Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

The mitochondrial calcium uniporter contributes to morphine tolerance through pCREB and CPEB1 in rat spinal cord dorsal horn.

BACKGROUND: The long-term use of opioid analgesics is limited by the development of unwanted side-effects, such as tolerance. The molecular mechanisms of morphine anti-nociceptive tolerance are still unclear. The mitochondrial calcium uniporter (MCU) is involved in painful hyperalgesia, but the role of MCU in morphine tolerance has not been uncharacterised. METHODS: Rats received intrathecal injection of morphine for 7 days to induce morphine tolerance. The mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. The effects of an MCU inhibitor, antisense oligodeoxynucleotide against cyclic adenosine monophosphate response element (CRE)-binding protein (CREB) or cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in morphine tolerance were examined. RESULTS: Spinal morphine tolerance was associated with an increased expression of neuronal MCU, phospho-CREB (pCREB), and CPEB1 in the spinal cord dorsal horn. MCU inhibition increased the mechanical threshold and thermal latency, and reduced the accumulation of mitochondrial calcium in morphine tolerance. Intrathecal antisense oligodeoxynucleotide against CREB or CPEB1 restored the anti-nociceptive effects of morphine compared with mismatch oligodeoxynucleotide in von Frey test and hotplate test. Chromatin immunoprecipitation with quantitative PCR assay showed that CREB knockdown reduced the interaction of pCREB with the ccdc109a gene (encoding MCU expression) promoter and decreased the MCU mRNA transcription. RNA immunoprecipitation assay suggested that CPEB1 binds to the MCU mRNA 3' untranslated region. CPEB1 knockdown decreased the expression of MCU protein. CONCLUSIONS: These findings suggest that spinal MCU is regulated by pCREB and CPEB1 in morphine tolerance, and that inhibition of MCU, pCREB, or CPEB1 may be useful in preventing the development of opioid tolerance.

MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats.

Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. However, the exact mechanisms of morphine withdrawal (MW) are not clear yet, and its treatment remains elusive. Periaqueductal gray (PAG) is one of the important sites in the pathogenesis of MW. Here, we used recombinant herpes simplex virus (HSV) vectors that encode the sod2 gene expressing manganese superoxide dismutase (MnSOD) to evaluate its therapeutic potential in MW. Microinjection of HSV vectors expressing MnSOD into the PAG reduced the MW syndrome. MnSOD vectors suppressed the upregulated mitochondrial superoxide, and endoplasmic reticulum stress markers (glucose-related protein 78 (GRP78) and activating transcription factor 6 alpha (ATF6α)) in the PAG induced by MW. Immunostaining showed that mitochondrial superoxide, GRP78 and ATF6α were colocalized with neuronal nuclei (a neuronal-specific marker), suggesting that they are located in the neurons in the PAG. These results suggest that overexpression of MnSOD by HSV vectors may relieve opioid dependence. This study may provide a novel therapeutic approach to morphine physical withdrawal response.

High glucose-induced oxidative stress increases IL-8 production in human gingival epithelial cells.

OBJECTIVE: Diabetes is often associated with increased prevalence and severity of periodontal disease. We hypothesized that gingival epithelial cells modify periodontal disease progression and predicted that hyperglycemia would activate an inflammatory response in human gingival epithelial cells (HGECs). MATERIALS AND METHODS: We tested our hypothesis in immortalized HGECs (epi 4 cells) isolated from periodontal tissue and transfected with the simian virus 40 T antigen. The epi 4 cells were cultured in high (25 mM, HG) and normal (6 mM, NG) glucose conditions. RESULTS: The epi 4 cells showed increased interleukin-8 (IL-8) protein secretion and mRNA expression when cultured in HG, compared with in NG. These effects were not associated with increased cell proliferation and were not observed in a hyperosmolar control group (normal glucose with 19 mM mannitol). Increased IL-8 secretion in HG was inhibited by pretreatment with an antioxidant, N-acetylcysteine, or a protein kinase C inhibitor, Ro31-8220. Hyperglycemia did not affect IL-8 secretion by gingival fibroblasts or periodontal ligament cells. In epi 4 cells, hyperglycemia also induced expression of toll-like receptor 2 (TLR2) but not TLR4. CONCLUSION: These findings suggest a potential participation of epithelial cells in periodontal disease during diabetes by evoking an excessive host inflammatory response.

New treatment of free-radical scavenger in adrenoleukodystrophy.

