Articles de revues sur le sujet « Gibbs-type priors »

Accelerated Life Testing (ALT) is an effective technique which has been used in different fields to obtain more failures in a shorter period of time. It is more economical than traditional reliability testing. In this article, we propose Bayesian inference approach for planning optimal constant stress ALT with Type I censoring. The lifetime of a test unit follows an exponentiated Lomax distribution. Bayes point estimates of the model parameters and credible intervals under uniform and log-normal priors are obtained. Besides, optimum test plan based on constant stress ALT under Type I censoring is developed by minimizing the pre-posterior variance of a specified low percentile of the lifetime distribution at use condition. Gibbs sampling method is used to find the optimal stress with changing time. The performance of the estimation methods is demonstrated for both simulated and real data sets. Results indicate that both the priors and the sample size affect the optimal Bayesian plans. Further, informative priors provide better results than non-informative priors.

This paper explores statistical inferences when the lifetime of product follows the inverse Nakagami distribution using progressive Type-II censored data. Likelihood-based and maximum product of spacing (MPS)-based methods are considered for estimating the parameters of the model. In addition, approximate confidence intervals are constructed via the asymptotic theory using both likelihood and product spacing functions. Based on traditional likelihood and the product of spacing functions, Bayesian estimates are also considered under a squared error loss function using non-informative priors, and Gibbs sampling based on the MCMC algorithm is proposed to approximate the Bayes estimates, where the highest posterior density credible intervals of the parameters are obtained. Numerical studies are presented to compare the proposed estimators using Monte Carlo simulations. To demonstrate the proposed methodology in a real-life scenario, a well-known data set on agricultural machine elevators with high defect rates is also analyzed for illustration.

A new three-parameter Type-II Lehmann Fréchet distribution (LFD-TII), as a reparameterized version of the Kumaraswamy–Fréchet distribution, is considered. In this study, using progressive Type-II censoring, different estimation methods of the LFD-TII parameters and its lifetime functions, namely, reliability and hazard functions, are considered. In a frequentist setup, both the likelihood and product of the spacing estimators of the considered parameters are obtained utilizing the Newton–Raphson method. From the normality property of the proposed classical estimators, based on Fisher’s information and the delta method, the asymptotic confidence interval for any unknown parametric function is obtained. In the Bayesian paradigm via likelihood and spacings functions, using independent gamma conjugate priors, the Bayes estimators of the unknown parameters are obtained against the squared-error and general-entropy loss functions. Since the proposed posterior distributions cannot be explicitly expressed, by combining two Markov-chain Monte-Carlo techniques, namely, the Gibbs and Metropolis–Hastings algorithms, the Bayes point/interval estimates are approximated. To examine the performance of the proposed estimation methodologies, extensive simulation experiments are conducted. In addition, based on several criteria, the optimum censoring plan is proposed. In real-life practice, to show the usefulness of the proposed estimators, two applications based on two different data sets taken from the engineering and physics fields are analyzed.

We introduce mixtures of species sampling sequences (mSSS) and discuss how these sequences are related to various types of Bayesian models. As a particular case, we recover species sampling sequences with general (not necessarily diffuse) base measures. These models include some “spike-and-slab” non-parametric priors recently introduced to provide sparsity. Furthermore, we show how mSSS arise while considering hierarchical species sampling random probabilities (e.g., the hierarchical Dirichlet process). Extending previous results, we prove that mSSS are obtained by assigning the values of an exchangeable sequence to the classes of a latent exchangeable random partition. Using this representation, we give an explicit expression of the Exchangeable Partition Probability Function of the partition generated by an mSSS. Some special cases are discussed in detail—in particular, species sampling sequences with general base measures and a mixture of species sampling sequences with Gibbs-type latent partition. Finally, we give explicit expressions of the predictive distributions of an mSSS.

The Topp Leone distribution (TLD) is a lifetime model having finite support and U-shaped hazard rate; these features distinguish it from the famous lifetime models such as gamma, Weibull, or Log-normal distribution. The Bayesian methods are very much linked to the Fuzzy sets. The Fuzzy priors can be used as prior information in the Bayesian models. This paper considers the posterior analysis of TLD, when the samples are doubly censored. The independent informative priors (IPs) which are very close to the Fuzzy priors have been proposed for the analysis. The symmetric and asymmetric loss functions have also been assumed for the analysis. As the marginal PDs are not available in a closed form, therefore, we have used a Quadrature method (QM), Lindley’s approximation (LA), Tierney and Kadane’s approximation (TKA), and Gibbs sampler (GS) for the approximate estimation of the parameters. A simulation study has been conducted to assess and compare the performance of various posterior estimators. In addition, a real dataset has been analyzed for the illustration of the applicability of the results obtained in the study. The study suggests that the TKA performs better than its counterparts.

In this paper, we provide an insight into the emergence of power-law and two-phase behavior in the financial market fluctuations by defining an analytical model for time evolution of stock share prices. The defined model can exhibit bimodal behavior in the supply-demand structure of the market. Moreover, it differs from existing Ising-type models. It turns out that the constructed model is a solution of a thermodynamic limit of a Gibbs probability measure when the number of investors and the number of stock shares approaches the infinity. The energy functional of the Gibbs probability measure is derived from the Nash equilibrium of the underlying game.

The coupling of the Stefan equation for the heat flow with the Gibbs–Thomson law relating the melting temperature to the mean curvature of the phase interface is considered. Solutions, global in time, are constructed which satisfy the natural a priori estimates. Mathematically the main difficulty is to prove a certain regularity in time for the temperature and the indicator function of the phase separately. A capacity type estimate is used to give an L1 bound for fractional time derivatives.

