Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity.

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails extensive epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer, although they can lead to muscular atrophy. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC and muscular atrophy.

Gravity Governs Shear Localization in Confined Dense Granular Flows.

The prediction of flow profiles of slowly sheared granular materials is a major geophysical and industrial challenge. Understanding the role of gravity is particularly important for future planetary exploration in varying gravitational environments. Using the principle of minimization of energy dissipation, and combining experiments and variational analysis, we disentangle the contributions of the gravitational acceleration, confining pressure, and layer thickness on shear strain localization induced by moving fault boundaries at the bottom of a granular layer. The flow profile is independent of the gravity for geometries with a free top surface. However, under a confining pressure or if the sheared layer withstands the weight of the upper layers, increasing gravity promotes the transition from closed shear zones buried in the bulk to open ones that intersect the top surface. We show that the center position and width of the shear zone and the axial angular velocity at the top surface follow universal scaling laws when properly scaled by the gravity, applied pressure, and layer thickness. Our finding that the flow profiles lie on a universal master curve opens the possibility to predict the quasistatic shear flow of granular materials in varying gravitational environments.

Compositional Control of Phase-Separated Cellular Bodies.

Cellular bodies such as P bodies and PML nuclear bodies (PML NBs) appear to be phase-separated liquids organized by multivalent interactions among proteins and RNA molecules. Although many components of various cellular bodies are known, general principles that define body composition are lacking. We modeled cellular bodies using several engineered multivalent proteins and RNA. In vitro and in cells, these scaffold molecules form phase-separated liquids that concentrate low valency client proteins. Clients partition differently depending on the ratio of scaffolds, with a sharp switch across the phase diagram diagonal. Composition can switch rapidly through changes in scaffold concentration or valency. Natural PML NBs and P bodies show analogous partitioning behavior, suggesting how their compositions could be controlled by levels of PML SUMOylation or cellular mRNA concentration, respectively. The data suggest a conceptual framework for considering the composition and control thereof of cellular bodies assembled through heterotypic multivalent interactions.

Mitotic Transcription Installs Sgo1 at Centromeres to Coordinate Chromosome Segregation.

Human sister chromatids at metaphase are primarily linked by centromeric cohesion, forming the iconic X shape. Premature loss of centromeric cohesion disrupts orderly mitotic progression. Shugoshin (Sgo1) binds to and protects cohesin at inner centromeres. The kinetochore kinase Bub1 phosphorylates histone H2A at T120 (H2A-pT120) and recruits Sgo1 to kinetochores, 0.5 µm from inner centromeres. Here, we show that Sgo1 is a direct reader of the H2A-pT120 mark. Bub1 also recruits RNA polymerase II (Pol II) to unattached kinetochores and promotes active transcription at mitotic kinetochores. Mitosis-specific inactivation of Pol II traps Sgo1 at kinetochores and weakens centromeric cohesion. Sgo1 interacts with Pol II in human cells and with RNA in vitro. We propose that Pol II-dependent transcription enables kinetochore-bound Sgo1 initially recruited by H2A-pT120 to reach cohesin embedded in centromeric chromatin. Our study implicates mitotic transcription in targeting regulatory factors to highly compacted mitotic chromatin.

The effect of image quality and forensic expertise in facial image comparisons.

Images of perpetrators in surveillance video footage are often used as evidence in court. In this study, identification accuracy was compared for forensic experts and untrained persons in facial image comparisons as well as the impact of image quality. Participants viewed thirty image pairs and were asked to rate the level of support garnered from their observations for concluding whether or not the two images showed the same person. Forensic experts reached their conclusions with significantly fewer errors than did untrained participants. They were also better than novices at determining when two high-quality images depicted the same person. Notably, lower image quality led to more careful conclusions by experts, but not for untrained participants. In summary, the untrained participants had more false negatives and false positives than experts, which in the latter case could lead to a higher risk of an innocent person being convicted for an untrained witness.

The neural representation of faces and bodies in motion and at rest.

The neural organization of person processing relies on brain regions functionally selective for faces or bodies, with a subset of these regions preferring moving stimuli. Although the response properties of the individual areas are well established, less is known about the neural response to a whole person in a natural environment. Targeting an area of cortex that spans multiple functionally-selective face and body regions, we examined the relationship among neural activity patterns elicited in response to faces, bodies, and people in static and moving displays. When both stimuli were static or moving, pattern classification analyses indicated highly discriminable responses to faces, bodies, and whole people. Neural discrimination transferred in both directions between representations created from moving or static stimuli. It transferred also to stimuli experienced across static and dynamic presentations (one static and the other dynamic). In both transfer cases, however, discrimination accuracy decreased relative to the case where the representations were both created and tested with static or moving forms. Next, we examined the relative contribution of activity pattern and response magnitude to discrimination by comparing classifiers that operated with magnitude-normalized scans with classifiers that retained pattern and magnitude information. When both stimuli were moving or static, response magnitude contributed to classification, but the spatially distributed activity pattern accounted for most of the discrimination. Across static and moving presentations, activity pattern accounted completely for the discriminability of neural responses to faces, bodies, and people, with no contribution from response magnitude. Combined, the results indicate redundant and flexible access to person-based shape codes from moving and static presentations. The transfer of shape information across presentation types that preferentially access dorsal and ventral visual processing streams indicates that a common shape code may ground functional divisions in the processing of face and body information.

Unaware person recognition from the body when face identification fails.

How does one recognize a person when face identification fails? Here, we show that people rely on the body but are unaware of doing so. State-of-the-art face-recognition algorithms were used to select images of people with almost no useful identity information in the face. Recognition of the face alone in these cases was near chance level, but recognition of the person was accurate. Accuracy in identifying the person without the face was identical to that in identifying the whole person. Paradoxically, people reported relying heavily on facial features over noninternal face and body features in making their identity decisions. Eye movements indicated otherwise, with gaze duration and fixations shifting adaptively toward the body and away from the face when the body was a better indicator of identity than the face. This shift occurred with no cost to accuracy or response time. Human identity processing may be partially inaccessible to conscious awareness.