ABSTRACT We report the first hard X-ray observations with NuSTAR of the BL Lac-type blazar PKS 2155-304, augmented with soft X-ray data from XMM-Newton and γ-ray data from the Fermi Large Area ...Telescope, obtained in 2013 April when the source was in a very low flux state. A joint NuSTAR and XMM spectrum, covering the energy range 0.5-60 keV, is best described by a model consisting of a log-parabola component with curvature and a (local) photon index 3.04 0.15 at photon energy of 2 keV, and a hard power-law tail with photon index 2.2 0.4. The hard X-ray tail can be smoothly joined to the quasi-simultaneous γ-ray spectrum by a synchrotron self-Compton component produced by an electron distribution with index p = 2.2. Assuming that the power-law electron distribution extends down to γmin = 1 and that there is one proton per electron, an unrealistically high total jet power of Lp ∼ 1047 erg s−1 is inferred. This can be reduced by two orders of magnitude either by considering a significant presence of electron-positron pairs with lepton-to-proton ratio , or by introducing an additional, low-energy break in the electron energy distribution at the electron Lorentz factor γbr1 ∼ 100. In either case, the jet composition is expected to be strongly matter-dominated.
Summary
We investigated the association between blood pressure variability measured by the coefficient of variation (CV) of blood pressure and hip fracture in older persons with diabetes. After ...excluding patients with acute complications and comorbidities, a positive association with similar magnitude of strength was found between BP variability and hip fracture, compared with that in the original analysis.
Introduction
Hypertension is a risk factor of osteoporosis and hip fracture, but studies have yet to investigate whether blood pressure variability measured by the CV of blood pressure can predict hip fracture in older persons with diabetes.
Methods
We conducted a retrospective cohort study on 21,160 patients who suffered from type 2 diabetes (age ≥ 50 years) and participated in the National Diabetes Care Management Program in Taiwan. The patients’ 1-year variability in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the baseline and subsequent hip fracture incidence for 8.2 years were analyzed.
Results
There were 937 recorded incident hip fractures. SBP-CV and DBP-CV were classified based on their tertiles. After multivariate adjustment was conducted, SBP-CV found to be a predictor of hip fracture, and its hazard ratio was 1.18 (95% CI 1.00–1.40) for the third tertile compared with the first tertile.
Conclusions
Our study suggests SBP stability is a predictor for hip fracture incidence in older persons with type 2 diabetes.
Current theories predict relativistic hadronic particle populations in clusters of galaxies in addition to the already observed relativistic leptons. In these scenarios hadronic interactions give ...rise to neutral pions which decay into gamma rays that are potentially observable with the Large Area Telescope (LAT) on board the Fermi space telescope. We present a joint likelihood analysis searching for spatially extended gamma-ray emission at the locations of 50 galaxy clusters in four years of Fermi-LAT data under the assumption of the universal cosmic-ray (CR) model proposed by Pinzke & Pfrommer. We find an excess at a significance of 2.7sigma, which upon closer inspection, however, is correlated to individual excess emission toward three galaxy clusters: A400, A1367, and A3112. We discuss these cases in detail and conservatively attribute the emission to unmodeled background systems (for example, radio galaxies within the clusters). Through the combined analysis of 50 clusters, we exclude hadronic injection efficiencies in simple hadronic models above 21% and establish limits on the CR to thermal pressure ratio within the virial radius, R sub(200), to be below 1.25%-1.4% depending on the morphological classification. In addition, we derive new limits on the gamma-ray flux from individual clusters in our sample.
Viral diseases have contributed significantly to worldwide morbidity and mortality throughout history. Despite the existence of therapeutic treatments for many viral infections, antiviral resistance ...and the threat posed by novel viruses highlight the need for an increased number of effective therapeutics. In addition to small molecule drugs and biologics, antimicrobial peptides (AMPs) represent an emerging class of potential antiviral therapeutics. While AMPs have traditionally been regarded in the context of their antibacterial activities, many AMPs are now known to be antiviral. These antiviral peptides (AVPs) have been shown to target and perturb viral membrane envelopes and inhibit various stages of the viral life cycle, from preattachment inhibition through viral release from infected host cells. Rational design of AMPs has also proven effective in identifying highly active and specific peptides and can aid in the discovery of lead peptides with high therapeutic selectivity. In this review, we highlight AVPs with strong antiviral activity largely curated from a publicly available AMP database. We then compile the sequences present in our AVP database to generate structural predictions of generic AVP motifs. Finally, we cover the rational design approaches available for AVPs taking into account approaches currently used for the rational design of AMPs.
The Large Area Telescope on board the Fermi satellite observed a gamma-ray flare in the Crab Nebula lasting for approximately nine days in April of 2011. The source, which at optical wavelengths has ...a size of approx =11 lt-yr across, doubled its gamma-ray flux within eight hours. The peak photon flux was (186 + or - 6) x 10 super(-7) cm super(-2) s super(-1) above 100 MeV, which corresponds to a 30-fold increase compared to the average value. During the flare, a new component emerged in the spectral energy distribution, which peaked at an energy of (375 + or - 26) MeV at flare maximum. The observations imply that the emission region was likely relativistically beamed toward us and that variations in its motion are responsible for the observed spectral variability.