WHAT IS KNOWN AND OBJECTIVE: Adrenoleukodystrophy (ALD) is an X-linked disorder and characterized by the accumulation of saturated very long-chain fatty acids. Treatment is still unsatisfactory. Our objective is to report on the effect of the free-radical scavenger, edaravone, in a patient with ALD. CASE SUMMARY: The patient was given edaravone intravenously twice. D-ROM in cerebral spinal fluid decreased dramatically, and a shortening of neuronal transmission time as estimated on somatosensory evoked potential was observed. After terminating the treatment, his symptoms progressively reappeared. WHAT IS NEW AND CONCLUSION: This is the first report of the use of edaravone in ALD. The drug is apparently effective in improving symptoms of ALD and should be evaluated more formally.

Cytokine and chemokine response in children with the 2009 pandemic influenza A (H1N1) virus infection.

We report the systemic cytokine and chemokine response in children with the 2009 pandemic influenza A (H1N1) virus infection. In patients with pneumonia, the serum levels of IFN-γ and IL-5 were significantly higher than those in patients without pneumonia. This tendency was also present for IL-6, IL-8, IL-10, IL-13, and MCP-1 in patients with pneumonia. Among patients with pneumonia, the levels of MCP-1 were significantly higher in the group of patients with pneumonia with severe respiratory failure than patients with mild pneumonia.

Sudden unexpected death associated with ileocecal duplication cyst and clinical review.

Duplications of the alimentary tract are very rare. A one-month-old female presented with symptoms of anorexia, vomiting and continuous watery diarrhea. The plain abdominal radiograph showed thickened intestinal wall and signs of small bowel obstruction. The fevers, vomiting, and continuous wartery diarrhea persisted despite antibiotics, and worsened. The patient failed to respond to medical managements, 27 hours after admission, the patient died due to multiple organ failures. The autopsy was performed, small bowel obstruction due to an ileocecal duplication cyst (3 × 3 cm) was recognized. The ileocecal duplication cyst was attached to the ileum which was changed edematous and necrotic. This potential diagnosis should be borne in mind for a patient who complains of abdominal symptoms with an unknown cause, and duplication cyst should be recognized as a fatal cause in infant.

Characterization of recombinant prolyl aminopeptidase from Aspergillus oryzae.

AIMS: Prolyl aminopeptidase (PAP) degrades only amino-terminal proline from peptides. The food-grade fungus Aspergillus oryzae produces this enzyme only in small amounts. In this paper, we present efficient production of recombinant PAP with an overexpression system of A. oryzae and characterization of its biochemical properties. METHODS AND RESULTS: The gene encoding PAP was overexpressed as a His-tag fusion protein under a taka-amylase gene (amyB) promoter with a limited expressing condition in A. oryzae. The PAP activity in the mycelia grown in rich medium containing glucose (repressing condition) was twice that in starch (inducing condition). The enzyme prepared as cell-free extract was partially purified through two-step column chromatography. The PAP was estimated to be a hexameric protein and exhibited salt tolerance against NaCl of up to 4 mol l(-1). CONCLUSIONS: Aspergillus oryzae PAP was produced under the repressing condition of amyB promoter in a PAP-overexpressing strain and purified 1800-folds. Overproduction of PAP under promoter-inducing conditions led to an increase in inactive PAP, possibly because of irregular folding. SIGNIFICANCE AND IMPACT OF THE STUDY: PAP with a high specific activity and salt tolerance may be used effectively in the manufacturing processes of fermented foods.

Efficient production and partial characterization of aspartyl aminopeptidase from Aspergillus oryzae.

AIMS: Aspartyl aminopeptidase (DAP) has a high degree of substrate specificity, degrading only amino-terminal acidic amino acids from peptides. Therefore, attention is focused here on the efficient production of this enzyme by a recombinant Aspergillus oryzae and characterization of its biochemical properties. METHODS AND RESULTS: The gene encoding DAP was overexpressed under a taka-amylase gene promoter, with His-tag linker in A. oryzae, during cultivation in a Co(2+)-containing medium. The enzyme was extracted from the mycelia and purified with immobilized nickel ion absorption chromatography using a buffer containing cobalt ion and imidazole. The active fraction was further purified with gel filtration chromatography. The resultant, electrophoretically pure enzyme displayed a molecular mass of 520 kDa. This enzyme displayed high reactivity towards peptide substrate rather than synthetic substrates. CONCLUSIONS: Recombinant A. oryzae DAP was purified to homogeneity with an increased specific activity, when cultivated in a Co(2+)-rich medium. Moreover, the use of suitable metal ions in microbial cultivation and purification processes may help in increasing the specific activity of other metalloproteases and their functional analysis. SIGNIFICANCE AND IMPACT OF THE STUDY: Recombinant DAP produced using a cobalt ion in culture media of A. oryzae and purification process allow high yield of the enzyme activity.