We show that in weakly confining conservative force fields, a subclass of diffusion-type (Smoluchowski) processes, admits a family of "heavy-tailed" non-Gaussian equilibrium probability density functions (pdfs), with none or a finite number of moments. These pdfs, in the standard Gibbs-Boltzmann form, can also be inferred directly from an extremum principle, set for Shannon entropy under a constraint that the mean value of the force potential has been a priori prescribed. That enforces the corresponding Lagrange multiplier to play the role of inverse temperature. Weak confining properties of the potentials are manifested in a thermodynamical peculiarity that thermal equilibria can be approached only in a bounded temperature interval 0 ≤ T < T max = 2ϵ0/kB, where ϵ0 sets an energy scale. For T ≥ T max no equilibrium pdf exists.

Introdução: O desenvolvimento de primers é extremamente importante para pesquisas moleculares. Objetivos: O presente estudo objetivou desenhar e validar primers in silico para detecção do vírus sincicial respiratório humano (RSVH). Materiais e Métodos: Foi construído um banco de 100 sequências de genoma completo do Vírus Sincicial Respiratório Humano (RSVH) depositadas no Genbank (NCBI). Realizado um alinhamento múltiplo global utilizando o algoritimo Clustal W, mapeadas as regiões conservadas e selecionado os primers. Posteriormente submetidos a análise dos parâmetros especificidade, pela ferramenta BLAST, concentração de GC%, TMelting, comprimento, formação de dímeros e hairpin utilizando o software Oligo Analyser, validando-os para uso in vitro. Para discussão dos resultados, foram selecionados 14 primers de estudos realizados, submetidos à metodologia proposta neste estudo, comparando os dados obtidos. A região alvo escolhida foi o gene da Glicoproteína G, pela presença de sítios conservados. Resultados: Os primers amplificam um fragmento de 381pb, que submetido a uma segunda PCR, resulta em 109 pb correspondente ao tipo A do vírus e 168 pb para o tipo B, permitindo a detecção viral e a distinção de genótipos. Os primers possuem tamanho de 21 a 24 pb, com uma temperatura de melting entre 48,9 oC e 55,3 oC. A concentração de GC% varia de 33,3% a 52,4%. O número de bases complementares na análise de dímeros e hairpin manteve-se abaixo de 5 bases. A Energia Livre de Gibbs (Delta G) acima de -9 kcal.moles(-1) como desejado. Conclusão: Os valores obtidos na validação dos primers estão em concordância com os já utilizados em estudos de referência, validando assim o seu uso in vitro. Introduction: Developing primers is extremely important to molecular researches. Objectives: This study aims to drawing and validate in silico primers for detection of Human Respiratory Syncytial Virus (RSVH). Materials and Methods: It was built a database of 100 complete genome sequences of Human Respiratory Syncytial Virus (RSVH) deposited in the Genbank (NCBI), carried out a global multiple alignment using the algoritm Clustal W, thus mapping the conserved regions, and selecting primers, subsequently submitted to analysis of parameters such as specificity, by the BLAST tool, concentration of GC% TMelting, length, and formation of dimers and hairpins using the software Oligo Analyser, validating them to use in vitro. For discussion of the results, we selected 14 primers of studies already carried out and submitted the methodology proposed in this study, comparing the data obtained. The selected target region was the gene encoding the Glycoprotein G, by the presence of conserved sites. Results: The primers selected amplifies a fragment of 381 bp in the 1st PCR, which subjected to a second PCR results in 109 bp corresponding to the type A of the virus and 168 base pairs for the type Bwhat allows not only viral detection, as the distinction of the type to which it belongs. The primers have size from 21 to 24 base pairs, having a melting temperature (Tmelting) between 48,9o C and 55,3o C and GC% concentration ranging from 33.3% to 52.4%. The number of complementary bases in the dimers and hairpins analysis was maintained below 5 bases, while the Gibbs free energy (Delta G) was kept above kcal.mole -9(-1) as desired. Conclusion: All values obtained in the validation of the primers are in agreement with the ones already used in the reference studies, thereby validating its use in vitro.

This paper presents Bayesian reliability sampling plans for the Weibull distribution based on progressively Type-II censored data with binomial removals. In constructing sampling plans, the decision theoretic approach is used. A dependent bivariate nonconjugate prior is employed. The total cost of the sampling plan consists of sampling, time-consuming, rejection, and acceptance costs. The decision rule is based on the Bayes estimator of the survival function. Lindley’s approximation is used to obtain Bayes estimates of the survival function under the quadratic and LINEX loss functions. However, the poor performance of Lindley’s approximation with small sample sizes can be observed. The Metropolis-within-Gibbs Markov Chain Monte Carlo (MCMC) algorithm show significantly improved performance compared to Lindley’s approximation. We use simulation studies to evaluate the Bayes risk and determine the optimal sampling plans for different sample sizes, observed number of failures, binomial removal probabilities and minimum acceptable reliability.

Abstract A new approach to forecasting regional and seasonal tropical cyclone (TC) frequency in the western North Pacific using the antecedent large-scale environmental conditions is proposed. This approach, based on TC track types, yields probabilistic forecasts and its utility to a smaller region in the western Pacific is demonstrated. Environmental variables used include the monthly mean of sea surface temperatures, sea level pressures, low-level relative vorticity, vertical wind shear, and precipitable water of the preceding May. The region considered is the vicinity of Taiwan, and typhoon season runs from June through October. Specifically, historical TC tracks are categorized through a fuzzy clustering method into seven distinct types. For each cluster, a Poisson or probit regression model cast in the Bayesian framework is applied individually to forecast the seasonal TC activity. With a noninformative prior assumption for the model parameters, and following Chu and Zhao for the Poisson regression model, a Bayesian inference for the probit regression model is derived. A Gibbs sampler based on the Markov chain Monte Carlo method is designed to integrate the posterior predictive distribution. Because cluster 5 is the most dominant type affecting Taiwan, a leave-one-out cross-validation procedure is applied to predict seasonal TC frequency for this type for the period of 1979–2006, and the correlation skill is found to be 0.76.

