The Askaryan Radio Array (ARA) is an ultra-high energy (>1017eV) cosmic neutrino detector in phased construction near the south pole. ARA searches for radio Cherenkov emission from particle cascades ...induced by neutrino interactions in the ice using radio frequency antennas (∼150-800MHz) deployed at a design depth of 200m in the Antarctic ice. A prototype ARA Testbed station was deployed at ∼30m depth in the 2010–2011 season and the first three full ARA stations were deployed in the 2011–2012 and 2012–2013 seasons. We present the first neutrino search with ARA using data taken in 2011 and 2012 with the ARA Testbed and the resulting constraints on the neutrino flux from 1017-1021eV.
The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the ...transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components.
The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying ...cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients 71 Alzheimer’s disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ
42
, total, and phosphorylated tau
181
were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14–17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses.
Abaloparatide is a 34–amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal ...osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE.
Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites.
At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds.
In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.
•Significantly more abaloparatide patients were all-site BMD responders versus placebo or teriparatide•At each individual anatomic site, there were significantly more abaloparatide BMD responders versus placebo•For TH, there were significantly more abaloparatide BMD responders for each threshold and timepoint versus teriparatide•For FN, at all timepoints, significantly more abaloparatide patients were >3% and >6% responders versus teriparatide•Results are consistent with the early nonvertebral fracture risk reduction with abaloparatide observed in ACTIVE
To assess the performance of diffusion-relaxation correlation spectrum imaging (DR-CSI) in the characterization of parotid gland tumors.
Twenty-five pleomorphic adenomas (PA) patients, 9 Warthin's ...tumors (WT) patients and 7 malignant tumors (MT) patients were prospectively recruited. DR-CSI (7 b-values combined with 5 TEs, totally 35 diffusion-weighted images) was scanned for pre-treatment assessment. Diffusion (D)-T2 signal spectrum summating all voxels were built for each patient, characterized by D-axis with range 0∼5 × 10−3 mm2/s, and T2-axis with range 0∼300ms. With boundaries of 0.5 and 2.5 × 10−3 mm2/s for D, all spectra were divided into three compartments labeled A (low D), B (mediate D) and C (high D). Volume fractions acquired from each compartment (VA, VB, VC) were compared among PA, WT and MT. Diagnostic performance was assessed using receiver operating characteristic analysis and area under the curve (AUC).
Each subtype of parotid tumors had their specific D-T2 spectrum. PA showed significantly lower VA (8.85 ± 4.77% vs 20.68 ± 10.85%), higher VB (63.40 ± 8.18% vs 43.05 ± 7.16%), and lower VC (27.75 ± 8.51% vs 36.27 ± 11.09) than WT (all p<0.05). VB showed optimal diagnostic performance (AUC 0.969, sensitivity 92.00%, specificity 100.00%). MT showed significantly higher VA (21.23 ± 12.36%), lower VB (37.09 ± 6.43%), and higher VC (41.68 ± 13.72%) than PA (all p<0.05). Similarly, VB showed optimal diagnostic performance (AUC 0.994, sensitivity 96.00%, specificity 100.00%). No significant difference of VA, VB and VC was found between WT and MT.
DR-CSI might be a promising and non-invasive way for characterizing parotid gland tumors.
•DR-CSI can be used to characterize the parotid gland tumors successfully.•Each subtype of parotid tumors has specific D-T2 spectrum.•Compartment volume fractions show higher diagnostic performance than conventional ADC.
Abstract In our previous study, we found that the sonic hedgehog (Shh) signaling pathway is activated in neurons under oxidative stress and plays a neuro-protective role Dai RL, et al. (2011) ...Neurochem Res 36:67–75; we are led to postulate that the Shh might be released by astrocytes, thereby protecting neurons against oxidant injury. In primary cultured astrocytes of rats, we found that treatment with 100 μM H 2 O 2 for 24 h induced a significant increase in the mRNA and protein levels of Shh, Patched1, and Gli-1, and the increase was substantially greater in astrocytes than in neurons. In the coculture systems of astrocytes and neurons under the H 2 O 2 treatment, blocking the Shh signaling pathway with 5E1 (an antibody against the N-terminal domain of Shh) could block the neuroprotective activity of astrocytes on cocultured neurons. In this study, we found that treatment with H 2 O 2 (100–800 μM) for 24 h caused cell death of astrocytes in a concentration-dependent manner. MTT reduction and Trypan Blue exclusion assay showed that exogenous Shh increased survival rate of the H 2 O 2 -treated astrocytes, whereas pretreatment with cyclopamine (a specific inhibitor of the Shh signaling pathway) or 5E1 decreased the survival rate of the H 2 O 2 -treated astrocytes. Shh also inhibited H 2 O 2 -induced apoptosis of astrocytes, and this effect could be partially reversed by cyclopamine. We also found that Shh promoted the phosphorylation of AKT, but had no significant effect on p38 or extracellular signal regulated kinases 1 and 2 (ERK 1/2) in H 2 O 2 -treated astrocytes. Blocking Shh or phosphoinositide 3-kinases (PI3-K)/AKT signaling pathway with cyclopamine or LY294002 decreased the survival rate of astrocytes, induced cell apoptosis, upregulated the expression of Bax, and downregulated the expression of Bcl-2. We are led to conclude that the oxidative stress induces astrocytes to secrete endogenous Shh and exogenous administration of Shh might protect the astrocytes from oxidative stress by activating PI3-K/AKT/Bcl-2 pathway.