Colorectal resection by a minilaparotomy approach vs. conventional operation for colon cancer. Results of a prospective randomized trial.

BACKGROUND/AIMS: The aim of this study was to evaluate the outcome of patients undergoing colorectal resection for colon cancer using a minilaparotomy approach or conventional surgical procedure. METHODOLOGY: In a prospective randomized trial, twenty consecutive patients undergoing colon resection by minilaparotomy and 26 patients undergoing conventional open colorectal resection were evaluated. Immunologic, metabolic and hemodynamic studies were performed in all patients. Cell surface markers were used to characterize Th1/2 balance, using flow cytometry. Indirect calorimetry to measure energy expenditure, and pulse dye densitometry for a hemodynamic study were performed in patients until 14 POD. RESULTS: The lengths of laparotomy incisions were 7.5+/-1.5 cm and 20.5+/-2.5 cm in the minilaparotomy and conventional group, respectively. Mean operative time, morbidity and postoperative hospital stay of the two groups was not significantly different. However, mean operative blood loss, days to p.o. liquids and walking, and amount of analgesic usage were significantly less in the minilaparotomy group. The postoperative ratio of Th1/2 in CD4+T cells was decreased in both groups, but no significant difference was seen between the groups. Significant increase of resting energy expenditure and cardiac index was seen until day 3 in the conventional group, whereas those values increased until day 1 in the minilaparotomy group. CONCLUSIONS: Compared with conventional colorectal resection for colon cancer, colorectal resection by minilaparotomy results in a more rapid return of bowel function, less pain and host response. However, the alternations of the host response for surgical stress between the two groups are similar in the early postoperative stage (days 1-2).

Postoperative host responses in elderly patients after gastrointestinal surgery.

BACKGROUND/AIMS: The age-associated dysregulation of hemodynamic, metabolic and immune responses contributes to the high incidence of complications after major abdominal surgery. METHODOLOGY: Ninety-five patients who underwent gastric resection (n=51) and colorectal resection (n=44) were divided according to age into Groups A (n=45, less than 70 years old), B (n=30, 70-79 years) and C (n=20, over 80 years). Flow cytometric analysis of CD4+ lymphocytes for interferon (IFN)-gamma and interleukin (IL)-4 production determined the Th1/2 balance. Energy expenditure was measured by indirect calorimetry, and hemodynamics were studied using pulse dye densitometry. RESULTS: Surgical procedures, operating time, blood loss and morbidity did not significantly differ among the three groups. The cardiac index (CI) in group A and B increased significantly over preoperative levels until POD 3, but there were no significant perioperative changes in the CI levels of group C. Resting energy expenditure levels changed similarly to those of CI. The postoperative Th1/2 ratio decreased from young to elderly to very elderly patients, although no differences were significant before surgery. The postoperative percentage of CD4+IFN-gamma +T cells (Th1) in group C decreased significantly despite of no significant changes in that of group A and B. In contrast, the ratio of CD4+IL-4+T cells (Th2) in the all groups significantly increased after surgery. CONCLUSIONS: Host responses in elderly patients after major abdominal surgery were more hyperdynamic and hypermetabolic than those of young patients. Postoperative dysregulation of the Th1/2 balance was also associated with aging. However, host responses appear to significantly differ between elderly and very elderly patients.

Costs and benefits of laparoscopic cholecystectomy: abdominal wall lifting vs. pneumoperitoneum procedure.

BACKGROUND/AIMS: Gasless laparoscopic surgery using the abdominal wall lifting (AWL) method was first developed in Japan and has been used in various surgical fields. The AWL method allows the use of conventional reusable surgical instruments. The purpose of this study was to compare the cost-effectiveness of laparoscopic cholecystectomy (LSC) using the AWL method in relation to that using pneumoperitoneum (P) method. METHODOLOGY: Retrospective analysis of 431 LSC procedures between 1991 and 2004 was performed. The two surgical groups consisted of consecutively operated patients with a diagnosis of cholecystolithiasis or gallbladder polyps. One group consisted of 224 LSC procedures performed using the P method from 1992 to 1998 and the other group comprised 207 LSC performed using the AWL method from 1998 to 2004. All instruments used in the P method were disposable, whereas trocars, scissors, dissectors, graspers and L-hook electrodes (excluding clips) used in the AWL method were reusable. Hospital expenses, length of hospital admission and complication rates were analyzed. RESULTS: Mean hospital cost per case for LSC using the AWL method (dollars 6743) was 7% less expensive than that using the P method (dolars 7215). Costs of operative equipment contributed to the difference (mean dollars 912 per case) in total cost. Conversion to open cholecystectomy occurred in 6 cases (2.9%) using the AWL method and 7 cases (3.1%) using the P method. There were no significant differences in length of hospital admission or complication rates between the two groups. CONCLUSIONS: LSC using AWL method was less expensive than that using P method. This is mainly due to the use of reusable instruments in the AWL method. If LSC is performed using the AWL method instead of using disposable equipment, considerable savings can be achieved without compromising patient safety.