The Burr type XII (BurrXII) distribution is very flexible for modeling and has earned much attention in the past few decades. In this study, the maximum likelihood estimation method and two Bayesian estimation procedures are investigated based on constant-stress accelerated life test (ALT) samples, which are obtained from the doubly truncated three-parameter BurrXII distribution. Because computational difficulty occurs for maximum likelihood estimation method, two Bayesian procedures are suggested to estimate model parameters and lifetime quantiles under the normal use condition. A Markov Chain Monte Carlo approach using the Metropolis–Hastings algorithm via Gibbs sampling is built to obtain Bayes estimators of the model parameters and to construct credible intervals. The proposed Bayesian estimation procedures are simple for practical use, and the obtained Bayes estimates are reliable for evaluating the reliability of lifetime products based on ALT samples. Monte Carlo simulations were conducted to evaluate the performance of these two Bayesian estimation procedures. Simulation results show that the second Bayesian estimation procedure outperforms the first Bayesian estimation procedure in terms of bias and mean squared error when users do not have sufficient knowledge to set up hyperparameters in the prior distributions. Finally, a numerical example about oil-well pumps is used for illustration.

During September 2006, moderate vine decline symptoms including vine collapse and wilt and root rot were observed on numerous watermelon plants growing in a commercial field in Sullivan County, Indiana. No symptoms were observed on the fruit. Six plants displaying typical vine decline symptoms were collected and assayed for potyvirus infection and subsequently for Squash vein yellowing virus (SqVYV) and Papaya ringspot virus type W (PRSV-W). SqVYV is a whitefly-transmitted member of the Potyviridae, recently shown to cause watermelon vine decline in Florida (1,4). Plants infected with SqVYV in Florida are also frequently infected with PRSV-W, although SqVYV is sufficient for watermelon vine decline. The six field samples harbored one or more potyviruses as determined by ELISA (Agdia, Elkhart, IN). Mechanical inoculation of squash (Cucurbita pepo) and watermelon with sap from three of the field samples induced mosaic symptoms in both that are typical of potyviruses. Vein yellowing in squash and plant death in watermelon typical of SqVYV (1) later developed in plants inoculated with one field sample. A coat protein gene fragment was amplified by reverse transcription (RT)-PCR with SqVYV primers (1) from total RNA of five of the six field samples and also from the symptomatic, inoculated plants. Nucleotide and deduced amino acid sequences of a 957-bp region of the RT-PCR product (primer sequences deleted prior to analysis) were 100% identical to SqVYV (GenBank accession No. DQ812125). PRSV-W also was identified in two of the five SqVYV-infected field samples by ELISA (Agdia) and by sequence analysis of a 3′ genome fragment amplified by RT-PCR with previously described degenerate potyvirus primers (3). No evidence for infection by other potyviruses was obtained. To our knowledge, this is the first report of SqVYV in Indiana and the first report of the virus anywhere outside of Florida. The whitefly (Bemisia tabaci, B strain) vector of SqVYV is relatively uncommon in Indiana and the cold winter temperatures make it unlikely that any SqVYV-infected watermelon vines or whiteflies will overseason, necessitating reintroductions of virus and vector each season. We feel that the moderate and restricted occurrence of SqVYV in Indiana observed in September 2006 should pose little or no threat to commercial watermelon production in Indiana and should not cause growers to alter their growing practices. The occurrence of SqVYV in Indiana does not appear to explain the similar symptoms of mature watermelon vine decline (MWVD) that has been observed in Indiana since the 1980s. In contrast with the insect vectored SqVYV, MWVD seems to be caused by a soilborne biological agent (2). References: (1) S. Adkins et al. Phytopathology 97:145, 2007. (2) D. S. Egel et al. Online publication. doi:10.1094/PHP-2000-1227-01-HN. Plant Health Progress, 2000. (3) A. Gibbs and A. Mackenzie. J. Virol. Methods 63:9, 1997. (4) P. Roberts et al. Citrus Veg. Mag. December 12, 2004.

Sesame (Sesamum indicum L.) is cultivated mainly in the central region of the Departamento de San Pedro in Paraguay from October to February and the seed are exported to Asia. The crop is grown on 100,000 ha annually and Escoba blanca is the most common cultivar. The crop plays an important socioeconomical role since it is cultivated mostly by small growers. A disease characterized by yellowing and curling down leaves and shortening of the internodes has been observed in almost all sesame-growing areas. It is referred to locally as “ka'are” because the affected sesame plant resembles Chenopodium ambrosioides L. This disease occurred occasionally and was of marginal importance prior to 2005, but during the last five growing seasons the disease incidence has increased substantially, with some growers losing the entire crop. To determine the causal agent, symptomatic leaf samples were collected from five commercial fields near Colonia San Pedro and Choré, Departamento San Pedro in December 2009. Preliminary transmission electron microscopy (TEM; Zeiss EM900) of extracts from symptomatic leaves revealed the presence of elongated flexible particles resembling a potyvirus. Mechanical transmission assays resulted in chlorotic local lesions on C. quinoa and C. amaranticolor, mosaic on Vigna unguiculata and Nicotiana benthamiana, and symptoms on sesame that are similar to those observed in the field. The disease could also be reproduced in sesame by aphid (Myzus persicae) transmission in a nonpersistent manner. TEM examination of leaf sections of these naturally or experimentally infected plants showed the presence of the type I cylindrical inclusions and masses of filamentous particles. Leaf extracts of naturally or experimentally infected sesame and test plants were positive for Cowpea aphid-borne mosaic virus (CABMV) on the basis of plate-trapped antigen (PTA)-ELISA. CABMV as the causal agent of “ka'are” disease of sesame in Paraguay was further confirmed by analyzing part of the nucleotide sequence of CABMV coat protein and 3′ nontranslated region that were obtained directly from reverse transcription-PCR product amplified with PV1-antisense primer (5′-gatttaggtgacactatagt17-3′) and WCIEN-sense primer (5′-atggtttggtgyatygaraat-3′) (1,2). Comparisons of the 676-bp nucleotide sequence of two sesame virus isolates (GenBank Accession Nos. HQ336402 and HQ336403) revealed 92% identity with the corresponding nucleotide sequence of CABMV available in the GenBank (Accession No. AF348210). Thus, all the assays indicated that the “ka'are” disease of sesame in Paraguay is caused by an isolate of CABMV. Several cowpea fields, nearby sesame diseased crops, also contained plants exhibiting mosaic symptoms. Transmission assays, electron microscopy, PTA-ELISA, and nucleotide sequence analysis indicated that they were also infected by CABMV and may play an important role in the epidemiology of this disease on sesame. CABMV isolates from passion fruit and cowpea from Brazil were mechanically transmitted to sesame but induced milder symptoms. CABMV-infected sesame was described in the United States (3), but to our knowledge, this is the first report of a severe disease on sesame caused by this virus in Paraguay. References: (1) A. Gibbs and A. Mackenzie. J. Virol. Methods 63:9, 1997. (2) L. D. C. Mota et al. Plant Pathol. 53:368, 2004. (3) H. R. Pappu et al. Arch. Virol. 142:1919, 1997.

