Disruption of CTCF-YY1-dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription.

The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1-dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis

Universal Spin Transport in a Strongly Interacting Fermi Gas

Transport of fermions is central in many elds of physics. Electron transport runs modern technology, de ning states of matter such as superconductors and insulators, and electron spin, rather than charge, is being explored as a new carrier of information [1]. Neutrino transport energizes supernova explosions following the collapse of a dying star [2], and hydrodynamic transport of the quark-gluon plasma governed the expansion of the early Universe [3]. However, our understanding of non-equilibrium dynamics in such strongly interacting fermionic matter is still limited. Ultracold gases of fermionic atoms realize a pristine model for such systems and can be studied in real time with the precision of atomic physics [4, 5]. It has been established that even above the super uid transition such gases ow as an almost perfect uid with very low viscosity [3, 6] when interactions are tuned to a scattering resonance. However, here we show that spin currents, as opposed to mass currents, are maximally damped, and that interactions can be strong enough to reverse spin currents, with opposite spin components reflecting off each other. We determine the spin drag coefficient, the spin di usivity, and the spin susceptibility, as a function of temperature on resonance and show that they obey universal laws at high temperatures. At low temperatures, the spin di usivity approaches a minimum value set by ħ/m, the quantum limit of di usion, where ħ is the reduced Planck's constant and m the atomic mass. For repulsive interactions, our measurements appear to exclude a metastable ferromagnetic state [7{9].National Science Foundation (U.S.)United States. Office of Naval ResearchUnited States. Army Research Office (DARPA OLE programme)Alfred P. Sloan FoundationUnited States. Air Force Office of Scientific Research. Multidisciplinary University Research InitiativeUnited States. Army Research Office. Multidisciplinary University Research InitiativeUnited States. Defense Advanced Research Projects Agency. Young Faculty AwardDavid & Lucile Packard Foundatio

Repulsive polarons and itinerant ferromagnetism in strongly polarized Fermi gases

We analyze the properties of a single impurity immersed in a Fermi sea. At positive energy and scattering lengths, we show that the system possesses a well-defined but metastable excitation, the repulsive polaron, and we calculate its energy, quasiparticle residue and effective mass. From a thermodynamic argument we obtain the number of particles in the dressing cloud, illustrating the repulsive character of the polaron. Identifying the important 2- and 3-body decay channels, we furthermore calculate the lifetime of the repulsive polaron. The stability conditions for the formation of fully spin polarized (ferromagnetic) domains are then examined for a binary mixture of atoms with a general mass ratio. Our results indicate that mass imbalance lowers the critical interaction strength for phase-separation, but that very short quasiparticle decay times will complicate the experimental observation of itinerant ferromagnetism. Finally, we present the spectral function of the impurity for various coupling strengths and momenta.Comment: Substantial improvements to the section describing quasiparticle decays (included a discussion of two-body and three-body processes), and to the criteria for the stability of the itinerant ferromagnetic phas

Transcranial Alternating Current Stimulation Enhances Individual Alpha Activity in Human EEG

Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS) has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS) has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP) selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity

Understanding Communication Signals during Mycobacterial Latency through Predicted Genome-Wide Protein Interactions and Boolean Modeling

About 90% of the people infected with Mycobacterium tuberculosis carry latent bacteria that are believed to get activated upon immune suppression. One of the fundamental challenges in the control of tuberculosis is therefore to understand molecular mechanisms involved in the onset of latency and/or reactivation. We have attempted to address this problem at the systems level by a combination of predicted functional protein∶protein interactions, integration of functional interactions with large scale gene expression studies, predicted transcription regulatory network and finally simulations with a Boolean model of the network. Initially a prediction for genome-wide protein functional linkages was obtained based on genome-context methods using a Support Vector Machine. This set of protein functional linkages along with gene expression data of the available models of latency was employed to identify proteins involved in mediating switch signals during dormancy. We show that genes that are up and down regulated during dormancy are not only coordinately regulated under dormancy-like conditions but also under a variety of other experimental conditions. Their synchronized regulation indicates that they form a tightly regulated gene cluster and might form a latency-regulon. Conservation of these genes across bacterial species suggests a unique evolutionary history that might be associated with M. tuberculosis dormancy. Finally, simulations with a Boolean model based on the regulatory network with logical relationships derived from gene expression data reveals a bistable switch suggesting alternating latent and actively growing states. Our analysis based on the interaction network therefore reveals a potential model of M. tuberculosis latency

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)