Cosmic-ray ionization of molecular clouds

Low-energy cosmic rays are a fundamental source of ionization for molecular clouds, influencing their chemical, thermal and dynamical evolution. The purpose of this work is to explore the possibility that a low-energy component of cosmic-rays, not directly measurable from the Earth, can account for the discrepancy between the ionization rate measured in diffuse and dense interstellar clouds. We collect the most recent experimental and theoretical data on the cross sections for the production of H2+ and He+ by electron and proton impact, and we discuss the available constraints on the cosmic-ray fluxes in the local interstellar medium. Starting from different extrapolations at low energies of the demodulated cosmic-ray proton and electron spectra, we compute the propagated spectra in molecular clouds in the continuous slowing-down approximation taking into account all the relevant energy loss processes. The theoretical value of the cosmic-ray ionization rate as a function of the column density of traversed matter is in agreement with the observational data only if either the flux of cosmic-ray electrons or of protons increases at low energies. The most successful models are characterized by a significant (or even dominant) contribution of the electron component to the ionization rate, in agreement with previous suggestions. However, the large spread of cosmic-ray ionization rates inferred from chemical models of molecular cloud cores remains to be explained. Available data combined with simple propagation models support the existence of a low-energy component (below about 100 MeV) of cosmic-ray electrons or protons responsible for the ionization of molecular cloud cores and dense protostellar envelopes.Comment: 14 pages, 15 figure

Doublet Pulse Coherent Laser Radar for Tracking of Resident Space Objects

In this paper, the development of a long range ladar system known as ExoSPEAR at NASA Langley Research Center for tracking rapidly moving resident space objects is discussed. Based on 100 W, nanosecond class, near-IR laser, this ladar system with coherent detection technique is currently being investigated for short dwell time measurements of resident space objects (RSOs) in LEO and beyond for space surveillance applications. This unique ladar architecture is configured using a continuously agile doublet-pulse waveform scheme coupled to a closed-loop tracking and control loop approach to simultaneously achieve mm class range precision and mm/s velocity precision and hence obtain unprecedented track accuracies. Salient features of the design architecture followed by performance modeling and engagement simulations illustrating the dependence of range and velocity precision in LEO orbits on ladar parameters are presented. Estimated limits on detectable optical cross sections of RSOs in LEO orbits are discussed

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Cardiovascular disease risk prediction using automated machine learning: A prospective study of 423,604 UK Biobank participants.

BACKGROUND: Identifying people at risk of cardiovascular diseases (CVD) is a cornerstone of preventative cardiology. Risk prediction models currently recommended by clinical guidelines are typically based on a limited number of predictors with sub-optimal performance across all patient groups. Data-driven techniques based on machine learning (ML) might improve the performance of risk predictions by agnostically discovering novel risk predictors and learning the complex interactions between them. We tested (1) whether ML techniques based on a state-of-the-art automated ML framework (AutoPrognosis) could improve CVD risk prediction compared to traditional approaches, and (2) whether considering non-traditional variables could increase the accuracy of CVD risk predictions. METHODS AND FINDINGS: Using data on 423,604 participants without CVD at baseline in UK Biobank, we developed a ML-based model for predicting CVD risk based on 473 available variables. Our ML-based model was derived using AutoPrognosis, an algorithmic tool that automatically selects and tunes ensembles of ML modeling pipelines (comprising data imputation, feature processing, classification and calibration algorithms). We compared our model with a well-established risk prediction algorithm based on conventional CVD risk factors (Framingham score), a Cox proportional hazards (PH) model based on familiar risk factors (i.e, age, gender, smoking status, systolic blood pressure, history of diabetes, reception of treatments for hypertension and body mass index), and a Cox PH model based on all of the 473 available variables. Predictive performances were assessed using area under the receiver operating characteristic curve (AUC-ROC). Overall, our AutoPrognosis model improved risk prediction (AUC-ROC: 0.774, 95% CI: 0.768-0.780) compared to Framingham score (AUC-ROC: 0.724, 95% CI: 0.720-0.728, p < 0.001), Cox PH model with conventional risk factors (AUC-ROC: 0.734, 95% CI: 0.729-0.739, p < 0.001), and Cox PH model with all UK Biobank variables (AUC-ROC: 0.758, 95% CI: 0.753-0.763, p < 0.001). Out of 4,801 CVD cases recorded within 5 years of baseline, AutoPrognosis was able to correctly predict 368 more cases compared to the Framingham score. Our AutoPrognosis model included predictors that are not usually considered in existing risk prediction models, such as the individuals' usual walking pace and their self-reported overall health rating. Furthermore, our model improved risk prediction in potentially relevant sub-populations, such as in individuals with history of diabetes. We also highlight the relative benefits accrued from including more information into a predictive model (information gain) as compared to the benefits of using more complex models (modeling gain). CONCLUSIONS: Our AutoPrognosis model improves the accuracy of CVD risk prediction in the UK Biobank population. This approach performs well in traditionally poorly served patient subgroups. Additionally, AutoPrognosis uncovered novel predictors for CVD disease that may now be tested in prospective studies. We found that the "information gain" achieved by considering more risk factors in the predictive model was significantly higher than the "modeling gain" achieved by adopting complex predictive models

