Theoretical basis to measure the impact of short-lasting control of an infectious disease on the epidemic peak

Background  

While many pandemic preparedness plans have promoted disease control effort to lower and delay an epidemic peak, analytical methods for determining the required control effort and making statistical inferences have yet to be sought. As a first step to address this issue, we present a theoretical basis on which to assess the impact of an early intervention on the epidemic peak, employing a simple epidemic model.     

Cell cycle arrest by monochloramine through the oxidation of retinoblastoma protein

Impairment of cell cycle control has serious effects on inflammation, tissue repair, and carcinogenesis. We report here the G1 cell cycle arrest by monochloramine (NH2Cl), a physiological oxidant derived from activated neutrophils, and its mechanism. When Jurkat cells were treated with NH2Cl (70 microM, 10 min) and incubated for 24 h, the S phase population decreased significantly with a slight increase in the hypodiploid cell population. The G0/ G1 phase and G2/M phase populations did not show marked changes. Three hours after NH2Cl treatment, the retinoblastoma protein (pRB) was dephosphorylated especially at Ser780 and Ser795, both of which are important phosphorylation sites for the G1 checkpoint function. The phosphorylation at Ser807/811 showed no apparent change. The expression of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors showed no apparent change. Moreover, the kinase activity that phosphorylates pRB remained constant even after NH2Cl treatment. The protein phosphatase activity that dephosphorylates pRB showed a marginal increase. Notably, when the recombinant pRB was oxidized by NH2Cl in vitro, the oxidized pRB became difficult to be phosphorylated by kinases, especially at Ser780 and Ser795, but not at Ser807/811. Amino acid analysis of oxidized pRB showed methionine oxidation to methionine sulfoxide. The NH2Cl-treated Jurkat cell proteins also showed a decrease in methionine. These observations suggested that direct pRB oxidation was the major cause of NH2Cl-induced cell cycle arrest. In the presence of 2 mM NH4+, NaOCl (200 microM) or activated neutrophils also induced a G1 cell cycle arrest. As protein methionine oxidation has been reported in inflammation and aging, cell cycle modulation by pRB oxidation may occur in various pathological conditions.     

Proteomic analysis of bone proteins adsorbed onto the surface of titanium dioxide

Osseointegration is the structural and functional connection between bone tissues and implants such as titanium dioxide (TiO₂). The bone-TiO₂ interface is thought to contain proteoglycans. However, exhaustive analysis of the proteins in this layer has not been performed. In this study, we evaluated the bone protein adhered on the surface of TiO₂ comprehensively. Pig bone protein was extracted by sequential elutions with guanidine, 0.1 M EDTA, and again with guanidine. The proteins obtained from these extractions were allowed to adhere to an HPLC column packed with TiO₂ and were eluted with 0.2 M NaOH. The eluted proteins were identified by LC/MS/MS and included not only proteoglycans but also other proteins such as extracellular matrix proteins, enzymes, and growth factors. Calcium depositions were observed on TiO₂ particles incubated with bone proteins, guanidine-extracted proteins adhered to TiO₂ displayed significantly high amounts of calcium depositions.     

Positive narrowing pharyngoplasty with forearm flap for functional restoration after extensive soft palate resection

The restoration of velopharyngeal function after extensive soft palate resection to treat malignant oropharyngeal tumors is a major challenge to reconstructive surgeons. The authors had previously reconstructed soft palatal defects routinely with the folded forearm flap. A patient who had more than half of the soft palate excised experienced postoperative velopharyngeal dysfunction. To restore efficient velopharyngeal function, pharyngoplasty was additively applied where the folded ridge of the forearm flap was sutured to the posterior pharyngeal wall in an inverse manner of the pharyngeal flap technique. The essence of the procedure was positive narrowing of the nasopharyngeal space. Five patients who underwent this pharyngoplasty and another five who did not were evaluated for postoperative functions of speech intelligibility and of nasal regurgitation during oral feeding. The velopharyngeal movements of all patients were examined under a nasopharyngeal endoscope. The evaluations demonstrated that this surgical procedure afforded satisfactory results. This positive narrowing pharyngoplasty technique is simple, easy, and minimally invasive to the remaining healthy tissue, and it is the method of choice for the reconstruction of the soft palate after malignant tumor resection.     

High glucose enhances interleukin-6-induced vascular endothelial growth factor 165 expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in gingival fibroblasts

Diabetic patients are susceptible to severe inflammatory periodontitis manifesting as swollen gingiva with bleeding, but the underlying mechanism is not well understood. Our purpose was to determine the effect of a high glucose (HG) condition on the interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-induced activation of signaling and vascular endothelial growth factor (VEGF) expression in human gingival fibroblasts (HGFs). In this study, HGFs were cultured for at least two passages under a normal glucose (NG; 5.5 mM) condition or high glucose (25 mM) condition. Importantly, the HG condition significantly induced expression of gp130 mRNA in HGFs compared with levels in control cells. Consistent with the expression of its mRNA, the HG condition also increased the expression of gp130 protein, and phosphorylation of the tyrosine residue by gp130 was enhanced significantly by IL-6/sIL-6R stimulation. Furthermore, the HG condition enhanced the IL-6/sIL-6R-induced phosphorylation of p44/42 MAPK and led to subsequent activation of CCAAT/enhancer binding protein in nuclei. In contrast, there was no significant difference in phosphorylation of JNK between the HG and NG condition. Interestingly, HGFs increased IL-6/sIL-6R-induced VEGF165 mRNA expression and VEGF165 secretion under the HG condition compared with levels under the NG condition. In contrast, the induction of VEGF165 secretion was partially inhibited by PD98059 (selective p44/42 MAPK inhibitor) under the HG condition. In addition, the VEGF165 secretion was completely inhibited by the combination of PD98059 and SP600125 (JNK inhibitor). Our findings suggest that the HG condition indirectly increases VEGF expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in HGFs. Thus, elevated VEGF secretion in HGFs under the HG condition may play a role in the development of the severe periodontitis observed in diabetic patients.     

A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver

We previously reported a new in vivo model named as "GFP/CCl(4) model" for monitoring the transdifferentiation of green fluorescent protein (GFP) positive bone marrow cell (BMC) into albumin-positive hepatocyte under the specific "niche" made by CCl(4) induced persistent liver damage, but the subpopulation which BMCs transdifferentiate into hepatocytes remains unknown. Here we developed a new monoclonal antibody, anti-Liv8, using mouse E 11.5 fetal liver as an antigen. Anti-Liv8 recognized both hematopoietic progenitor cells in fetal liver at E 11.5 and CD45-positive hematopoietic cells in adult bone marrow. We separated Liv8-positive and Liv8-negative cells and then transplanted these cells into a continuous liver damaged model. At 4 weeks after BMC transplantation, more efficient repopulation and transdifferentiation of BMC into hepatocytes were seen with Liv8-negative cells. These findings suggest that the subpopulation of Liv8-negative cells includes useful cells to perform cell therapy on repair damaged liver.     

Suppression of a DNA double-strand break repair gene,Ku70, increases radio- and chemosensitivity in a human lung carcinoma cell line

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.