Inhibition of Fungi and Gram-Negative Bacteria by Bacteriocin BacTN635 Produced by Lactobacillus plantarum sp. TN635

The aim of this study was to evaluate 54 lactic acid bacteria (LAB) strains isolated from meat, fermented vegetables and dairy products for their capacity to produce antimicrobial activities against several bacteria and fungi. The strain designed TN635 has been selected for advanced studies. The supernatant culture of this strain inhibits the growth of all tested pathogenic including the four Gram-negative bacteria (Salmonella enterica ATCC43972, Pseudomonas aeruginosa ATCC 49189, Hafnia sp. and Serratia sp.) and the pathogenic fungus Candida tropicalis R2 CIP203. Based on the nucleotide sequence of the 16S rRNA gene of the strain TN635 (1,540 pb accession no FN252881) and the phylogenetic analysis, we propose the assignment of our new isolate bacterium as Lactobacillus plantarum sp. TN635 strain. Its antimicrobial compound was determined as a proteinaceous substance, stable to heat and to treatment with surfactants and organic solvents. Highest antimicrobial activity was found between pH 3 and 11 with an optimum at pH = 7. The BacTN635 was purified to homogeneity by a four-step protocol involving ammonium sulfate precipitation, centrifugal microconcentrators with a 10-kDa membrane cutoff, gel filtration Sephadex G-25, and C18 reverse-phase HPLC. SDS-PAGE analysis of the purified BacTN635, revealed a single band with an estimated molecular mass of approximately 4 kDa. The maximum bacteriocin production (5,000 AU/ml) was recorded after a 16-h incubation in Man, Rogosa, and Sharpe (MRS) medium at 30 °C. The mode of action of the partial purified BacTN635 was identified as bactericidal against Listeria ivanovii BUG 496 and as fungistatic against C. tropicalis R2 CIP203

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

Healthy Campus Trial: A multiphase optimization strategy (MOST) fully factorial trial to optimize the smartphone cognitive behavioral therapy (CBT) app for mental health promotion among university students: Study protocol for a randomized controlled trial

This is the final version. Available from the publisher via the DOI in this record.After the publication of the primary findings, the de-identified and completely anonymized individual participant-level dataset will be posted on the UMIN-ICDR website (http://www.umin.ac.jp/icdr/index-j.html) so that it can be accessed by qualified researchers.Background: Youth in general and college life in particular are characterized by new educational, vocational, and interpersonal challenges, opportunities, and substantial stress. It is estimated that 30-50% of university students meet criteria for some mental disorder, especially depression, in any given year. The university has traditionally provided many channels to promote students' mental health, but until now only a minority have sought such help, possibly owing to lack of time and/or to stigma related to mental illness. Smartphone-delivered cognitive behavioral therapy (CBT) shows promise for its accessibility and effectiveness. However, its most effective components and for whom it is more (or less) effective are not known. Methods/design: Based on the multiphase optimization strategy framework, this study is a parallel-group, multicenter, open, fully factorial trial examining five smartphone-delivered CBT components (self-monitoring, cognitive restructuring, behavioral activation, assertion training, and problem solving) among university students with elevated distress, defined as scoring 5 or more on the Patient Health Questionnaire-9 (PHQ-9). The primary outcome is change in PHQ-9 scores from baseline to week 8. We will estimate specific efficacy of the five components and their interactions through the mixed-effects repeated-measures analysis and propose the most effective and efficacious combinations of components. Effect modification by selected baseline characteristics will be examined in exploratory analyses. Discussion: The highly efficient experimental design will allow identification of the most effective components and the most efficient combinations thereof among the five components of smartphone CBT for university students. Pragmatically, the findings will help make the most efficacious CBT package accessible to a large number of distressed university students at reduced cost; theoretically, they will shed light on the underlying mechanisms of CBT and help further advance CBT for depression

Worldwide trends in mortality from biliary tract malignancies

BACKGROUND: Intrahepatic cholangiocarcinomas are malignant tumors arising from the intrahepatic biliary tract. The pathogenesis of these tumors remains unknown. Although there is a marked global variation in prevalence, some recent studies have suggested an increase in mortality from intrahepatic cholangiocarcinoma in several regions of low endemicity. As the study of mortality trends may yield clues to possible etiological factors, we analyzed worldwide time trends in mortality from biliary tract malignancies. METHODS: Annual age-standardized rates for individual countries were compiled for deaths from biliary tract malignancies using the WHO database. These data were used to analyze gender and site-specific trends in mortality rates. RESULTS: An increasing trend for mortality from intrahepatic cholangiocarcinoma was noted in most countries. The average estimated annual percentage change (EAPC) in mortality rates for males was 6.9 ± 1.5, and for females was 5.1 ± 1.0. Increased mortality rates were observed in all geographic regions. Within Europe, increases were higher in Western Europe than in Central or Northern Europe. In contrast, mortality rates for extrahepatic biliary tract malignancies showed a decreasing trend in most countries, with an overall average EAPC of -0.3 ± 0.4 for males, but -1.3 ± 0.4 for females. CONCLUSIONS: There has been a marked global increase in mortality from intrahepatic, but not extra-hepatic, biliary tract malignancies

