellar pocket in trypanosoma brucei

We have previously identified homologs for nearly half of the approximately 30 known yeast Atg's in the genome database of the human sleeping sickness parasite Trypanosoma brucei. So far, only a few of these homologs have their role in autophagy experimentally confirmed. Among the candidates was the ortholog of Atg24 that is involved in pexophagy in yeast. In T. brucei, the peroxisome-like organelles named glycosomes harbor core metabolic processes, especially glycolysis. In the autotrophic yeast, autophagy is essential for adaptation to different nutritional environments by participating in the renewal of the peroxisome population. We hypothesized that autophagic turnover of the parasite's glycosomes plays a role in differentiation during its life cycle, which demands adaptation to different host environments and associated dramatic changes in nutritional conditions. We therefore characterized T. brucei ATG24, the T. brucei ortholog of yeast Atg24 and mammalian SNX4, and found it to have a regulatory role in autophagy and differentiation as well as endocytic trafficking. ATG24 partially localized on endocytic membranes where it was recruited via PI3-kinase III/VPS34. ATG24 silencing severely impaired receptor-mediated endocytosis of transferrin, but not adsorptive uptake of a lectin, and caused a major enlargement of the flagellar pocket. ATG24 silencing approximately doubled the number of autophagosomes, suggesting a role in repressing autophagy, and strongly accelerated differentiation, in accordance with a role of autophagy in parasite differentiation. Overexpression of the two isoforms of T. brucei ATG8 fused to GFP slowed down differentiation, possibly by a dominant-negative effect. This was overcome by ATG24 depletion, further supporting its regulatory role

Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1/3 Degrader NX-2127

INTRODUCTION: Bruton’s tyrosine kinase (BTK) is a nonreceptor kinase in the B cell receptor (BCR) signaling cascade critical for B cell survival. As such, chronic lymphocytic leukemia (CLL) and other B cell cancers are sensitive to inhibition of BTK. Covalent and noncovalent inhibitors of BTK have revolutionized the treatment of these cancers. Therefore, understanding mechanisms by which acquired mutation in BTK confer drug resistance and developing new therapies to overcome resistance are critically important. RATIONALE: We recently discovered BTK mutations that confer resistance across covalent and noncovalent BTK inhibitors. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling. We therefore set out to understand the nonenzymatic functions of BTK and explored targeted protein degradation to overcome the oncogenic scaffold function of mutant BTK. This effort included evaluation of BTK degradation in patients with CLL treated in a phase 1 clinical trial of NX-2127, a first-in-class BTK degrader (NCT04830137). RESULTS: BTK enzymatic activity assays revealed that drug resistance mutations in BTK fall into two distinct groups: kinase proficient and kinase impaired. Immunoprecipitation mass spectrometry of kinase-impaired BTK L528W (Leu528→Trp) revealed a scaffold function of BTK with downstream signaling and survival dependent on surrogate kinases that bind to kinase-impaired BTK proteoforms. To target the nonenzymatic functions of BTK, we developed NX-2127, a heterobifunctional molecule that engages the ubiquitin-proteasome system to simultaneously bind both BTK and the cereblon E3 ubiquitin ligase complex, inducing polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK. The activity of NX-2127 on BTK degradation was further demonstrated in patients with CLL treated in a phase 1 clinical trial of NX-2127, where \u3e80% BTK degradation was achieved and clinical responses were also seen in 79% of evaluable patients, independent of mutant BTK genotypes. CONCLUSION: We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category

Schizophrenia and the Scaffolded Self

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recordA family of recent externalist approaches in philosophy of mind argues that our psychological capacities are synchronically and diachronically “scaffolded” by external (i.e., beyond-the-brain) resources. Despite much interest in this topic, however, it has not found its way to philosophy of psychiatry in a substantive way. I here consider how these “scaffolded” approaches to mind and self might inform debates in phenomenological psychopathology. First, I introduce the idea of “affective scaffolding”. I distinguish three forms of affective scaffolding and support this taxonomy by appealing to different sources of empirical work. Second, I put the idea of affective scaffolding to work. Using schizophrenia as a case study, I argue — along with others in phenomenological psychopathology — that schizophrenia is fundamentally a self-disturbance. However, I offer a subtle reconfiguration of these approaches. I argue that schizophrenia is not simply a disruption of ipseity or minimal self-consciousness but rather a disruption of the scaffolded self, established and regulated via its ongoing engagement with the world and others. I conclude that this way of thinking about the scaffolded self is potentially transformative both for our theoretical as well as practical understanding of the causes and character of schizophrenic experience, insofar as it suggests the need to consider new forms of intervention and treatment