Postoperative metabolic and circulatory responses in patients that express SIRS after major digestive surgery.

BACKGROUND/AIMS: Systemic inflammatory response syndrome (SIRS) includes a number of pathologic states because of its loose definition. This study assessed differences in metabolic and circulatory host responses in various patients with SIRS perioperatively. METHODOLOGY: Fifty-four patients who underwent abdominal surgeries [gastric resection (n=20), colorectal resection (n=24), hepatic resection (n=8)] were divided into two groups: Group A; SIRS (+) on 1 postoperative day (POD), (n=29), B; SIRS (-) on 1 POD, (n=25). The other eight non-operated patients with SIRS caused by infection were enrolled in Group C, as common SIRS. Indirect calorimetry, body impedance measurement to assess water compartments and pulse dye-densitometry for hemodynamic examination were performed in subjects until 14 POD. RESULTS: The ratio of energy expenditure to basal energy expenditure (%REE) was significantly increased postoperatively, and there were significant differences on %REE from 3 POD to 14 POD between groups A and B. However, %REE in group C was 162+/-23%, which was significantly increased compared with that at 1 POD of groups A (130 +/- 17%) and B (125+/-18%). Cardiac output in group A showed a significant increase until 3 POD compared with that in group B but was significantly lower than that in group C. CONCLUSIONS: Subjects with common SIRS caused by infection were significantly more hypermetabolic than subjects with postoperative SIRS. Adequate energy intake and circulatory management should be cautiously determined according to the severity of SIRS.

Hepatic resection leads to predominance of the T helper-2 lymphocyte phenotype.

Recent studies have shown that the type 1/2 T helper (Th1/2) cell balance is shifted toward a Th2-type immune response not only by malignancy but also by surgical stress. This study evaluates in immune responses to surgical stress from liver surgery in comparison with other major abdominal surgeries. PATIENTS AND METHODS:: Eighty-five patients who underwent abdominal surgeries were divided into three groups: hepatic resection (n = 17), gastric resection (n = 38), and colorectal resection (n = 30). Blood sampling was performed before surgery, and on postoperative days (POD) 2 and 14. Cell surface markers were used to characterize Th1/2 balance by flow cytometry and a ratio of the percent IFN-gamma-producing (Th1) cells to IL-4-producing (Th2) cells were expressed as the Th1/2 balance. RESULTS:: The postoperative ratio of Th1 to Th2 was decreased significantly in all subjects to 4.5 +/- 3.0 on POD 2 from 6.7 +/- 4.2. The ratio of Th1 to Th2 in patients who underwent hepatic resection markedly decreased to 2.8 +/- 1.6 on POD 2, significantly different from those in patients undergoing gastric resection or colorectal resection. However, on POD 14 there were no longer any significant differences among the three surgical groups. CONCLUSIONS:: This study shows that hepatic resection induces a more marked shift of the Th1/2 balance toward Th2 than other major abdominal surgeries.

Hepatic resection induces a shift in the Th 1/2 balance toward Th 2 and produces hypermetabolic and hyperhemodynamic states.