Benchmark performance of low-cost Sb2Se3 photocathodes for unassisted solar overall water splitting

Determining cost-effective semiconductors exhibiting desirable properties for commercial photoelectrochemical water splitting remains a challenge. Herein, we report a Sb2Se3 semiconductor that satisfies most requirements for an ideal high-performance photoelectrode, including a small band gap and favourable cost, optoelectronic properties, processability, and photocorrosion stability. Strong anisotropy, a major issue for Sb2Se3, is resolved by suppressing growth kinetics via close space sublimation to obtain high-quality compact thin films with favourable crystallographic orientation. The Sb2Se3 photocathode exhibits a high photocurrent density of almost 30mAcm(-2) at 0V against the reversible hydrogen electrode, the highest value so far. We demonstrate unassisted solar overall water splitting by combining the optimised Sb2Se3 photocathode with a BiVO4 photoanode, achieving a solar-to-hydrogen efficiency of 1.5% with stability over 10h under simulated 1 sun conditions employing a broad range of solar fluxes. Low-cost Sb2Se3 can thus be an attractive breakthrough material for commercial solar fuel production. While photoelectrochemical water splitting offers an integrated means to convert sunlight to a renewable fuel, cost-effective light-absorbers are rare. Here, authors report Sb2Se3 photocathodes for high-performance photoelectrochemical water splitting devices

Experimental observation of the optical spin-orbit torque

Spin polarized carriers electrically injected into a magnet from an external polarizer can exert a spin transfer torque (STT) on the magnetization. The phe- nomenon belongs to the area of spintronics research focusing on manipulating magnetic moments by electric fields and is the basis of the emerging technologies for scalable magnetoresistive random access memories. In our previous work we have reported experimental observation of the optical counterpart of STT in which a circularly polarized pump laser pulse acts as the external polarizer, allowing to study and utilize the phenomenon on several orders of magnitude shorter timescales than in the electric current induced STT. Recently it has been theoretically proposed and experimentally demonstrated that in the absence of an external polarizer, carriers in a magnet under applied electric field can develop a non-equilibrium spin polarization due to the relativistic spin-orbit coupling, resulting in a current induced spin-orbit torque (SOT) acting on the magnetization. In this paper we report the observation of the optical counterpart of SOT. At picosecond time-scales, we detect excitations of magnetization of a ferromagnetic semiconductor (Ga,Mn)As which are independent of the polarization of the pump laser pulses and are induced by non-equilibrium spin-orbit coupled photo-holes.Comment: 4 figure, supplementary information. arXiv admin note: text overlap with arXiv:1101.104

Neutrophils Are Resistant to Yersinia YopJ/P-Induced Apoptosis and Are Protected from ROS-Mediated Cell Death by the Type III Secretion System

The human innate immune system relies on the coordinated activity of macrophages and polymorphonuclear leukocytes (neutrophils or PMNs) for defense against bacterial pathogens. Yersinia spp. subvert the innate immune response to cause disease in humans. In particular, the Yersinia outer protein YopJ (Y. pestis and Y. pseudotuberculosis) and YopP (Y. enterocolitica) rapidly induce apoptosis in murine macrophages and dendritic cells. However, the effects of Yersinia Yop J/P on neutrophil fate are not clearly defined.In this study, we utilized wild-type and mutant strains of Yersinia to test the contribution of YopJ and YopP on induction of apoptosis in human monocyte-derived macrophages (HMDM) and neutrophils. Whereas YopJ and YopP similarly induced apoptosis in HMDMs, interaction of human neutrophils with virulence plasmid-containing Yersinia did not result in PMN caspase activation, release of LDH, or loss of membrane integrity greater than PMN controls. In contrast, interaction of human PMNs with the virulence plasmid-deficient Y. pestis strain KIM6 resulted in increased surface exposure of phosphatidylserine (PS) and cell death. PMN reactive oxygen species (ROS) production was inhibited in a virulence plasmid-dependent but YopJ/YopP-independent manner. Following phagocytic interaction with Y. pestis strain KIM6, inhibition of PMN ROS production with diphenyleneiodonium chloride resulted in a reduction of PMN cell death similar to that induced by the virulence plasmid-containing strain Y. pestis KIM5.Our findings showed that Yersinia YopJ and/or YopP did not induce pronounced apoptosis in human neutrophils. Furthermore, robust PMN ROS production in response to virulence plasmid-deficient Yersinia was associated with increased PMN cell death, suggesting that Yersinia inhibition of PMN ROS production plays a role in evasion of the human innate immune response in part by limiting PMN apoptosis

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study

<p>Abstract</p> <p>Background</p> <p>To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs).</p> <p>Methods</p> <p>A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in <it>GSTP1</it>, and deletions in <it>GST-M1 </it>and <it>GST-T1</it>. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.</p> <p>Results</p> <p>All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either <it>GSTP1-AG </it>or <it>GSTP1</it>-<it>AA</it>, the 37 TCSs with the genotype <it>GSTP1-GG</it>, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]).</p> <p>Conclusion</p> <p>In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in <it>GSTP1 </it>and <it>GSTM1</it>. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.</p

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day−1 of cimetidine orally together with 200 mg day−1 of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sLx) and A (sLa). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sLx and sLa antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sLx, of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sLx and sLa