Challenges and perspectives in computational deconvolution in genomics data

Deciphering cell type heterogeneity is crucial for systematically understanding tissue homeostasis and its dysregulation in diseases. Computational deconvolution is an efficient approach to estimate cell type abundances from a variety of omics data. Despite significant methodological progress in computational deconvolution in recent years, challenges are still outstanding. Here we enlist four significant challenges from availability of the reference data, generation of simulation data, limitations of computational methodologies, and benchmarking design and implementation. Finally, we make recommendations on reference data generation, new directions of computational methodologies and strategies to promote rigorous benchmarking

Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance

MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family

Assessment of heterogeneity amongaAssessment of Heterogeneity Among Participants in the Parkinson’s Progression Markers Initiative Cohort Using α-Synuclein Seed Amplification: A Cross-Sectional Study participants in the Parkinson\u27s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson\u27s disease from healthy controls. We used the well characterised, multicentre Parkinson\u27s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson\u27s disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson\u27s disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson\u27s disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson\u27s disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson\u27s disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson\u27s disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson\u27s disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson\u27s disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson\u27s disease. Our results show that the assay classifies people with Parkinson\u27s disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson\u27s disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinson\u27s Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson\u27s, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity

Proteomics in food: Quality, safety, microbes, and allergens

Food safety and quality and their associated risks pose a major concern worldwide regarding not only the relative economical losses but also the potential danger to consumer's health. Customer's confidence in the integrity of the food supply could be hampered by inappropriate food safety measures. A lack of measures and reliable assays to evaluate and maintain a good control of food characteristics may affect the food industry economy and shatter consumer confidence. It is imperative to create and to establish fast and reliable analytical methods that allow a good and rapid analysis of food products during the whole food chain. Proteomics can represent a powerful tool to address this issue, due to its proven excellent quantitative and qualitative drawbacks in protein analysis. This review illustrates the applications of proteomics in the past few years in food science focusing on food of animal origin with some brief hints on other types. Aim of this review is to highlight the importance of this science as a valuable tool to assess food quality and safety. Emphasis is also posed in food processing, allergies, and possible contaminants like bacteria, fungi, and other pathogens

Anthropogenic contributions to global carbonyl sulfide, carbon disulfide and organosulfides fluxes

Previous studies of the global sulfur cycle have focused almost exclusively on oxidized species and just a few sulfides. This focus is expanded here to include a wider range of reduced sulfur compounds. Inorganic sulfides tend to be bound into sediments, and sulfates are present both in sediments and the oceans. Sulfur can adopt polymeric forms that include S-S bonds. This review examines the global anthropogenic sources of reduced sulfur, updating emission inventories and widening the consideration of industrial sources. It estimates the anthropogenic fluxes of key sulfides to the atmosphere (units Gg S a-1) as: carbonyl sulfide (total 591: mainly from pulp and pigment 171, atmospheric oxidation of carbon disulfide 162, biofuel and coal combustion, 133, natural 898 Gg S a-1), carbon disulfide (total 746: rayon 395, pigment 205, pulp 78, natural 330 Gg S a-1), methanethiol (total 2119: pulp 1680, manure 330, rayon and wastewater 102, natural 6473 Gg S a-1), dimethyl sulfide (total 2197: pulp 1462, manure 660 and rayon 36, natural 31 657 Gg S a-1), dimethyl disulfide (total 1103: manure 660, pulp 273; natural 1081 Gg S a-1). The study compares the magnitude of the natural sources: marine, vegetation and soils, volcanoes and rain water with the key anthropogenic sources: paper industry, rayon-cellulose manufacture, agriculture and pigment production. Industrial sources could be reduced by better pollution control, so their impact may lessen over time. Anthropogenic emissions dominate the global budget of carbon disulfide, and some aromatic compounds such as thiophene, with emissions of methanethiol and dimethyl disufide also relatively important. Furthermore, industries related to coal and bitumen are key sources of multi-ringed thiophenes, while food production and various wastes may account for the release of significant amounts of dimethyl disulfide and dimethyl trisulfide

Stratospheric aerosol - Observations, processes, and impact on climate

Interest in stratospheric aerosol and its role in climate have increased over the last decade due to the observed increase in stratospheric aerosol since 2000 and the potential for changes in the sulfur cycle induced by climate change. This review provides an overview about the advances in stratospheric aerosol research since the last comprehensive assessment of stratospheric aerosol was published in 2006. A crucial development since 2006 is the substantial improvement in the agreement between in situ and space-based inferences of stratospheric aerosol properties during volcanically quiescent periods. Furthermore, new measurement systems and techniques, both in situ and space based, have been developed for measuring physical aerosol properties with greater accuracy and for characterizing aerosol composition. However, these changes induce challenges to constructing a long-term stratospheric aerosol climatology. Currently, changes in stratospheric aerosol levels less than 20% cannot be confidently quantified. The volcanic signals tend to mask any nonvolcanically driven change, making them difficult to understand. While the role of carbonyl sulfide as a substantial and relatively constant source of stratospheric sulfur has been confirmed by new observations and model simulations, large uncertainties remain with respect to the contribution from anthropogenic sulfur dioxide emissions. New evidence has been provided that stratospheric aerosol can also contain small amounts of nonsulfate matter such as black carbon and organics. Chemistry-climate models have substantially increased in quantity and sophistication. In many models the implementation of stratospheric aerosol processes is coupled to radiation and/or stratospheric chemistry modules to account for relevant feedback processes

The effect of Z-group modification on the RAFT polymerization of N-vinylpyrrolidone controlled by "switchable" N-pyridyl-functional dithiocarbamates

This is an accepted manuscript of an article published by Royal Society of Chemistry in the Polymer Chemistry on 24/08/2015, available online: https://doi.org/10.1039/C5PY01021G The accepted version of the publication may differ from the final published version.The ability of a RAFT agent to control the polymerization of a monomer is dictated by the structures of both the monomer and the RAFT agent. In this paper, the polymerization of N-vinylpyrrolidone was examined with a series of cyanomethyl N-aryl-N-pyridyldithiocarbamates [(4-R′Ph)N(py)C(S)SCH2CN] varying in the substituent (R′) at the 4-position on the phenyl ring. The polymerization of N-vinylpyrrolidone was best controlled when R′ was methoxy; one of the least active RAFT agents in the series. The preservation of RAFT agent functionality was demonstrated by chain extension experiments with further N-vinylpyrrolidone. Again best control again was found for the RAFT agent with R′ = MeOPh. The utility of this RAFT agent was also proved with the preparation of poly(N-isopropylacrylamide)-block-poly(N-vinylpyrrolidone).The authors gratefully acknowledge the Australian Government for award of an Australian Postgraduate Award to S.J.S., the CSIRO Manufacturing Flagship and the School of Science and Technology at the University of New England for project funding.Published versio

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good