Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Early Signal of Emerging Nuclear Collectivity in Neutron-Rich 129Sb

Radioactive 129Sb, which can be treated as a proton plus semimagic 128Sn core within the particle-core coupling scheme, was studied by Coulomb excitation. Reduced electric quadrupole transition probabilities, B(E2), for the 2+ ⊗ πg7=2 multiplet members and candidate πd5=2 state were measured. The results indicate that the total electric quadrupole strength of 129Sb is a factor of 1.39(11) larger than the 128Sn core, which is in stark contrast to the expectations of the empirically successful particle-core coupling scheme. Shell-model calculations performed with two different sets of nucleon-nucleon interactions suggest that this enhanced collectivity is due to constructive quadrupole coherence in the wave functions stemming from the proton-neutron residual interactions, where adding one nucleon to a core near a double-shell closure can have a pronounced effect. The enhanced electric quadrupole strength is an early signal of the emerging nuclear collectivity that becomes dominant away from the shell closure.The authors gratefully acknowledge the HRIBF operations staff for providing the beams used in this study and T. Papenbrock, A. Volya, and J. L. Wood for fruitful discussions. This material is based upon work supported by the U.S. Department of Energy (DOE), Office of Science, Office of Nuclear Physics, under Contract No. DE-AC05- 00OR22725, and this research used resources of the Holifield Radioactive Ion Beam Facility of Oak Ridge National Laboratory, which was a DOE Office of Science User Facility. This research was also sponsored by the Australian Research Council under Grants No. DP0773273 and No. DP170101673, and by the U.S. DOE under Contract No. DE-FG02-96ER40963 (U. T. K.). T. J. G. acknowledges the support of the Australian Government Research Training Program. E. P.-R. acknowledges the financial support of Tecnológica-Universidad Nacional Autónoma de M´exico, Grant No. PAPIIT-IN110418

Emerging nuclear collectivity in 124-130Te

The emergence of nuclear collectivity near doubly-magic 132Sn was explored along the stable, eveneven 124−130Te isotopes. Preliminary measurements of the B(E2; 41+ → 21+) transition strengths are reported from Coulomb excitation experiments primarily aimed at measuring the g factors of the 41+ states. Isotopically enriched Te targets were excited by 198-205 MeV 58Ni beams. A comparison of transition strengths obtained is made to large-scale shell-model calculations with successes and limitations discussed

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma

Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). Patients and methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen

Gamma-ray and radio properties of six pulsars detected by the fermi large area telescope

We report the detection of pulsed γ-rays for PSRs J0631+1036, J0659+1414, J0742-2822, J1420-6048, J1509-5850, and J1718-3825 using the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (formerly known as GLAST). Although these six pulsars are diverse in terms of their spin parameters, they share an important feature: their γ-ray light curves are (at least given the current count statistics) single peaked. For two pulsars, there are hints for a double-peaked structure in the light curves. The shapes of the observed light curves of this group of pulsars are discussed in the light of models for which the emission originates from high up in the magnetosphere. The observed phases of the γ-ray light curves are, in general, consistent with those predicted by high-altitude models, although we speculate that the γ-ray emission of PSR J0659+1414, possibly featuring the softest spectrum of all Fermi pulsars coupled with a very low efficiency, arises from relatively low down in the magnetosphere. High-quality radio polarization data are available showing that all but one have a high degree of linear polarization. This allows us to place some constraints on the viewing geometry and aids the comparison of the γ-ray light curves with high-energy beam models

New Haven Dialect The Linguistic Impact of Southern Italian Immigrants in Connecticut

This thesis will focus primarily on the dialect which exists in New Haven, Connecticut. In order to identify the features specific to this dialect, the standard American English vernacular, General American, will first be outlined so that the distinct differences between the two can be clearly identified. In addition, this thesis will also attempt to explain the rationale behind what has caused the specific features of this dialect to occur. The main reason of this is believed to be the strong im-pact which Italian immigrants in the New Haven area have had on the language over time. Therefore, the characteristics of Standard Italian will also be examined, as well as those of Southern Italian Dialect. From there, comparisons will be made to show how certain aspects of New Haven Dialect mimic specific characters innate to Southern Italian Dialect. Lastly, other research findings pertaining to cultural behaviors in New Haven will be re-viewed as they relate to the culture of Southern Italy. In addition, potentialities for future work will be outlined

Electromagnetic Moments of Radioactive Te 136 and the Emergence of Collectivity 2 p a2 n Outside of Double-Magic Sn 132

Radioactive Te136 has two valence protons and two valence neutrons outside of the Sn132 double shell closure, providing a simple laboratory for exploring the emergence of collectivity and nucleon-nucleon interactions. Coulomb excitation of Te136 on a titanium target was utilized to determine an extensive set of electromagnetic moments for the three lowest-lying states, including B(E2;01+→21+), Q(21+), and g(21+). The results indicate that the first-excited state, 21+, composed of the simple 2pa2n system, is prolate deformed, and its wave function is dominated by excited valence neutron configurations, but not to the extent previously suggested. It is demonstrated that extreme sensitivity of g(21+) to the proton and neutron contributions to the wave function provides unique insight into the nature of emerging collectivity, and g(21+) was used to differentiate among several state-of-the-art theoretical calculations. Our results are best described by the most recent shell model calculationsThis material is based upon work supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics, under Contract No. DE-AC05- 00OR22725, and this research used resources of the Holifield Radioactive Ion Beam Facility of Oak Ridge National Laboratory, which was a DOE Office of Science User Facility. This research was also sponsored by the Australian Research Council under Grant No. DP0773273, by the U.S. DOE under Contract No. DE-FG02-96ER40963 (UTK), and by the National Science Foundation, Grant No. PHY-1404442