Recent studies indicate that cancer stem cells (CSCs) exist in most hematological and solid tumors. CSCs are characterized by their ability to self-renew and their capacity to differentiate into the ...multitude of cells that comprise the tumor mass. Moreover, these cells have been shown to be intrinsically resistant to conventional anticancer therapies. Despite their fundamental role in cancer pathogenesis, the cellular origin of CSCs remains highly controversial. The aim of this study was to examine whether heterogeneous cancer cells can acquire stem cell-like properties in response to chemotherapy. We demonstrate that carboplatin can induce the self-renewal (spherogenesis) and pluripotency (Sox2 and Oct3/4 expression) of hepatocellular carcinoma (HCC) cells grown under stem cell culture conditions. Moreover, we show that non-CSC cells, obtained by side population flow cytometric sorting using Hoechst 33342, can acquire stem-like properties after exposure to carboplatin. Finally, we show that knockdown of Sox2 and Oct3/4 gene expression in HCC cells can reduce carboplatin-mediated increases in sphere formation and increase cellular sensitivity to chemotherapy. Taken together, our data indicate that bulk cancer cells may be an important source of CSCs during tumor development, and that targeting Sox2 and/or Oct3/4 may be a promising approach for targeting CSCs in clinical cancer treatment.
Aim
To examine the associations between continuous overlapping net glycaemic action (CONGA), percentage time in hyperglycaemia (%HG) or normoglycaemia (%NG) and peripheral nerve structure and ...function in type 1 diabetes.
Methods
Twenty‐seven participants with type 1 diabetes underwent continuous glucose monitoring followed by corneal confocal microscopy and nerve excitability assessments. CONGA, %HG (> 10.0 mmol/l) and %NG (3.9–10.0 mmol/l) were correlated against corneal nerve fibre length and density in the central cornea and inferior whorl region, corneal microneuromas, and a nerve excitability score while controlling for age, sex, diabetes duration and HbA1c.
Results
An increase in CONGA median 2.5 (2.0–3.1) mmol/l or %HG (mean 46 ± 18%) was associated with a worse nerve excitability score (r = –0.433, P = 0.036 and r = –0.670, P = 0.0012, respectively). By contrast, greater %NG (51 ± 17%) correlated with better nerve excitability scores (r = 0.672, P = 0.0011). Logistic regression revealed that increasing %HG increased the likelihood of abnormal nerve function odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01–1.23; P = 0.037). An increase in CONGA and %HG were associated with worsening nerve conduction measures, whereas longer %NG correlated with improved nerve conduction variables. CONGA and %HG were associated with inferior whorl corneal nerve fibre length (r = 0.483, P = 0.034 and r = 0.591, P = 0.021, respectively) and number of microneuromas (r = 0.433, P = 0.047 and r = 0.516, P = 0.020, respectively).
Conclusions
Short‐term measures of glucose control are associated with impaired nerve function and alterations in corneal nerve morphology.
What’s new?
Acute measures of glucose control have been associated with retinopathy and microalbuminuria, but their relationship with neuropathy requires exploration.
Greater glucose variability and percentage time above range was associated with worsening nerve function.
Higher percentage time in range was correlated with better nerve function.
Increasing glucose variability and time above range was associated with greater corneal nerve length in the inferior whorl and higher counts of microneuromas.
Monitoring of acute measures of glucose control may have more utility than HbA1c in the prevention of diabetic neuropathy.
RNA interference (RNAi) has become an indispensable technology for biomedical research and has demonstrated the potential to become a new class of therapeutic. Current RNAi technology in mammalian ...cells relies on short interfering RNA (siRNA) consisting of symmetrical duplexes of 19-21 base pairs (bp) with 3' overhangs. Here we report that asymmetric RNA duplexes with 3' and 5' antisense overhangs silence mammalian genes effectively. An asymmetric interfering RNA (aiRNA) of 15 bp was incorporated into the RNA-induced silencing complex (RISC) and mediated sequence-specific cleavage of the target mRNA between base 10 and 11 relative to the 5' end of the antisense strand. The gene silencing mediated by aiRNA was efficacious, durable and correlated with reduced off-target silencing by the sense strand. These results establish aiRNA as a scaffold structure for designing RNA duplexes to induce RNAi in mammalian cells.
Background and purpose
Large‐scale studies of utilization of medical services among patients with Alzheimer's disease (AD) are lacking. We aimed to investigate the usage of Western medicine and ...traditional Chinese medicine (TCM) among these patients in Taiwan.
Methods
We analyzed one million samples from the National Health Insurance Research Database in Taiwan. Patients (n = 1814) newly diagnosed with AD in 2001–2010 were divided into TCM users (n = 528) and non‐TCM users (n = 1286).
Results
Compared with non‐TCM users, TCM users were younger, had a higher female:male ratio and higher utilization rate of Western medicine. The median interval between diagnosis and the first TCM consultation was 7.92 months. Donepezil and rivastigmine were commonly prescribed medications. Chinese herbal medicine was the most popular treatment among TCM users.
Conclusions
This study revealed the specific usage patterns of TCM and non‐TCM medical services among patients with AD. The information could be used for improving the healthcare of patients with AD.
Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of ...organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.
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