Primary cosmic-ray elemental spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass (CREAM) experiment since 2004. The third CREAM payload (CREAM-III) flew for 29 days ...during the 2007-2008 Antarctic season. Energies of incident particles above 1 TeV are measured with a calorimeter. Individual elements are clearly separated with a charge resolution of ∼0.12 e (in charge units) and ∼0.14 e for protons and helium nuclei, respectively, using two layers of silicon charge detectors. The measured proton and helium energy spectra at the top of the atmosphere are harder than other existing measurements at a few tens of GeV. The relative abundance of protons to helium nuclei is 9.53 0.03 for the range of 1 TeV/n to 63 TeV/n. This ratio is considerably smaller than other measurements at a few tens of GeV/n. The spectra become softer above ∼20 TeV. However, our statistical uncertainties are large at these energies and more data are needed.
BACKGROUND AND PURPOSE Kaempferol, a dietary flavonoid and phyto‐oestrogen, is known to have anti‐inflammatory properties. Microglial activation has been implicated in various neurodegenerative ...diseases. Anti‐inflammatory effects of kaempferol and the underlying mechanisms were investigated by using LPS‐stimulated microglial BV2 cells.
EXPERIMENTAL APPROACH Cell viability was measured using MTT and neutral red assays. elisa, Western blot, immunocytochemistry and electrophoretic mobility‐shift assay were used to analyse NO, PGE2, TNF‐α and IL‐1β production, inducible NOS (iNOS), COX‐2 expression and the involvement of signalling pathways such as toll‐like receptor‐4 (TLR4), MAPK cascades, PKB (AKT) and NF‐κB. Accumulation of reaction oxygen species (ROS) was measured by nitroblue tetrazolium and 2′7′‐dichlorofluorescein diacetate assay. Matrix metalloproteinase activity was investigated by zymography and immunoblot assay. Phagocytotic activity was assessed by use of latex beads.
KEY RESULTS Kaempferol significantly attenuated LPS‐induced NO, PGE2, TNF‐α, IL‐1β and ROS production and phagocytosis in a concentration‐dependent manner. Kaempferol suppressed the expression of iNOS, COX‐2, MMP‐3 and blocked the TLR4 activation. Moreover, kaempferol inhibited LPS‐induced NF‐κB activation and p38 MAPK, JNK and AKT phosphorylation.
CONCLUSION AND IMPLICATIONS Kaempferol was able to reduce LPS‐induced inflammatory mediators through the down‐regulation of TLR4, NF‐κB, p38 MAPK, JNK and AKT suggesting that kaempferol has therapeutic potential for the treatment of neuroinflammatory diseases.
Aim
We isolated Lactobacillus brevis G‐101 from kimchi lactic acid bacteria (LAB) strains, which induced IL‐10 expression in lipopolysaccharide (LPS)‐stimulated peritoneal macrophages. To evaluate ...the inflammatory effect of G‐101, we examined its inhibitory effect in 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitic mice.
Materials and Results
The colitic mice were prepared by intrarectal injection of TNBS. We measured intestinal mucosal cytokines by enzyme‐linked immunosorbent assay; activation of transcription factors, by immunoblotting; and macrophage polarization markers, by real‐time polymerase chain reaction. Of 200 LAB strains tested, Lact. brevis G‐101 showed most potent activity for induction of IL‐10 expression in LPS‐stimulated peritoneal macrophages. However, it significantly inhibited the expression of TNF‐α, IL‐1β and IL‐6 and the phosphorylation of IRAK1 and AKT, and activated NF‐κB and MAPKs. Treatment with TNBS caused colon shortening; increased myeloperoxidase activity; and increased IL‐1β, IL‐6 and TNF‐α expression in mice. Oral administration of Lact. brevis G‐101 significantly inhibited these activities. Lactobacillus brevis G‐101 inhibited TNBS‐induced IRAK‐1 phosphorylation and NF‐κB activation, as well as the expression of COX‐2 and iNOS. Lactobacillus brevis G‐101 inhibited the expression of M1 macrophage markers, but increased the expression of M2 macrophages in the colons of TNBS‐treated mice.
