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Trismus/reduced mouth opening (RMO) is a common side effect of radiotherapy (RT) for head and neck cancer (HNC). The objective was to measure RMO, identify risk factors for RMO, and determine its impact on quality of life (QOL). OraRad is an observational, prospective, multicenter cohort study of patients receiving curative intent RT for HNC. Interincisal mouth opening measurements (n = 565) and patient-reported outcomes were recorded before RT and every 6 months for 2 years. Linear mixed-effects models were used to evaluate change in mouth opening and assess the relationship between trismus history and change in QOL measures. Interincisal distance decreased from a mean (SE) of 45.1 (0.42) mm at baseline to 42.2 (0.44) at 6 months, with slight recovery at 18 months (43.3, 0.46 mm) but no additional improvement by 24 months. The odds of trismus (opening <35 mm) were significantly higher at 6 months (odds ratio [OR] = 2.21, 95% CI: 1.30 to 3.76) and 12 months (OR = 1.87, 95% CI: 1.08 to 3.25) compared with baseline. Females were more likely to experience trismus at baseline and during follow-up (P <.01). Patients with oral cavity cancer had the highest risk for trismus at baseline and post-RT (P <.01). RMO was associated with higher RT dose to the primary site and receiving concomitant chemotherapy (P <.01). Trismus was associated with self-reported difficulty opening the mouth and dry mouth (P <.01). A decrease in mouth opening is a common treatment-related toxicity after RT, with some recovery by 18 months. Trismus has a significant impact on survivor QOL. [ABSTRACT FROM AUTHOR]

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine-enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine-enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of L-serine supplementation as a first treatment option for this disorder., Introduction Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is caused by several missense mutations in the SPTLC1 and SPTLC2 genes, which encode 2 of 3 subunits of the enzyme [...]

Objective: The aim of this study was to examine effects of radiation therapy (RT) for head and neck cancer (HNC) on periodontal disease and relationships to caries.Study Design: A multicenter prospective observational cohort study (OraRad) was conducted in patients undergoing RT for HNC. Assessments were conducted by calibrated examiners at the pre-RT (baseline) visit (n = 533), the 12-month visit (n = 414), and the 24-month visit (n = 365).Results: The average whole mouth mean (standard error (SE)) distance from the cementoenamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43 (0.04) mm at baseline to 0.24 (0.04) mm at 12 months and 0.11 (0.04) mm at 24 months (P ≤ .001). Whole mouth mean (SE) percentage of sites with CEJ-GM distance of <0 mm increased significantly from 23.3% (1.0%) at baseline to 28.5% (1.0%) at 12 months and 30.5% (1.1%) at 24 months (P ≤ .02). Higher mean radiation dose to the mandible was associated with a greater increase in the percentage of mandibular sites with CEJ-GM distance of <0 mm (P = .003). Both mean CEJ-GM distance and the percentage of sites with a CEJ-GM distance <0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (P < .001), with greater gingival recession associated with increased caries.Conclusions: RT for HNC leads to mandibular gingival recession in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients. [ABSTRACT FROM AUTHOR]

Abstract Background Genomic sequencing of SNPs is increasingly prevalent, though the amount of familial information these data contain has not been quantified. Methods We provide a framework for measuring the risk to siblings of a patient's SNP genotype disclosure, and demonstrate that sibling SNP genotypes can be inferred with substantial accuracy. Results Extending this inference technique, we determine that a very low number of matches at commonly varying SNPs is sufficient to confirm sib-ship, demonstrating that published sequence data can reliably be used to derive sibling identities. Using HapMap trio data, at SNPs where one child is homozygotic major, with a minor allele frequency ≤ 0.20, (N = 452684, 65.1%) we achieve 91.9% inference accuracy for sibling genotypes. Conclusion These findings demonstrate that substantial discrimination and privacy risks arise from use of inferred familial genomic data.

