Potassium is the most abundant ion to face both plasma and organelle membranes. Extensive research over the past seven decades has characterized how K(+) permeates the plasma membrane to control fundamental processes such as secretion, neuronal communication, and heartbeat. However, how K(+) permeates organelles such as lysosomes and endosomes is unknown. Here, we directly recorded organelle K(+) conductance and discovered a major K(+)-selective channel KEL on endosomes and lysosomes. KEL is formed by TMEM175, a protein with unknown function. Unlike any of the ∼80 plasma membrane K(+) channels, TMEM175 has two repeats of 6-transmembrane-spanning segments and has no GYG K(+) channel sequence signature-containing, pore-forming P loop. Lysosomes lacking TMEM175 exhibit no K(+) conductance, have a markedly depolarized ΔΨ and little sensitivity to changes in [K(+)], and have compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Thus, TMEM175 comprises a K(+) channel that underlies the molecular mechanism of lysosomal K(+) permeability.

The human RNA editing enzyme ADAR1 (double-stranded RNA deaminase I) deaminates adenine in pre-mRNA to yield inosine, which codes as guanine. ADAR1 has two left-handed Z-DNA binding domains, Z alpha and Z beta, at its NH(2)-terminus and preferentially binds Z-DNA, rather than B-DNA, with high binding affinity. The cocrystal structure of Z alpha(ADAR1) complexed to Z-DNA showed that one monomeric Z alpha(ADAR1) domain binds to one strand of double-stranded DNA and a second Z alpha(ADAR1) monomer binds to the opposite strand with 2-fold symmetry with respect to DNA helical axis. It remains unclear how Z alpha(ADAR1) protein specifically recognizes Z-DNA sequence in a sea of B-DNA to produce the stable Z alpha(ADAR1)-Z-DNA complex during the B-Z transition induced by Z alpha(ADAR1). In order to characterize the molecular recognition of Z-DNA by Z alpha(ADAR1), we performed circular dichroism (CD) and NMR experiments with complexes of Zalpha(ADAR1) bound to d(CGCGCG)(2) (referred to as CG6) produced at a variety of protein-to-DNA molar ratios. From this study, we identified the intermediate states of the CG6-Z alpha(ADAR1) complex and calculated their relative populations as a function of the Z alpha(ADAR1) concentration. These findings support an active B-Z transition mechanism in which the Z alpha(ADAR1) protein first binds to B-DNA and then converts it to left-handed Z-DNA, a conformation that is then stabilized by the additional binding of a second Z alpha(ADAR1) molecule.

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Intramural hematomas of the colon are rare. Intramural hematomas of the gastrointestinal tract often result from blunt trauma, although they may also occur spontaneously in patients taking anticoagulants or those with blood dyscrasia. Affected patients present with abdominal pain and lower gastrointestinal bleeding, as well as occasional signs of intestinal obstruction. The diagnosis is made using colonoscopy and abdominal CT. Resection of the involved bowel segment is accepted as the standard therapy; however, experience with conservative treatment has also been reported. We herein report the case of a 62-year-old woman taking warfarin who was diagnosed with a colonic intramural hematoma and completely recovered with conservative management.

In the present study, the antinociceptive profiles of vanillin were examined in ICR mice. Vanillin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of vanillin maintained at least for 30 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 microg) or glutamate (20 microg) injection was not affected by vanillin. Intraperitoneal (i.p.) pretreatment with yohimbine (alpha2-adrenergic receptor antagonist) or naloxone (opioid receptor antagonist) attenuated antinociceptive effect induced by vanillin in the writhing test. However, phentolamine (alpha1-adrenergic receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by vanillin in the writhing test. Our results suggest that vanillin exerts a selective antinociceptive property in the acetic acid-induced visceral inflammatory pain model. Furthermore, this antinociceptive effect of vanillin may be mediated by alpha2-adrenergic and opioid receptors, but not alpha1-adrenergic and serotonergic receptors.