Histone H1 chaperone activity of TAF‐I is regulated by its subtype‐dependent intramolecular interaction

Linker histone H1 is involved in the regulation of gene activity through the maintenance of higher‐order chromatin structure. Previously, we have shown that template activating factor‐I (TAF‐I or protein SET) is involved in linker histone H1 dynamics as a histone H1 chaperone. In human and murine cells, two TAF‐I subtypes exist, namely TAF‐Iα and TAF‐Iβ. TAF‐I has a highly acidic amino acid cluster in its C‐terminal region and forms homo‐ or heterodimers through its dimerization domain. Both dimer formation and the C‐terminal region of TAF‐I are essential for the histone chaperone activity. TAF‐Iα exhibits less histone chaperone activity compared with TAF‐Iβ even though TAF‐Iα and β differ only in their N‐terminal regions. However, it is unclear how subtype‐specific TAF‐I activities are regulated. Here, we have shown that the N‐terminal region of TAF‐Iα autoinhibits its histone chaperone activity via intramolecular interaction with its C‐terminal region. When the interaction between the N‐ and C‐terminal regions of TAF‐Iα is disrupted, TAF‐Iα shows a histone chaperone activity similar to that of TAF‐Iβ. Taken together, these results provide mechanistic insights into the concept that fine tuning of TAF‐I histone H1 chaperone activity relies on the subtype compositions of the TAF‐I dimer.     

Ruptured fusiform aneurysm of the proximal anterior cerebral artery (A1 segment)

A 42-year-old man presented with a ruptured fusiform aneurysm of the proximal anterior cerebral artery (A(1) segment) manifesting as sudden onset of severe headache. Brain computed tomography revealed subarachnoid hemorrhage in the basal cisterns, and left carotid angiography demonstrated a fusiform aneurysm of the left A(1) segment. He underwent surgery via the left pterional approach. The left A(1) segment exhibited a fusiform configuration. Adequate development of the anterior communicating artery was confirmed. Trapping of the aneurysm was performed. The aneurysm was associated with atherosclerotic changes. The postoperative course was uneventful, and the patient was discharged without neurological deficits 1 month after surgery. Fusiform aneurysm of the A(1) segment is quite rare, and tends to bleed, so must be treated. The atherosclerotic origin indicates long-term follow up to identify subsequent lesions.     

Molecular cloning and characterization of porcine Mx2 gene

Mx, an interferon-inducible protein, is found in various vertebrates and confers resistance to several RNA viruses. At least two Mx proteins occur in vertebrates, and these proteins are key components of innate defense against viral infection. In mice and humans, the two Mx genes have different antiviral activities. Both Mx1 and Mx2 have also been detected in pigs, although only a partial sequence of porcine Mx2 has been reported, and there is no information on its antiviral activity. Here, we report the structure of the intact porcine Mx2 gene having an open reading frame of 2136 bp. We also determined the sequence of the genomic region containing the entire porcine Mx2 gene in addition to Mx1 gene. A weak constitutive expression of porcine Mx2 mRNA and endogenous Mx2 protein was observed in interferon-untreated cells. Porcine endogenous Mx2 protein showed nuclear localization. Furthermore, assays using NIH3T3 cells transfected with Mx genes showed that porcine Mx2 possessed antiviral activity against influenza, although this activity was lower than that of human MxA. This report is the first to describe the intact porcine Mx2 gene, which is a functional gene that may play a key role in the clearance of viruses in pigs.     

A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance

BACKGROUND: Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. OBJECTIVES: This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. METHODS: This was a multicenter, open-label, parallel-group trial. Patients with LDL-C levels>or=140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. RESULTS: Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of >or=6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P=0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P=0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (-40.1 vs -33.0, respectively; P=0.002), as were the percent changes in non-HDL-C (-37.4 vs -31.1; P=0.004), Apo B (-35.1 vs -28.2; P<0.001), and Apo E (-28.1 vs -17.8; P<0.001). The significant results for these parameters were unchanged when all 189 subjects who received>or=1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group (P=NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value>3 times the upper limit of normal (P=NS). CONCLUSIONS: In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.