We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ϳ48°C (high) or 47°C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.

No abstract

Sulfolobus acidocaldarius is the closest experimentally tractable archaeal relative of eukaryotes and, despite lacking obvious cyclin-dependent kinase and cyclin homologs, has an ordered eukaryote-like cell cycle with distinct phases of DNA replication and division. Here, in exploring the mechanism of cell division in S. acidocaldarius, we identify a role for the archaeal proteasome in regulating the transition from the end of one cell cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome and show that its degradation triggers division by allowing constriction of the CdvB1:CdvB2 ESCRT-III division ring. These findings offer a minimal mechanism for ESCRT-III–mediated membrane remodeling and point to a conserved role for the proteasome in eukaryotic and archaeal cell cycle control.

PTEN dephosphorylates the 3-position phosphate of phosphatidylinositol 3,4,5 triphosphate (PIP(3)), thereby inhibiting AKT activation. Although attenuation of PTEN function has a major role in tumourigenesis, the underlying mechanisms remain unclear. Here we show that α-mannosidase 2C1 (MAN2C1) inhibits PTEN function in prostate cancer (PC) cells and is associated with a reduction in PTEN function in primary PC. MAN2C1 activates AKT and promotes the formation of PTEN-positive DU145 cell-derived xenograft tumours by imparing endogenous PTEN function. In 659 PC patients who were examined, ~60% of tumours were PTEN positive with elevated AKT activation. Of these, 80% display MAN2C1 overexpression that co-localizes with PTEN. Increases in MAN2C1 were detected only in PTEN-positive prostatic intraepithelial neoplasia and carcinomas, and showed a significant association with PC recurrence only in patients with PTEN-positive PCs. Mechanistically, MAN2C1 binds PTEN thereby inhibiting its PIP(3) phosphatase activity. These findings show that MAN2C1 function as a PTEN-negative regulator in PC cells.