ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD(+) Depletion

ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

Rapid tryptophan depletion improves decision-making cognition in healthy humans without affecting reversal learning or set shifting

Rapid tryptophan (Trp) depletion (RTD) has been reported to cause deterioration in the quality of decision making and impaired reversal learning, while leaving attentional set shifting relatively unimpaired. These findings have been attributed to a more powerful neuromodulatory effect of reduced 5-HT on ventral prefrontal cortex (PFC) than on dorsolateral PFC. In view of the limited number of reports, the aim of this study was to independently replicate these findings using the same test paradigms. Healthy human subjects without a personal or family history of affective disorder were assessed using a computerized decision making/gambling task and the CANTAB ID/ED attentional set-shifting task under Trp-depleted (n=17; nine males and eight females) or control (n=15; seven males and eight females) conditions, in a double-blind, randomized, parallel-group design. There was no significant effect of RTD on set shifting, reversal learning, risk taking, impulsivity, or subjective mood. However, RTD significantly altered decision making such that depleted subjects chose the more likely of two possible outcomes significantly more often than controls. This is in direct contrast to the previous report that subjects chose the more likely outcome significantly less often following RTD. In the terminology of that report, our result may be interpreted as improvement in the quality of decision making following RTD. This contrast between studies highlights the variability in the cognitive effects of RTD between apparently similar groups of healthy subjects, and suggests the need for future RTD studies to control for a range of personality, family history, and genetic factors that may be associated with 5-HT function.

Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo.

In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previously recorded from a sympathetic fiber innervating the rat tail artery. All stimuli evoked greater changes in TVR than FVR. Judging from the effects of the -adrenoceptor antagonist phentolamine, the purinergic receptor antagonist suramin, or ,-methylene ATP (which desensitizes P2X receptors), we propose that NE has a major role in the constriction evoked by the couplet, as well as by the short train and by the low- and high-frequency components of the natural pattern, but that considerable synergy occurred between the actions of ATP and NE. This contrasts with previous in vitro studies that indicated that ATP dominates vascular responses evoked by sympathetic stimulation with a few impulses at low frequency and that NE dominates responses to longer trains or at high frequencies.

Boron abundances in B-type stars: A test of rotational depletion during main-sequence evolution

Boron abundances have been derived for seven main-sequence B- type stars from Hubble Space Telescope STIS spectra around the B III lambda2066 line. In two stars, boron appears to be undepleted with respect to the presumed initial abundance. In one star, boron is detectable but is clearly depleted. In the other four stars, boron is undetectable, implying depletions of 1-2 dex. Three of these four stars are nitrogen enriched, but the fourth shows no enrichment of nitrogen. Only rotationally induced mixing predicts that boron depletions are unaccompanied by nitrogen enrichments. The inferred rate of boron depletion from our observations is in good agreement with these predictions. Other boron-depleted nitrogen-normal stars are identified from the literature. In addition, several boron- depleted nitrogen-rich stars are identified, and while all fall on the boron-nitrogen trend predicted by rotationally induced mixing, a majority have nitrogen enrichments that are not uniquely explained by rotation. The spectra have also been used to determine iron group (Cr, Mn, Fe, and Ni) abundances. The seven B-type stars have near-solar iron group abundances, as expected for young stars in the solar neighborhood. We have also analyzed the halo B-type star PG 0832 + 676. We find [Fe/H] = -0.88 +/- 0.10, and the absence of the B III line gives the upper limit [B/H] <-2.5. These and other published abundances are used to infer the star's evolutionary status as a post-asymptotic giant branch star.