Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy

In principal-agent models, a principal offers a contract to an agent to perform a certain task. The agent exerts a level of effort that maximizes her utility. The principal is oblivious to the agent's chosen level of effort, and conditions her wage only on possible outcomes. In this work, we consider a model in which the principal is unaware of the agent's utility and action space. She sequentially offers contracts to identical agents, and observes the resulting outcomes. We present an algorithm for learning the optimal contract under mild assumptions. We bound the number of samples needed for the principal obtain a contract that is within $\epsilon$ of her optimal net profit for every $\epsilon>0$

In silico Identification and Validation of a Linear and Naturally Immunogenic B-Cell Epitope of the Plasmodium vivax Malaria Vaccine Candidate Merozoite Surface Protein-9

Submitted by sandra infurna ([email protected]) on 2016-05-31T17:35:39Z No. of bitstreams: 1 dalma_banic_etal_IOC_2016.PDF: 1194916 bytes, checksum: b3b7e7ecb81de1803e07ac4391fc1c17 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-06-02T12:56:12Z (GMT) No. of bitstreams: 1 dalma_banic_etal_IOC_2016.PDF: 1194916 bytes, checksum: b3b7e7ecb81de1803e07ac4391fc1c17 (MD5)Made available in DSpace on 2016-06-02T12:56:12Z (GMT). No. of bitstreams: 1 dalma_banic_etal_IOC_2016.PDF: 1194916 bytes, checksum: b3b7e7ecb81de1803e07ac4391fc1c17 (MD5) Previous issue date: 2016Made available in DSpace on 2016-06-03T12:34:16Z (GMT). No. of bitstreams: 2 dalma_banic_etal_IOC_2016.PDF: 1194916 bytes, checksum: b3b7e7ecb81de1803e07ac4391fc1c17 (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Grupo de Modelagem Computacional. Fortaleza, CE, Brasil.Emory University. Yerkes National Primate Research Center. Emory Vaccine Center. Atlanta, GA, USA.Emory University. Yerkes National Primate Research Center. Emory Vaccine Center. Atlanta, GA, USA.Emory University. Environmental Health and Safety Office. Atlanta, GA, USA.Fundação Nacional de Saúde. Departamento de Entomologia. Laboratório central. Porto Velho, RO, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Referência Nacional de Simulídeos e Oncocercose. Rio de Janeiro, RJ, Brasil.Emory University. Yerkes National Primate Research Center. Emory Vaccine Center. Atlanta, GA, USA / Emory University. Emory University School of Medicine. Department of Medicine. Division of Infectious Diseases. Atlanta, GA, USA.Emory University. Yerkes National Primate Research Center. Emory Vaccine Center. Atlanta, GA, USA / Emory University. Emory University School of Medicine. Department of Medicine. Division of Infectious Diseases. Atlanta, GA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ, Brasil.Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly- available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9.We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and experimentally confirmed the potential of PvMSP9E795-A808 as an immunogenic linear B cell epitope within the P. vivax malaria vaccine candidate PvMSP9 and support its inclusion in future subunit vaccines

Three-dimensional structure prediction of the PvMSP9 RIRII domain.

<p>(A) 3D model of the PvMSP9 domain constructed using the Robetta algorithm. Red structures depict alpha helices, while the disordered region is represented in green. A small beta sheet was found between residues 850 and 858. (B) B-factor as calculated by GROMACS after 10ns simulation. The thicker segments represent the most flexible regions, while the thinnest represent the most rigid. (C) Electrostatic surface of the disordered region, showing a predominantly negative segment in red. (D) Same region show in B, without the electrostatic surface, showing the region 793–866 highlighted in green. The color scale was set from 5 kT/e (red) to 5 kT/e (blue), as calculated by APBS.</p

Frequency of total IgG and IgG subclasses responders to PvMSP9-RIRII and to PvMSP9_E795-A808.

<p>(A) Frequency of total IgG responders to PvMSP9-RIRII (red pie slice) and PvMSP9_E795-A808 (blue bar). (B) Frequency of IgG subclasses responders to PvMSP9-RIRII and PvMSP9_E795-A808 presented no statistically significant difference. (*) Indicates that the difference was significant (p < 0.05) for a comparison between a particular IgG subclass over the others IgG subclasses for the same antigen by chi-square test.</p

IgG reactivity index to PvMSP9-RIRII and PvMSP9_E795-A808.

<p>(A) Comparison of IgG reactivity index against PvMSP9-RIRII and PvMSP9-RII among responders and non-responders to PvMSP9_E795-A808. The lines indicate geometric means with 95% of confidence interval. The Mann Whitney test was used to compare medians of IgG reactivity indexes against recombinant proteins on responders and non-responders to synthetic peptide. Significant differences were indicated by *. (*) p<0.05; (**) p<0.001; *** p<0.0001 (B) Correlation between IgG reactivity indexes against PvMSP9_E795-A808 and against PvMSP9-RIRII. The correlation was assessed by Spearman’s rank test.</p

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

© 2020 Elsevier Ltd. All rights reserved.Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.info:eu-repo/semantics/publishedVersio

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field