Abstract Background: Radiation therapy has immune-modulating effects resulting from apoptosis of tumor cells and DNA damage. The downstream generation of cytosolic DNA activates the cyclic GMP-AMP Synthase (cGAS)-STimulator of INterferon Gene (STING) signaling axis in both tumor and nearby immune cells, leading to increased induction of type I interferon (IFN-I) and other immune stimulating molecules. TAK-676 is a novel synthetic STING agonist being investigated (+/- pembrolizumab) in an ongoing first-in-human phase 1 study (NCT04420884). TAK-676 is a potent modulator of the innate immune system and leads to downstream activation of the adaptive immune system to produce antitumor responses in preclinical studies. In contrast to intratumorally injected STING agonists, TAK-676 is optimally designed for reduced serum degradation and enhanced permeability, allowing systemic IV delivery and access to tumor sites and lymphatics. The addition of TAK-676 following radiation therapy may enhance the immune response by increasing the STING-mediated IFN-I release and further stimulate T cell-mediated antitumor immunity, particularly in combination with anti-PD-1/PD-L1 therapies. Impaired IFN signaling has been linked to checkpoint inhibitor (CPI) resistance. Preclinical studies show that addition of a STING agonist may reverse the mechanisms of resistance in tumors with prior exposure to CPIs. This phase 1 trial was designed to investigate the safety and preliminary antitumor activity of TAK-676 + pembrolizumab following radiation therapy (NCT04879849). Methods: Patients aged ≥18 years with advanced NSCLC, TNBC, or SCCHN who have progressed on CPIs with ≥2 lesions, one of which can be targeted with radiation, are being enrolled. Patients receive 8 Gy x 3 fractions of image-guided radiation therapy followed by (after a minimum of 40 hours) IV pembrolizumab 200 mg on day 1 plus escalating doses of IV TAK-676 on days 1, 8, and 15 of a 21-day cycle. TAK-676 dose escalation is guided by the Bayesian Optimal Interval design. Patients receive TAK-676 + pembrolizumab until disease progression, intolerance, or withdrawal of consent. Once pharmacologically active dose levels of TAK-676 have been observed, paired biopsies will be collected in patients with a safely accessible lesion outside the radiation field at screening and between days 15 and 21 of cycle 1. The primary objective is to determine the safety and tolerability of TAK-676 + pembrolizumab following radiation therapy; secondary objectives are to determine the recommended phase 2 dose of TAK-676 + pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (in the radiation field) and systemically (non-radiated lesions). As of January 2022, nearly 10% of the planned patients have been enrolled. Citation Format: Benjamin Cooper, Steven J. Chmura, Jason J. Luke, Stephen L. Shiao, Reva K. Basho, Wade T. Iams, David B. Page, Cong Li, Richard C. Gregory, Michael H. Shaw, Kristin H. Horn, John P. Gibbs, Vicky A. Appleman, Allison J. Berger, Adnan O. Abu-Yousif, Neil B. Lineberry, Kate F. Stumpo, Aymen Elfiky, Naamit K. Gerber. Phase 1 study of TAK-676 + pembrolizumab following radiation therapy in patients with advanced non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT243.