BACKGROUND/AIMS: Recent studies have shown that the type 1/2 T-helper (Th 1/2) cell balance is shifted toward a Th 2-type immune response not only by malignancy but also by surgical stress. The present study evaluated surgical stress as a result of liver surgery in comparison with that of other major abdominal surgeries. Immune, metabolic and circulatory responses to surgery were measured for determination of surgical stress. METHODOLOGY: Eighty-five patients who underwent abdominal surgeries were divided into three groups: hepatic resection (n=17), gastric resection (n=38), colorectal resection (n= 30). Blood sampling was performed before surgery, and on postoperative days (POD) 2 and 14. The Th 1/2 helper T cell balance was determined by flow cytometric analysis of interferon-gamma and interleukin-4 expression. Energy expenditure was measured by indirect calorimetry, and hemodynamics was studied using pulse dye densitometry until POD 14. RESULTS: Following surgery Th 1/2 ratios decreased significantly. Additionally, the Th 1/2 balance in patients with hepatic resection on POD 2 was significantly lower than that of patients with other major surgeries. However, on POD 14 there were no significant differences among the three groups. Resting energy expenditure and cardiac index on postoperative days 1 and 3 in patients with hepatic resection increased significantly above levels in the other surgical groups. Conversely, blood volume in the hepatic resection patients was significantly lower than that of other patients until POD 3. Ten patients who developed postoperative complications had significantly lower Th 1/2 ratios and more hypermetabolism. CONCLUSIONS: This study reveals that hepatic resection induces a more marked shift toward a Th 2 helper T cell response and significantly more hypermetabolism than other major surgeries. A distinct pattern of Th 1/2 ratio changes during the early phase of the postoperative course in hepatic resection may be related to changes in metabolism and circulation. Therefore, determination of Th 1/2 balance may be of help in evaluating different surgical procedures, and management of energy intake and circulatory management may be cautiously determined based on the shift in Th 1/2 balance.

NOx (nitrite/nitrate) in cerebral spinal fluids obtained from patients with influenza-associated encephalopathy.

It has become evident that the number of patients with a new type of influenza-associated encephalopathy is increasing in Japan. Nitric oxide (NO), a simple free radical gas, elicits a wide range of physiological and pathophysiological effects. We measured the nitrite/nitrate (NO x ) levels in cerebral spinal fluid obtained from patients with influenza-associated encephalopathy in order to evaluate the correlation between the NO production and the process of influenza-associated encephalopathy. Fifteen children were enrolled, aged from 1 to 9 years. As control we used 14 cerebral spinal fluids obtained from patients with urinary tract infection, respiratory infection or mumps meningitis without any sequela. NO 3 in influenza-associated encephalopathy was significantly higher than that of control group. On the other hand NO 2 was not significantly higher than that of control group. In particular, 4 out of 5 fatal cases revealed high NO 2 or NO 3. One case having normal levels in NO 2 and NO 3 showed that NH 3 was high. These results revealed that NO plays a role in influenza-associated encephalopathy through indirect effects of NO.

Telomeric repeat sequence of Aspergillus oryzae consists of dodeca-nucleotides.

Four telomeres in the chromosomes of Aspergillus oryzae NFRI1599 were cloned and sequenced. The telomeric repeat sequence of A. oryzae consisted of dodeca-nucleotides: TTAGGGTCAACA. The length of the telomeric repeat tract was 114-136 bp, which corresponds to 9-11 repeats of the dodeca-nucleotide sequence. Compared to a chromosome internal control (18S rDNA), the telomeric sequences were found to be sensitive to BAL31 exonuclease digestion, thus proving that the identified telomeric repeat sequences were located at the most terminal tract of the chromosomes. The length of the telomeric repeat tract of A. oryzae is similar to that of Aspergillus nidulans, whose repeat unit is TTAGGG, indicating that the regulatory mechanism of telomere length might be conserved among Aspergillus species.

Cytomegalovirus DNA among children attending two day-care centers in Tokyo.

BACKGROUND: In the USA, a high prevalence rate of cytomegalovirus (CMV) excretion among children in day-care centres was reported. However, there is no research about the prevalence rate of CMV among children in day-care centres in Japan. METHODS: The CMV excretion was studied in 54 children's saliva samples, collected from two different day-care centres in Tokyo. As a control, the prevalence of CMV was studied among 61 healthy children who did not attend any day-care centers. The CMV DNA in saliva were examined by polymerase chain reaction (PCR) analysis with one pair of primers for the immediate early region. The sequence of CMV genomes were examined in CMV PCR positive samples. RESULTS: Of the 54 saliva samples, 20.6% (6/29) and 24% (6/25) were CMV PCR positive in children at A and B day-care centres, respectively. The overall positivity of CMV PCR in saliva was 22.2% (12/54). Of the 61 saliva samples as the control study, 6.5% (4/61) were CMV PCR positive. There was a difference in the positivity in each age group of day-care centres and normal control. Each sample of the same day-care center gave conclusive and identical sequence results. CONCLUSION: We suspected that in each day-care center that there was one prevailing viral strain. We suppose that CMV infections were acquired inside the day-care centres. This is a first report which described viral transmission in day-care centres in Japan.