Background Males have a higher incidence of bladder cancer than females, but the reason remains unknown. Unlike prostate cancer, human bladder cancer is not generally considered to be dependent on ...hormone activity. We investigated the possible involvement of androgens and the androgen receptor (AR) in bladder cancer. Methods We used N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) to induce bladder cancer in wild-type male and female mice, with and without castration in males, and in AR knockout (ARKO) male and female mice, with and without dihydrotestosterone (DHT) supplementation in males. We also treated human bladder cancer cell lines, including TCC-SUP and UMUC3, and mouse xenograft models established from these same lines with androgen deprivation therapy (antiandrogen treatment or castration), AR–small-interfering RNA (AR-siRNA), or the anti-AR molecule ASC-J9, which causes selective degradation of the AR. Results More than 92% of wild-type male and 42% of wild-type female mice treated with BBN eventually developed bladder cancer, whereas none of the male or female ARKO mice did. Treatment with BBN induced bladder cancer in 25% of ARKO mice supplemented with DHT and in 50% of castrated wild-type male mice. Androgen deprivation of AR-positive human bladder cancer cells by androgen depletion in vitro or castration in mice and/or by treatment with the antiandrogen flutamide in vitro or in vivo, as well as AR knockdown by AR-siRNA or by ASC-J9, suppressed cell proliferation in vitro and xenograft tumor growth in vivo. Conclusions Our findings implicate the involvement of both androgens and the AR in bladder cancer. Targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for bladder cancer.
Black carbon (BC) aerosol at high altitudes of the Qinghai–Tibetan Plateau has potential effects on the regional climate and hydrological cycle. An intensive measurement campaign was conducted at ...Qinghai Lake (~ 3200 m above sea level) at the edge of the northeastern Qinghai–Tibetan Plateau during winter using a ground-based single particle soot photometer (SP2) and a photoacoustic extinctiometer (PAX). The average concentration of refractory BC (rBC) and number fraction of coated rBC were found to be 160 ± 190 ng m−3 and 59 % for the entire campaign, respectively. Significant enhancements of rBC loadings and number fraction of coated rBC were observed during a pollution episode, with an average value of 390 ng m−3 and 65 %, respectively. The mass size distribution of rBC particles showed log-normal distribution, with a peak diameter of ~ 187 nm regardless of the pollution level. Five-day backward trajectory analysis suggests that the air masses from north India contributed to the increased rBC loadings during the campaign. The potential source contribution function (PSCF) model combined with the fire counts map further proves that biomass burning from north India is an important potential source influencing the northeastern Qinghai–Tibetan Plateau during the pollution episode. The rBC mass absorption cross section (MACrBC) at λ = 532 nm was slightly larger in clean days (14.9 m2 g−1) than during the pollution episode (9.3 m2 g−1), likely due to the effects of brown carbon and the uncertainty of the MACrBC calculation. The MACrBC was positively correlated with number fraction of coated rBC during the pollution episode with an increasing rate of 0.18 (m2 g−1) %−1. The number fraction of coated rBC particles showed positive correlation with light absorption, suggesting that the increase of coated rBC particles will enhance the light absorption. Compared to rBC mass concentration, rBC mixing sate is more important in determining absorption during the pollution episode, estimated from the same percentage-wise increment of either rBC mass concentration or the number fraction of coated rBC. The estimated BC direct radiative forcing was +0.93 W m−2 for the pollution episode, which is 2 times larger than that in clean days. Our study provides insight into the potential climatic impacts of rBC aerosol transported to the Qinghai–Tibetan Plateau from south Asian regions, and is also useful for future modeling studies.
Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases (HDAC) are important regulators to maintain chromatin ...structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, especially under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addition to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells. Using genetic and pharmacological approaches, we show that HDAC3 contributes to chemotherapy resistance by regulating the activation of AKT, a well-documented factor in drug resistance development. HDAC3 binds to AKT and deacetylates it at the site Lys20, thereby promoting the phosphorylation of AKT. Chemotherapy drug exposure enhances the interaction between HDAC3 and AKT, resulting in decrease in AKT acetylation and increase in AKT phosphorylation. Whereas HDAC3 depletion or inhibition abrogates these responses and meanwhile sensitizes leukemia cells to chemotoxicity-induced apoptosis. Importantly, in vivo HDAC3 suppression reduces leukemia progression and sensitizes MLL-AF9
leukemia to chemotherapy. Our findings suggest that combination therapy with HDAC3 inhibitor and genotoxic agents may constitute a successful strategy for overcoming chemotherapy resistance.
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