Abstract Background: TAK-981 is the first small-molecule inhibitor of SUMOylation to enter clinical trials. SUMOylation is a post-translational modification in which small ubiquitin-like modifier (SUMO) proteins are activated and covalently attached to substrate proteins. SUMOylation has a central role in constraining type I interferon (IFN-I)-dependent responses (Decque Nat Immunol 2016). By blocking SUMOylation, TAK-981 promotes IFN-I production and increases innate immunity. The ability of TAK-981 to promote activation of macrophages and NK cells and increase their cytotoxic/phagocytic activity provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis. Preclinical studies have demonstrated synergistic antitumor activity between TAK-981 and the anti-CD20 monoclonal antibody rituximab in xenograft models of human B cell lymphoma (Nakamura AACR 2019). Based on these data, and a single-agent TAK-981 study (TAK-981-1002), this phase 1b/2, open-label, dose-escalation and expansion study is investigating the safety and efficacy of TAK-981 plus rituximab in adults with CD20-positive R/R NHL (NCT04074330); here, we report data from the phase 1b dose-escalation part of the study. Methods: Eligible pts were aged ≥18 years with CD20-positive, R/R aggressive B-cell NHL (aNHL) or indolent NHL (iNHL). aNHL included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and grade 3b follicular lymphoma (FL); iNHL included grade 1-3a FL and marginal zone lymphoma. aNHL pts had to have received prior R-CHOP or equivalent plus 1 additional line of therapy in the R/R setting; iNHL pts had to be refractory to rituximab or another anti-CD20 mAb, and to have received at least 1 prior therapy for R/R disease. TAK-981 IV was given at increasing doses (starting: 10 mg) on days 1 and 8 (QW) or days 1, 4, 8, and 11 (BIW) of 21-day cycles. Rituximab 375 mg/m 2 IV was given on days 1, 8, and 15 of cycle 1 and on day 1 thereafter. Dose escalation was based on adaptive Bayesian logistic regression modelling with overdose control based on the posterior probability of having a dose-limiting toxicity (DLT). Primary phase 1b objectives were safety, tolerability, and recommended phase 2 dose (RP2D) of TAK-981 in combination with rituximab; data cutoff was 28 June 2021. Results: 24 pts have been enrolled and treated: 19 QW (10-120 mg) and 5 BIW (90 mg); 4 are currently on treatment. Enrollment continues in the 90 mg BIW and 120 mg QW cohorts. Median age was 65 years (range 29-80); 67% were male. No DLTs have been reported to date. RP2D and schedule will be determined based on safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Treatment-emergent adverse events (TEAEs) are shown in the Table. Most common TEAEs (≥15%) were similar between the QW/BIW schedules with the exception of dizziness (2 pts at 10 mg, 2 at 40 mg, and 1 at 90 mg) and hypokalemia (1 pt at 40 mg, 2 at 90 mg, and 1 at 120 mg); all QW. TEAEs were consistent with induction of IFN signalling (transient flu-like symptoms: fever, chills, fatigue) and with those observed in the single-agent study (data on file); no further TAK-981- or immune-related TEAEs were observed. Grade ≥3 TEAEs related to TAK-981 were reported in 2 pts: grade 3 atrial fibrillation (ongoing cardiac history) and grade 4 neutropenia; both in the 40 mg QW cohort and transient. In this population of rituximab-refractory pts, there were 5 objective responses in 17 response-evaluable pts: 4 partial responses (2 at 10 mg, FL and DLBCL; 1 at 60 mg, DLBCL; 1 at 90 mg, primary mediastinal thymic large B-cell lymphoma) and 1 complete response (40 mg, MCL), all in the QW cohort. TAK-981 PK was linear and declined in a tri-phasic manner. TAK-981 exhibited PD activity in peripheral blood including target engagement, decreased SUMOylation, and increased IFN-regulated gene expression (Figure). Conclusion: The combination of TAK-981 and rituximab was well tolerated in pts across each dose level and schedule. TAK-981 PK showed minimal accumulation after repeat dosing and PD assays confirmed inhibition of SUMOylation and activation of IFN-I signalling. More importantly, the combination of TAK-981 and rituximab resulted in promising clinical activity (ORR 29%) in the R/R setting, supporting the continued development of this combination in pts with NHL. Figure 1 Figure 1. Disclosures Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Roche/Genentech: Research Funding; Eli Lilly: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment. Mehta: Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy. Phillips: Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Danilov: Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding. Doucet: Amgen: Consultancy; Novartis: Consultancy; Astra-Zeneca: Consultancy; BMS: Consultancy; Jannsen: Consultancy; Servier: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Gilead: Consultancy. Park: Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Gilead: Speakers Bureau; Takeda: Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Gomez-Pinillos: Takeda: Current Employment. Martinez: Takeda: Current Employment. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Gibbs: Takeda: Current Employment. Friedlander: Takeda: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Caimi: TG Therapeutics: Consultancy; Kite: Consultancy; ADC Therapeutics: Consultancy; Verastem: Consultancy; Amgen: Consultancy; XaTek Inc.: Patents & Royalties; Celgene: Speakers Bureau.

Our previous articles demonstrated how to analyze psychophysical data from a group of participants using generalized linear mixed models (GLMM) and two-level methods. The aim of this article is to revisit hierarchical models in a Bayesian framework. Bayesian models have been previously discussed for the analysis of psychometric functions although this approach is still seldom applied. The main advantage of using Bayesian models is that if the prior is informative, the uncertainty of the parameters is reduced through the combination of prior knowledge and the experimental data. Here, we evaluate uncertainties between and within participants through posterior distributions. To demonstrate the Bayesian approach, we re-analyzed data from two of our previous studies on the tactile discrimination of speed. We considered different methods to include a priori knowledge in the prior distribution, not only from the literature but also from previous experiments. A special type of Bayesian model, the power prior distribution, allowed us to modulate the weight of the prior, constructed from a first set of data, and use it to fit a second one. Bayesian models estimated the probability distributions of the parameters of interest that convey information about the effects of the experimental variables, their uncertainty, and the reliability of individual participants. We implemented these models using the software Just Another Gibbs Sampler (JAGS) that we interfaced with R with the package rjags. The Bayesian hierarchical model will provide a promising and powerful method for the analysis of psychometric functions in psychophysical experiments.