Tributaries provide spawning habitat for three of four major sub-stocks of Lake Erie walleye (Sander vitreus). Despite anthropogenic degradation and the extirpation of other potamodromous species, the Maumee River, Ohio, USA continues to support one of the largest fish migrations in the Laurentian Great Lakes. To determine if spawning habitat availability and quality could limit production of Maumee River walleye, two habitat suitability models were created for the lower 51 km of the Maumee River and the distribution and numbers of walleye eggs deposited in a 25 km stretch of river were assessed. Walleye eggs were collected using a diaphragm pump at 7 and 10 sites from March/April to May 2014 and 2015. The habitat suitability models showed that <3% of the river yielded 'good' walleye spawning habitat and 11–38% yielded 'moderate' walleye spawning habitat, depending on the model. However, a large set of rapids at river kilometer 28 and more than five river kilometers of less suitable habitat separated areas of 'good' habitat. The rapids may present a migratory barrier for many spawning walleye, as modeled water velocities exceed maximum estimated walleye swim speeds 71–100% of days during pre-spawn migration and spawning during the study period. In both study years, there was a sharp decline in mean egg numbers from spawning sites downstream of the rapids (439.7 eggs/2 min tow ± 990.6 SD) to upstream sites (5.9 eggs/2 min tow ± 19.4 SD). Physical barriers like rapids may reduce spawning habitat connectivity and could limit walleye production in the Maumee River. [ABSTRACT FROM AUTHOR]

The most luminous quasars at high-redshift harbour the fastest growing and most massive black holes in the early Universe. They are exceedingly rare and hard to find. Here, we present our search for the most luminous quasars in the redshift range from z = 4.5 to 5 using data from SkyMapper, Gaia , and WISE. We use colours to select likely high-redshift quasars and reduce the stellar contamination of the candidate set with parallax and proper motion data. In ∼12 500 deg2 of Southern sky, we find 92 candidates brighter than Rp = 18.2. Spectroscopic follow-up has revealed 21 quasars at z ≥ 4 (16 of which are within z = [4.5, 5]), as well as several red quasars, Broad-Absorption-Line (BAL) quasars and objects with unusual spectra, which we tentatively label OFeLoBALQSOs at redshifts of z ≈ 1 to 2. This work lifts the number of known bright z ≥ 4.5 quasars in the Southern hemisphere from 10 to 26 and brings the total number of quasars known at Rp < 18.2 and z ≥ 4.5 to 42. [ABSTRACT FROM AUTHOR]

A typical Ia supernova model, a white dwarf, accumulates matter till it reaches the Chandrashekar Mass and explodes. This may be caused by helium detonation at the surface due to the accretion of materials rich in hydrogen, which would burn in helium to form an explosive layer ignited by the carbon-oxygen core. Two-dimensional hydrodynamic models show that helium explosion in the interface between layers rich with helium and carbon results in a second explosion in the core. The SN1991bg indicates that the mass of the white dwarf is low and that its companion star is nondegenerate.

The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots. [ABSTRACT FROM AUTHOR]

G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Presently, a>3σ tension exists between values of the Hubble constant H0 derived from analysis of fluctuations in the cosmic microwave background by Planck, and local measurements of the expansion using calibrators of Type Ia supernovae (SNe Ia). We perform a blinded reanalysis of Riess et al. (2011) to measure H0 from low-redshift SNe Ia, calibrated by Cepheid variables and geometric distances including to NGC 4258. This paper is a demonstration of techniques to be applied to the Riess et al. (2016) data. Our end-to-end analysis starts from available Harvard -Smithsonian Center for Astrophysics (CfA3) and Lick Observatory Supernova Search (LOSS) photometries, providing an independent validation of Riess et al. (2011). We obscure the value of H0 throughout our analysis and the first stage of the referee process, because calibration of SNe Ia requires a series of often subtle choices, and the potential for results to be affected by human bias is significant. Our analysis departs from that of Riess et al. (2011) by incorporating the covariance matrix method adopted in Supernova Legacy Survey and Joint Lightcurve Analysis to quantify SN Ia systematics, and by including a simultaneous fit of all SN Ia and Cepheid data. We find H0 = 72.5 ± 3.1(stat) ± 0.77(sys) km s-1 Mpc-1 with a three-galaxy (NGC 4258+LMC+MW) anchor. The relative uncertainties are 4.3 per cent statistical, 1.1 per cent systematic, and 4.4 per cent total, larger than in Riess et al. (2011) (3.3 per cent total) and the Efstathiou (2014) re-analysis (3.4 per cent total). Our error budget for H0 is dominated by statistical errors due to the small size of the SN sample, whilst the systematic contribution is dominated by variation in the Cepheid fits, and for the SNe Ia, uncertainties in the host galaxy mass dependence and Malmquist bias. [ABSTRACT FROM AUTHOR]