Glycogen synthase kinase 3 (GSK-3) inactivation compensates for the lack of CD28 in the priming of CD8+ cytotoxic T-cells: implications for anti-PD-1 immunotherapy

The rescue of exhausted CD8+ cytolytic T-cells (CTLs) by anti-PD-1 blockade has been found to require CD28 expression. At the same time, we have shown that the inactivation of the serine/threonine kinase GSK‐3α/β with small interfering RNAs (siRNAs) and small molecule inhibitors (SMIs) specifically down-regulate PD-1 expression for enhanced CD8+ CTL function and clearance of tumours and viral infections.  Despite this, it has been unclear whether the GSK‐3α/β pathway accounts for CD28 co‐stimulation of CD8+ CTL function.  In this paper, we show that inactivation of GSK‐3α/β through siRNA or by SMIs during priming can substitute CD28 stimulation in the potentiation of cytotoxic CD8+ CTL function. This increased response was observed in the blockade of CD28 co-receptor by CTLA-4-IgG in OT-1 T-cells responding to OVA peptide as presented by the lymphoma cell line EL4. The effect was seen using several GSK-3 SMIs, and was accompanied by an increase in Lamp-1 and GZMB expression. Conversely, CD28 crosslinking obviated the need for GSK‐3α/β inhibition in its enhancement of CTL function.  Our findings support a model where GSK‐3 is the central co-signal for CD28 priming of CD8+ CTLs in anti-PD-1 immunotherapy

Balmer-Dominated Shocks: A Concise Review

A concise and critical review of Balmer-dominated shocks (BDSs) is presented, summarizing the state of theory and observations, including models with/without shock precursors and their synergy with atomic physics. Observations of BDSs in supernova remnants are reviewed on an object-by-object basis. The relevance of BDSs towards understanding the acceleration of cosmic rays in shocks is emphasized. Probable and possible detections of BDSs in astrophysical objects other than supernova remnants, including pulsar wind nebulae and high-redshift galaxies, are described. The case for the continued future of studying BDSs in astrophysics is made, including their relevance towards understanding electron-ion temperature equilibration in collisionless shocks.Comment: 20 pages, 7 figures (double-columned, font size 10). Accepted by PASA. Incorporates two rounds of comments by the refere

Weak lensing reconstruction through cosmic magnification I: a minimal variance map reconstruction

We present a concept study on weak lensing map reconstruction through the cosmic magnification effect in galaxy number density distribution. We propose a minimal variance linear estimator to minimize both the dominant systematical and statistical errors in the map reconstruction. It utilizes the distinctively different flux dependences to separate the cosmic magnification signal from the overwhelming galaxy intrinsic clustering noise. It also minimizes the shot noise error by an optimal weighting scheme on the galaxy number density in each flux bin. Our method is in principle applicable to all galaxy surveys with reasonable redshift information. We demonstrate its applicability against the planned Square Kilometer Array survey, under simplified conditions. Weak lensing maps reconstructed through our method are complementary to that from cosmic shear and CMB and 21cm lensing. They are useful for cross checking over systematical errors in weak lensing reconstruction and for improving cosmological constraints.Comment: 12 pages, 9 figures, published in MNRA

Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39).

Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of 'nausea' in ferrets. Cisplatin induced 37.2 ± 2.3 and 59.0 ± 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased (P<0.05) the dominant frequency of gastric myoelectric activity from 9.4 ± 0.1 to 10.4 ± 0.41 cpm and decreased the dominant power (DP) during acute emesis; there was a reduction in the % power of normogastria and an increase in the % power of tachygastria; food and water intake was reduced. DP decreased further during delayed emesis, where normogastria predominated. Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to 'sympathetic dominance'. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % (P<0.05) and antagonised the hypothermic response (P<0.05); systolic, diastolic and mean arterial BP increased during the delayed phase. In conclusion, blocking GLP-1 receptors in the brain reduces cisplatin-induced acute but not delayed emesis. Restoring power and structure to slow waves may represent a novel approach to treat the side effects of chemotherapy