AbstractThe spatio-temporal epidemic type aftershock sequence (ETAS) model is widely used to describe the self-exciting nature of earthquake occurrences. While traditional inference methods provide only point estimates of the model parameters, we aim at a fully Bayesian treatment of model inference, allowing naturally to incorporate prior knowledge and uncertainty quantification of the resulting estimates. Therefore, we introduce a highly flexible, non-parametric representation for the spatially varying ETAS background intensity through a Gaussian process (GP) prior. Combined with classical triggering functions this results in a new model formulation, namely the GP-ETAS model. We enable tractable and efficient Gibbs sampling by deriving an augmented form of the GP-ETAS inference problem. This novel sampling approach allows us to assess the posterior model variables conditioned on observed earthquake catalogues, i.e., the spatial background intensity and the parameters of the triggering function. Empirical results on two synthetic data sets indicate that GP-ETAS outperforms standard models and thus demonstrate the predictive power for observed earthquake catalogues including uncertainty quantification for the estimated parameters. Finally, a case study for the l’Aquila region, Italy, with the devastating event on 6 April 2009, is presented.

Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of ‘allelic manifolds’, a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP andσ70RNA polymerase. Doing so, we consistently obtained energetic measurements precise to∼0.1kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

AbstractFifty groundwater samples were obtained pre and post-monsoon seasons in parts of hard rock terrain in Andhra Pradesh, South India, in order to assess the drinking water quality. PIG values of groundwater samples ranged from 0.95–1.53 and 0.83–1.28 during pre and post-monsoon seasons. PIG values are slightly higher in the pre-monsoon season when compared to the post-monsoon season. In the pre monsoon season, 96% of the groundwater samples showed insignificant pollution class (< 1), 4% of the groundwater samples are low pollution (1–1.5). 82% of the groundwater samples showed insignificant pollution status (< 1), 18% of the groundwater samples fall under the low pollution (1–1.5), is noticed in post-monsoon season, respectively. WQI values of groundwater samples ranged from 108.5–204 mg/L and 112.6–170 mg/L during pre and post-monsoon seasons; its shows that 100% are very poor for drinking purpose. Piper diagram reveals that groundwater is majorly mixed Ca2+-Mg2+-Cl−, Ca2+-Mg2+-Cl−-SO42−, Na+-K+-Cl−- SO42− type in this region. The Gibbs plot indicates that groundwater samples fall within the field of rock dominance. Through applying GIS techniques, the spatial distribution of groundwater quality analysis reveals that most of the groundwater samples do not comply drinking water quality standards and water needs to be prior treatment before consumption.

Abstract Motivation Mendelian randomization (MR) is a valuable tool to examine the causal relationships between health risk factors and outcomes from observational studies. Along with the proliferation of genome-wide association studies (GWASs), a variety of two-sample MR methods for summary data have been developed to account for horizontal pleiotropy (HP), primarily based on the assumption that the effects of variants on exposure (γ) and horizontal pleiotropy (α) are independent. In practice, this assumption is too strict and can be easily violated because of the correlated HP. Results To account for this correlated HP, we propose a Bayesian approach, MR-Corr2, that uses the orthogonal projection to reparameterize the bivariate normal distribution for γ and α, and a spike-slab prior to mitigate the impact of correlated HP. We have also developed an efficient algorithm with paralleled Gibbs sampling. To demonstrate the advantages of MR-Corr2 over existing methods, we conducted comprehensive simulation studies to compare for both type-I error control and point estimates in various scenarios. By applying MR-Corr2 to study the relationships between exposure-outcome pairs in complex traits, we did not identify the contradictory causal relationship between HDL-c and CAD. Moreover, the results provide a new perspective of the causal network among complex traits. Availability The developed R package and code to reproduce all the results are available at https://github.com/QingCheng0218/MR.Corr2. Supplementary information Supplementary data are available at Bioinformatics online.

