To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor ...suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.
A soft-landing actuation waveform was designed to reduce the bounce of a single-pole single-throw (SPST) ohmic radio frequency (RF) microelectromechanical systems (MEMS) switch during actuation. The ...waveform consisted of an actuation voltage pulse, a coast time, and a hold voltage. The actuation voltage pulse had a short duration relative to the transition time of the switch and imparted the kinetic energy necessary to close the switch. After the actuation pulse was stopped, damping and restoring forces slowed the switch to near-zero velocity as it approached the closed position. This is referred to as the coast time. The hold voltage was applied upon reaching closure to keep the switch from opening. An ideal waveform would close the switch with near zero impact velocity. The switch dynamics resulting from an ideal waveform were modeled using finite element methods and measured using laser Doppler vibrometry. The ideal waveform closed the switch with an impact velocity of less than 3 cm/s without rebound. Variations in the soft-landing waveform closed the switch with impact velocities of 12.5 cm/s with rebound amplitudes ranging from 75 to 150 nm compared to impact velocities of 22.5 cm/s and rebound amplitudes of 150 to 200 nm for a step waveform. The ideal waveform closed the switch faster than a simple step voltage actuation because there was no rebound and it reduced the impact force imparted on the contacting surfaces upon closure
Nanostructures exhibit strong adhesion, which gives rise to friction even without normal loads. For technological applications, friction involves non-zero compressive loads. However, such frictional ...behavior of the 1D nanostructures remains unknown. Taking SiC-SiO(2) core-shell nanowire films (NWFs) as a prototype, this paper reports strong friction of the 1D nanostructures. The maximum static frictional force between an NWF and a macroscopic solid surface is 5-12 times that between two macroscopic solids; the frictional coefficient scales similarly.
Previous research on semantic priming in schizophrenia has produced conflicting findings. While several studies provided evidence for an enhanced cognitive spreading of activation in schizophrenia ...patients with formal thought disorder, other research has failed to replicate. The aim of the present study was to resolve some of the ambiguities in the literature. Thirty-two schizophrenic patients (12 with and 20 without symptoms of formal thought disorder according to the PANADSS) and 65 healthy controls were compared in a semantic priming task using word pronunciation.
Irrespective of baseline condition (neutral or unrelated condition) patients with formal thought disorder (TD) exhibited a significantly greater indirect semantic priming effect than both non-TD patients and healthy controls. Known confounding variables such as length of illness, neuroleptic dosage and psychomotor slowness did not moderate priming.
Results further strengthen the spreading activation model of formal thought disorder put forward by Maher/Manschreck and Spitzer. Data indicate that hyper-priming is not confined to lexical decision tasks. Possible reasons why several studies have failed to replicate greater priming in TD schizophrenic patients are discussed.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a predominantly latent infection in the infected host. Importantly, during latency, only a small number of viral encoded genes are ...expressed. This viral gene expression pattern contributes to the establishment of long-term infection as well as the ability of the virus to evade the immune system. Previous studies have been shown that the
replication and
transcription
activator (RTA) encoded by ORF50 activates it downstream genes and initiates viral lytic reactivation through functional interaction with RBP–Jκ, the major downstream effector of the Notch signaling pathway. This indicates that RTA can usurp the conserved Notch signaling pathway and mimic the activities of intracellular Notch1 to modulate gene expression. In this report, we show that the activated intracellular domain of Notch1 (ICN) is aberrantly accumulated in KSHV latently infected pleural effusion lymphoma (PEL) cells. ICN activated the RTA promoter in a dose-dependent manner, and forced expression of ICN in latently infected KSHV-positive cells initiated full blown lytic replication with the production of infectious viral progeny. However, latency-associated nuclear antigen (LANA) which is predominantly expressed during latency can specifically down-modulate ICN-mediated transactivation of RTA and so control KSHV for lytic reactivation. These results demonstrate that LANA can inhibit viral lytic replication by antagonizing ICN function and suggest that LANA is a critical component of the regulatory control mechanism for switching between viral latent and lytic replication by directly interacting with effectors of the conserved cellular Notch1 pathway.
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