Conclusions
Lactobacillus brevis G‐101 may improve colitis by inhibiting the IRAK1/NF‐κB, MAPK and AKT pathways and by polarizing M1 macrophages to M2‐like macrophages.
Significance and Impact of the Study
These results suggest that IL‐10 expression‐inducing LAB can ameliorate colitis by inhibiting NF‐κB activation and macrophage polarization.
Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig‐to‐nonhuman primate (NHP) model has not been ...demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen‐free (DPF) miniature pigs and infused intraportally into streptozotocin‐induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti‐thymocyte globulin (ATG) induction and maintenance with anti‐CD154 monoclonal antibody and low‐dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90–110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow‐up period showed excellent glucose disposal capacity and porcine C‐peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.
The authors report control of diabetes for longer than six months in four consecutive nonhuman primates by the transplantation of adult pig islets using a modest immunosuppressive regimen with an acceptable adverse effect profile.
A new object tracking mask-based novel-look-up-table (OTM-NLUT) method is proposed and implemented on graphics-processing-units (GPUs) for real-time generation of holographic videos of ...three-dimensional (3-D) scenes. Since the proposed method is designed to be matched with software and memory structures of the GPU, the number of compute-unified-device-architecture (CUDA) kernel function calls and the computer-generated hologram (CGH) buffer size of the proposed method have been significantly reduced. It therefore results in a great increase of the computational speed of the proposed method and enables real-time generation of CGH patterns of 3-D scenes. Experimental results show that the proposed method can generate 31.1 frames of Fresnel CGH patterns with 1,920 × 1,080 pixels per second, on average, for three test 3-D video scenarios with 12,666 object points on three GPU boards of NVIDIA GTX TITAN, and confirm the feasibility of the proposed method in the practical application of electro-holographic 3-D displays.
Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin ...sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.
Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden ...of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3′,5′‐cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off‐the‐shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity.
Clinical Pharmacology & Therapeutics (2013); 95 1, 53–66 advance online publication 13 November 2013. doi:10.1038/clpt.2013.204
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA).
...We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. (123)IN-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ((123)IFP-CIT) SPECT was done in the patients with SNCA multiplication and their family members.
Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. (123)IFP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers.
SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.
To investigate the role of spinocerebellar ataxia type 17 (SCA17) in the development of parkinsonism.
We screened 1,155 parkinsonian patients (931 with Parkinson disease and 224 with multiple system ...atrophy) and 400 normal subjects for SCA17. 99mTc-TRODAT-1 SPECT was used to evaluate the striatal dopamine transporter (DAT) status.
Trinucleotide expansion in the SCA17 gene was found in 10 parkinsonian patients (8 with Parkinson disease, 2 with multiple system atrophy) using 42 repeats as an upper normal limit. The repeat sizes in the patients ranged from 43 to 46, which are considered to be low-range expansions. All patients had interrupted sequences. Three probands and three asymptomatic carriers underwent 99mTc-TRODAT-1 SPECT. Striatal DAT binding was markedly reduced in all probands and mildly decreased in one asymptomatic carrier. Among the 400 normal control subjects, there was one individual with an expansion of 44 repeats, another with 43 repeats, and two with 42 repeats. Striatal DAT binding was decreased not only in the control subjects with 44 or 43 repeats, but in ones with 42 repeats, suggesting that an expansion as low as 42 repeats might constitute a susceptibility gene for parkinsonism.
Low-range expansion of the SCA17 gene is not a rare genetic cause of parkinsonism without ataxia in our population. Reduced penetrance or variable expressivity in low-range expansion might be an explanation for the blurred cutoff point for normal expansion in SCA17.
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