IntroductionOn 4 December 2016, a man entered a Washington, D.C., pizza parlor armed with an AR-15 assault rifle in an attempt to save the victims of an alleged satanic pedophilia ring run by prominent members of the Democratic Party. While the story had already been discredited (LaCapria), at the time of the incident, nearly half of Trump voters were found to give a measure of credence to the same rumors that had apparently inspired the gunman (Frankovic). Was we will discuss here, the bizarre conspiracy theory known as "Pizzagate" had in fact originated a month earlier on 4chan/pol/, a message forum whose very raison d’être is to protest against “political correctness” of the liberal establishment, and which had recently become a hub for “loose coordination” amongst members the insurgent US ‘alt-right’ movement (Hawley 48). Over a period of 25 hours beginning on 3 November 2016, contributors to the /pol/ forum combed through a cache of private e-mails belonging to Hillary Clinton’s campaign manager John Podesta, obtained by Russian hackers (Franceschi-Bicchierai) and leaked by Julian Assange (Wikileaks). In this short time period contributors to the forum thus constructed the basic elements of a narrative that would be amplified by a newly formed “right-wing media network”, in which the “repetition, variation, and circulation” of “repeated falsehoods” may be understood as an “important driver towards a ‘post-truth’ world” (Benkler et al). Heavily promoted by a new class of right-wing pundits on Twitter (Wendling), the case of Pizzagate prompts us to reconsider the presumed progressive valence of social media protest (Zuckerman).While there is literature, both popular and academic, on earlier protest movements associated with 4chan (Stryker; Olson; Coleman; Phillips), there is still a relative paucity of empirical research into the newer forms of alt-right collective action that have emerged from 4chan. And while there have been journalistic exposés tracing the dissemination of the Pizzagate rumors across social media as well as deconstructing its bizarre narrative (Fisher et al.; Aisch; Robb), as of yet there has been no rigorous analysis of the provenance of this particular story. This article thus provides an empirical study of how the Pizzagate conspiracy theory developed out of a particular set of collective action techniques that were in turn shaped by the material affordances of 4chan’s most active message board, the notorious and highly offensive /pol/.Grammatised Collective ActionOur empirical approach is partially inspired by the limited data-scientific literature of 4chan (Bernstein et al.; Hine et al.; Zannettou et al.), and combines close and distant reading techniques to study how the technical design of 4chan ‘grammatises’ new forms of collective action. Our coinage of grammatised collective action is based on the notion of “grammars of action” from the field of critical information studies, which posits the radical idea that innovations in computational systems can also be understood as “ontological advances” (Agre 749), insofar as computation tends to break the flux of human activity into discrete elements. By introducing this concept our intent is not to minimise individual agency, but rather to emphasise the ways in which computational systems can be conceptualised in terms of an individ­ual-milieu dyad where the “individual carries with it a certain inheritance […] animated by all the potentials that characterise [...] the structure of a physical system” (Simondon 306). Our argument is that grammatisation may be thought to create new kinds of niches, or affordances, for new forms of sociality and, crucially, new forms of collective action — in the case of 4chan/pol/, how anonymity and ephemerality may be thought to afford a kind of post-truth protest.Affordance was initially proposed as a means by which to overcome the dualistic tendency, inherited from phenomenology, to bracket the subject from its environment. Thus, affordance is a relational concept “equally a fact of the environment and a fact of behaviour” (Gibson 129). While, in the strictly materialist sense affordances are “always there” (Gibson 132), their capacity to shape action depends upon their discovery and exploitation by particular forms of life that are capable of perceiving them. It is axiomatic within ethology that forms of life can be understood to thrive in their own dynamic, yet in some real sense ontologically distinct, lifeworlds (von Uexküll). Departing from this axiom, affordances can thus be defined, somewhat confusingly but accurately, as an “invariant combination of variables” (Gibson 134). In the case of new media, the same technological object may afford different actions for specific users — for instance, the uses of an online platform appears differently from the perspective of the individual users, businesses, or a developer (Gillespie). Recent literature within the field of new media has sought to engage with this concept of affordance as the methodological basis for attending to “the specificity of platforms” (Bucher and Helmond 242), for example by focussing on how a platform’s affordances may be used as a "mechanism of governance" (Crawford and Gillespie 411), how they may "foster democratic deliberation" (Halpern and Gibbs 1159), and be implicated in the "production of normativity" (Stanfill 1061).As an anonymous and essentially ephemeral peer-produced image-board, 4chan has a quite simple technical design when compared with the dominant social media platforms discussed in the new media literature on affordances. Paradoxically however in the simplicity of their design 4chan boards may be understood to afford rather complex forms of self-expression and of coordinated action amongst their dedicated users, whom refer to themselves as "anons". It has been noted, for example, that the production of provocative Internet memes on 4chan’s /b/ board — the birthplace of Rickrolling — could be understood as a type of "contested cultural capital", whose “media literate” usage allows anons to demonstrate their in-group status in the absence of any persistent reputational capital (Nissenbaum and Shiffman). In order to appreciate how 4chan grammatises action it is thus useful to study its characteristic affordances, the most notable of which is its renowned anonymity. We should thus begin by noting how the design of the site allows anyone to post anything virtually anonymously so long as comments remain on topic for the given board. Indeed, it was this particular affordance that informed the emergence of the collective identity of the hacktivist group “Anonymous”, some ten years before 4chan became publicly associated with the rise of the alt-right.In addition to anonymity the other affordance that makes 4chan particularly unique is ephemerality. As stated, the design of 4chan is quite straightforward. Anons post comments to ongoing threaded discussions, which start with an original post. Threads with the most recent comments appear first in order at the top of a given board, which result in the previous threads getting pushed down the page. Even in the case of the most popular threads 4chan boards only allow a finite number of comments before threads must be purged. As a result of this design, no matter how popular a discussion might be, once having reached the bump-limit threads expire, moving down the front page onto the second and third page either to be temporarily catalogued or else to disappear from the site altogether (see Image 1 for how popular threads on /pol/, represented in red, are purged after reaching the bump-limit).Image 1: 55 minutes of all 4chan/pol/ threads and their positions, sampled every 2 minutes (Hagen)Adding to this ephemerality, general discussion on 4chan is also governed by moderators — this in spite of 4chan’s anarchic reputation — who are uniquely empowered with the ability to effectively kill a thread, or a series of threads. Autosaging, one of the possible techniques available to moderators, is usually only exerted in instances when the discussion is deemed as being off-topic or inappropriate. As a result of the combined affordances, discussions can be extremely rapid and intense — in the case of the creation of Pizzagate, this process took 25 hours (see Tokmetzis for an account based on our research).The combination of 4chan’s unique affordances of anonymity and ephemerality brings us to a third factor that is crucial in order to understand how it is that 4chan anons cooked-up the Pizzagate story: the general thread. This process involves