Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells

First measurement of neutrino oscillation parameters using neutrinos and antineutrinos by NOvA

The NOvA experiment has seen a 4.4σ signal of ν̄e appearance in a 2 GeV ν̄μ beam at a distance of 810 km. Using 12.33×1020 protons on target delivered to the Fermilab NuMI neutrino beamline, the experiment recorded 27 ν̄μ→ν̄e candidates with a background of 10.3 and 102 ν̄μ→ν̄μ candidates. This new antineutrino data are combined with neutrino data to measure the parameters |Δm322|=2.48-0.06+0.11×10-3 eV2/c4 and sin2θ23 in the ranges from (0.53-0.60) and (0.45-0.48) in the normal neutrino mass hierarchy. The data exclude most values near δCP=π/2 for the inverted mass hierarchy by more than 3σ and favor the normal neutrino mass hierarchy by 1.9σ and θ23 values in the upper octant by 1.6σ

Fungal volatile organic compounds: emphasis on their plant growth-promoting

Fungal volatile organic compounds (VOCs) commonly formed bioactive interface between plants and countless of microorganisms on the above- and below-ground plant-fungus interactions. Fungal-plant interactions symbolize intriguingly biochemical complex and challenging scenarios that are discovered by metabolomic approaches. Remarkably secondary metabolites (SMs) played a significant role in the virulence and existence with plant-fungal pathogen interaction; only 25% of the fungal gene clusters have been functionally identified, even though these numbers are too low as compared with plant secondary metabolites. The current insights on fungal VOCs are conducted under lab environments and to apply small numbers of microbes; its molecules have significant effects on growth, development, and defense system of plants. Many fungal VOCs supported dynamic processes, leading to countless interactions between plants, antagonists, and mutualistic symbionts. The fundamental role of fungal VOCs at field level is required for better understanding, so more studies will offer further constructive scientific evidences that can show the cost-effectiveness of ecofriendly and ecologically produced fungal VOCs for crop welfare

Provider imposed restrictions to clients’ access to family planning in urban Uttar Pradesh, India: a mixed methods study

BACKGROUND: Medical barriers refer to unnecessary policies or procedures imposed by health care providers that are not necessarily medically advised; these restrictions impede clients’ access to family planning (FP). This mixed methods study investigates provider imposed barriers to provision of FP using recent quantitative and qualitative data from urban Uttar Pradesh, India. METHODS: Baseline quantitative data were collected in six cities in Uttar Pradesh, India from service delivery points (SDP), using facility audits, exit interviews, and provider surveys; for this study, the focus is on the provider surveys. More than 250 providers were surveyed in each city. Providers were asked about the FP methods they provide, and if they restrict clients’ access to each method based on age, parity, partner consent, or marital status. For the qualitative research, we conducted one-on-one interviews with 21 service providers in four of the six cities in Uttar Pradesh. Each interview lasted approximately 45 minutes. RESULTS: The quantitative findings show that providers restrict clients’ access to spacing and long-acting and permanent methods of FP based on age, parity, partner consent and marital status. Qualitative findings reinforce that providers, at times, make judgments about their clients’ education, FP needs and ability to understand FP options thereby imposing unnecessary barriers to FP methods. CONCLUSIONS: Provider restrictions on FP methods are common in these urban Uttar Pradesh sites. This means that women who are young, unmarried, have few or no children, do not have the support of their partner, or are less educated may not be able to access or use FP or their preferred method. These findings highlight the need for in-service training for staff, with a focus on reviewing current guidelines and eligibility criteria for provision of methods

Kinome Profiling Reveals an Interaction Between Jasmonate, Salicylate and Light Control of Hyponastic Petiole Growth in Arabidopsis thaliana

Plants defend themselves against infection by biotic attackers by producing distinct phytohormones. Especially jasmonic acid (JA) and salicylic acid (SA) are well known defense-inducing hormones. Here, the effects of MeJA and SA on the Arabidopsis thaliana kinome were monitored using PepChip arrays containing kinase substrate peptides to analyze posttranslational interactions in MeJA and SA signaling pathways and to test if kinome profiling can provide leads to predict posttranslational events in plant signaling. MeJA and SA mediate differential phosphorylation of substrates for many kinase families. Also some plant specific substrates were differentially phosphorylated, including peptides derived from Phytochrome A, and Photosystem II D protein. This indicates that MeJA and SA mediate cross-talk between defense signaling and light responses. We tested the predicted effects of MeJA and SA using light-mediated upward leaf movement (differential petiole growth also called hyponastic growth). We found that MeJA, infestation by the JA-inducing insect herbivore Pieris rapae, and SA suppressed low light-induced hyponastic growth. MeJA and SA acted in a synergistic fashion via two (partially) divergent signaling routes. This work demonstrates that kinome profiling using PepChip arrays can be a valuable complementary ∼omics tool to give directions towards predicting behavior of organisms after a given stimulus and can be used to obtain leads for physiological relevant phenomena in planta

Analysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser

Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations. Mitochondrial oxidation-induced cell death is an important physiological process activated by cancer therapeutics, but its investigation is challenging. Here, the authors report a multifunctional iridium(III) photosensitiser, Ir-OA, able to induce mitochondrial oxidative stress and monitor the corresponding changes in mitochondrial properties

Measurement of neutrino-induced neutral-current coherent π0 production in the NOvA near detector

The cross section of neutrino-induced neutral-current coherent π0 production on a carbon-dominated target is measured in the NOvA near detector. This measurement uses a narrow-band neutrino beam with an average neutrino energy of 2.7 GeV, which is of interest to ongoing and future long-baseline neutrino oscillation experiments. The measured, flux-averaged cross section is σ=13.8±0.9(stat)±2.3(syst)×10−40cm2/nucleus, consistent with model prediction. This result is the most precise measurement of neutral-current coherent π0 production in the few-GeV neutrino energy region

First measurement of neutrino oscillation parameters using neutrinos and antineutrinos by NOvA

The NOvA experiment has seen a 4.4 σ signal of ¯ ν e appearance in a 2 GeV ¯ ν μ beam at a distance of 810 km. Using 12.33 × 10 20 protons on target delivered to the Fermilab NuMI neutrino beamline, the experiment recorded 27 ¯ ν μ → ¯ ν e candidates with a background of 10.3 and 102 ¯ ν μ → ¯ ν μ candidates. This new antineutrino data are combined with neutrino data to measure the parameters | Δ m 2 32 | = 2.4 8 + 0.11 − 0.06 × 10 − 3     eV 2 / c 4 and sin 2 θ 23 in the ranges from (0.53–0.60) and (0.45–0.48) in the normal neutrino mass hierarchy. The data exclude most values near δ C P = π / 2 for the inverted mass hierarchy by more than 3 σ and favor the normal neutrino mass hierarchy by 1.9 σ and θ 23 values in the upper octant by 1.6 σ