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.Perspective: We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model. [ABSTRACT FROM AUTHOR]

The problem of classifying traffic flows in networks has become more and more important in recent times, and much research has been dedicated to it. In recent years, there has been a lot of interest in classifying traffic flows by application, based on the statistical features of each flow. Information about the applications that are being used on a network is very useful in network design, accounting, management, and security. In our previous work we proposed a classification algorithm for Internet traffic flow classification based on Artificial Immune Systems (AIS). We also applied the algorithm on an available data set, and found that the algorithm performed as well as other algorithms, and was insensitive to input parameters, which makes it valuable for embedded systems. It is also very simple to implement, and generalizes well from small training data sets. In this research, we expanded on the previous research by introducing several optimizations in the training and classification phases of the algorithm. We improved the design of the original algorithm in order to make it more predictable. We also give the asymptotic complexity of the optimized algorithm as well as draw a bound on the generalization error of the algorithm. Lastly, we also experimented with several different distance formulas to improve the classification performance. In this paper we have shown how the changes and optimizations applied to the original algorithm do not functionally change the original algorithm, while making its execution 50–60% faster. We also show that the classification accuracy of the Euclidian distance is superseded by the Manhattan distance for this application, giving 1–2% higher accuracy, making the accuracy of the algorithm comparable to that of a Naïve Bayes classifier in previous research that uses the same data set. [ABSTRACT FROM AUTHOR]

Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy initiative worked to develop the characteristics of an optimal diagnostic system. After the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (ie, bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (ie, chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability, and validity and extension to other cancer-related pain syndromes.Perspective: The ACTTION-APS chronic cancer pain taxonomy provides an evidence-based classification for 3 prevalent syndromes, namely malignant bone pain, pancreatic cancer pain, and chemotherapy-induced peripheral neuropathy. This taxonomy provides consistent diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms for these potentially serious cancer pain conditions that can be extended and applied with other cancer-related pain syndromes. [ABSTRACT FROM AUTHOR]

Cosmological models predict the oldest stars in the Galaxy should be found closest to the centre of the potential well, in the bulge. The Extremely Metal-poor BuLge stars with AAOmega survey (EMBLA) successfully searched for these old, metal-poor stars by making use of the distinctive SkyMapper photometric filters to discover candidate metal-poor stars in the bulge. Their metal-poor nature was then confirmed using the AAOmega spectrograph on the Anglo-Australian Telescope. Here we present an abundance analysis of 10 bulge stars with -2.8 < [Fe/H] < -1.7 from MIKE/Magellan observations, in total determining the abundances of 22 elements. Combining these results with our previous high-resolution data taken as part of the Gaia-ESO Survey, we have started to put together a picture of the chemical and kinematic nature of the most metal-poor stars in the bulge. The currently available kinematic data are consistent with the stars belonging to the bulge, although more accurate measurements are needed to constrain the stars' orbits. The chemistry of these bulge stars deviates from that found in halo stars of the same metallicity. Two notable differences are the absence of carbonenhanced metal-poor bulge stars, and the α element abundances exhibit a large intrinsic scatter and include stars which are underabundant in these typically enhanced elements. [ABSTRACT FROM AUTHOR]