anons combing through previous discussion threads in order to create a new thread that compiles all the salient details on a given topic often archiving this data with services like Pastebin — an online content hosting service usually used to share snippets of code — or Google Docs since the latter tend to be less ephemeral than 4chan.In addition to keeping a conversation alive after a thread has been purged, in the case of Pizzagate we noticed that general threads were crucial to the process of framing those discussions going forward. While multiple general threads might emerge on a given topic, only one will consolidate the ongoing conversation thereby affording significant authority to a single author (as opposed to the anonymous mass) in terms of deciding on which parts of a prior thread to include or exclude. While general threads occur relatively commonly in 4chan, in the case of Pizzagate, this process seemed to take on the form of a real-time collective research effort that we will refer to as bullshit accumulation.The analytic philosopher Harry Frankfurt argues that bullshit is form of knowledge-production that appears unconcerned with objective truth, and as such can be distinguished from misinformation. Frankfurt sees bullshit as “more ambitious” than misinformation defining it as “panoramic rather than particular” since it is also prepared to “fake the context”, which in his estimation makes bullshit a “greater enemy of the truth” than lies (62, 52). Through an investigation into the origins of Pizzagate on /pol/, we thus are able to understand how grammatised collective action assists in the accumulation of bullshit in the service of a kind of post-truth political protest.Bullshit Accumulation4chan has a pragmatic and paradoxical relationship with belief that has be characterised in terms of kind of quasi-religious ironic collectivism (Burton). Because of this "weaponizing [of] irony" (Wilson) it is difficult to objectively determine to what extent anons actually believed that Pizzagate was real, and in a sense it is beside the point. In combination then with the site’s aforementioned affordances, it is this peculiar relationship with the truth which thus makes /pol/ so uniquely productive of bullshit. Image 2: Original pizzagate post on 4chan/pol/When #Pizzagate started trending on Twitter on 4 November 2017, it became clear that much of the narrative, and in particular the ‘pizza connection’, was based on arcane (if not simply ridiculous) interpretations of a cache of e-mails belonging to Hillary Clinton’s campaign manager John Podesta released by Wikileaks during the final weeks of the campaign. While many of the subsequent journalistic exposé would claim that Pizzagate began on 4chan, they did not explore its origins, perhaps because of the fact that 4chan does not consistently archive its threads. Our analysis overcame this obstacle by using a third party archive, Archive4plebs, which allowed us to pinpoint the first instance of a thread (/pol/) that discussed a connection between the keyword “pizza” and the leaked e-mails (Image 2).Image 3: 4chan/pol/ Pizzagate general threadsStarting with the timestamp of the first thread, we identified a total of 18 additional general threads related to the topic of Pizzagate (see Image 3). This establishes a 25-hour timeframe in which the Pizzagate narrative was formed (from Wednesday 2 November 2016, 22:17:20, until Thursday 3 November 2016, 23:24:01). We developed a timeline (Image 4) identifying 13 key moments in the development of the Pizzagate story such as the first attempts at disseminating the narrative to other platforms such as the Reddit forum r/The_Donald a popular forum whose reactionary politics had arguably set the broader tone for the Trump campaign (Heikkila).Image 4: timeline of the birth of Pizzagate. Design by Elena Aversa, information design student at Density Design Lab.The association between the Clinton campaign and pedophilia came from another narrative on 4chan known as ‘Orgy Island’, which alleged the Clintons flew to a secret island for sex tourism aboard a private jet called "Lolita Express" owned by Jeffrey Epstein, an American financier who had served 13 months in prison for soliciting an underage prostitute. As with the Pizzagate story, this narrative also appears to have developed through the shared infrastructure of Pastebin links included in general posts (Pastebin) often alongside Wikileaks links.Image 5: Clues about “pizza” being investigatedOrgy Island and other stories were thus combined together with ‘clues’, many of which were found in the leaked Podesta e-mails, in order to imagine the connections between pedophila and pizza. It was noticed that several of Podesta’s e-mails, for example, mentioned the phrase ‘cheese pizza’ (see Image 5), which on 4chan had long been used as a code word for ‘child pornography’ , the latter which is banned from the site.Image 6: leaked Podesta e-mail from Marina AbramovicIn another leaked e-mail, for example, sent to Podesta from the renowned performance artist Marina Abramovich (see Image 6), a reference to one of her art projects, entitled ‘Spirit Cooking’ — an oblique reference to the mid-century English occultist Aleister Crowley — was interpreted as evidence of Clinton’s involvement in satanic rituals (see Image 7). In the course of this one-day period then, many if not most of the coordinates for the Pizzagate narrative were thus put into place subsequently to be amplified by a new breed of populist social media activists in protest against a corrupt Democratic establishment.Image 7: /pol/ anon’s reaction to the e-mail in Image 6During its initial inception on /pol/, there was the apparent need for visualisations in order make sense of all the data. Quite early on in the process, for example, one anon posted:my brain is exploding trying to organize the connections. Anyone have diagrams of these connections?In response, anons produced numerous conspiratorial visualisations, such as a map featuring all the child-related businesses in the neighbourhood of the D.C. pizza parlor — owned by the boyfriend of the prominent Democratic strategist David Brock — which seemed to have logos of the same general shape as the symbols apparently used by pedophiles, and whose locations seems furthermore to line up in the shape of a satanic pentagram (see Image 8). Such visualisations appear to have served three purposes: they helped anons to identify connections, they helped them circumvent 4chan’s purging process — indeed they were often hosted on third-party sites such as Imgur — and finally they helped anons to ultimately communicate the Pizzagate narrative to a broader audience.Image 8. Anonymously authored Pizzagate map revealing a secret pedophilia network in D.C.By using an inductive approach to categorise the comments in the general threads a set of non-exclusive codes emerged, which can be grouped into five overarching categories: researching, interpreting, soliciting, archiving and publishing. As visualised in Image 9, the techniques used by anons in the genesis of Pizzagate appears as a kind of vernacular rendition of many of the same “digital methods” that we use as Internet researchers. An analysis of these techniques thus helps us to understanding how a grammatised form of collective action arises out of anons’ negotiations with the affordances of 4chan — most notably the constant purging of threads — and how, in special circumstances, this can lead to bullshit accumulation.Image 9: vernacular digital methods on /pol/ ConclusionWhat this analysis ultimately reveals is how 4chan/pol/’s ephemerality affordance contributed to an environment that is remarkably productive of bullshit. As a type of knowledge-accumulation, bullshit confirms preconceived biases through appealing to emotion — this at the expense of the broader shared epistemic principles, an objective notion of “truth” that arguably forms the foundation for public reason in large and complex liberal societies (Lynch). In this sense, the bullshit of Pizzagate resonates with Hannah Arendt’s analysis of totalitarian discourse which nurtures a conspiratorial redefining of emotional truth as “whatever respectable society had hypocritically passed over, or covered with corruption" (49).As right-wing populism establishes itself evermore firmly in many countries in which technocratic liberalism had formerly held sway, the demand for emotionally satisfying post-truth, will surely keep the new online bullshit factories like /pol/ in business. 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