Gradual Program Analysis

Dataflow analysis and gradual typing are both well-studied methods to gain information about computer programs in a finite amount of time. The gradual program analysis project seeks to combine those two techniques in order to gain the benefits of both. This thesis explores the background information necessary to understand gradual program analysis, and then briefly discusses the research itself, with reference to publication of work done so far. The background topics include essential aspects of programming language theory, such as syntax, semantics, and static typing; dataflow analysis concepts, such as abstract interpretation, semilattices, and fixpoint computations; and gradual typing theory, such as the concept of an unknown type, liftings of predicates, and liftings of functions

Trend analysis of the long-term Swiss ozone measurements

Trend analyses, assuming a linear trend which started at 1970, were performed from total ozone measurements from Arosa (Switzerland, 1926-1991). Decreases in monthly mean values were statistically significant for October through April showing decreases of about 2.0-4 percent per decade. For the period 1947-91, total ozone trends were further investigated using a multiple regression model. Temperature of a mountain peak in Switzerland (Mt. Santis), the F10.7 solar flux series, the QBO series (quasi biennial oscillation), and the southern oscillation index (SOI) were included as explanatory variables. Trends in the monthly mean values were statistically significant for December through April. The same multiple regression model was applied to investigate the ozone trends at various altitudes using the ozone balloon soundings from Payerne (1967-1989) and the Umkehr measurements from Arosa (1947-1989). The results show four different vertical trend regimes: On a relative scale changes were largest in the troposphere (increase of about 10 percent per decade). On an absolute scale the largest trends were obtained in the lower stratosphere (decrease of approximately 6 per decade at an altitude of about 18 to 22 km). No significant trends were observed at approximately 30 km, whereas stratospheric ozone decreased in the upper stratosphere

Gradual Program Analysis for Null Pointers

Static analysis tools typically address the problem of excessive false positives by requiring programmers to explicitly annotate their code. However, when faced with incomplete annotations, many analysis tools are either too conservative, yielding false positives, or too optimistic, resulting in unsound analysis results. In order to flexibly and soundly deal with partially-annotated programs, we propose to build upon and adapt the gradual typing approach to abstract-interpretation-based program analyses. Specifically, we focus on null-pointer analysis and demonstrate that a gradual null-pointer analysis hits a sweet spot, by gracefully applying static analysis where possible and relying on dynamic checks where necessary for soundness. In addition to formalizing a gradual null-pointer analysis for a core imperative language, we build a prototype using the Infer static analysis framework, and present preliminary evidence that the gradual null-pointer analysis reduces false positives compared to two existing null-pointer checkers for Infer. Further, we discuss ways in which the gradualization approach used to derive the gradual analysis from its static counterpart can be extended to support more domains. This work thus provides a basis for future analysis tools that can smoothly navigate the tradeoff between human effort and run-time overhead to reduce the number of reported false positives

Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with alpha-synuclein at the single molecule level

Background: Fibrillar amyloid-like deposits and co-deposits of tau and alpha-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and alpha-synuclein are not well understood. Results: We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with alpha-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3 beta exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of alpha-synuclein in pre-formed tau oligomers. Conclusions: Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration

Addition of Standard Enzalutamide Medication Shows Synergistic Effects on Response to [177Lu]Lu-PSMA-617 Radioligand Therapy in mCRPC Patients with Imminent Treatment Failure—Preliminary Evidence of Pilot Experience

Well-received strong efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) does not prevent patients from either early or eventual disease progression under this treatment. In this study, we investigated co-medication with enzalutamide as a potential re-sensitizer for PSMA-RLT in patients with imminent treatment failure on standard 177Lu-based PSMA-RLT. Ten mCRPC patients who exhibited an insufficient response to conventional [177Lu]Lu PSMA-617 RLT received oral medication of enzalutamide 160 mg/d as an adjunct to continued PSMA RLT. Prostate-specific antigen (PSA) and standard toxicity screening lab work-up were performed to assess the treatment efficacy and safety in these individuals. The mean PSA increase under PSMA-RLT before starting the re-sensitizing procedure was 22.4 ± 26.5%. After the introduction of enzalutamide medication, all patients experienced a PSA decrease, –43.4 ± 20.0% and –48.2 ± 39.0%, after one and two cycles of enzalutamide-augmented PSMA-RLT, respectively. A total of 70% of patients (7/10) experienced partial remission, with a median best PSA response of –62%. Moreover, 5/6 enzalutamide-naïve patients and 2/4 patients who had previously failed enzalutamide exhibited a partial remission. There was no relevant enzalutamide-induced toxicity observed in this small cohort. This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of 177Lu-based PSMA-RLT ± enzalutamide

Privacy Concerns in Responses to Sensitive Questions. A Survey Experiment on the Influence of Numeric Codes on Unit Nonresponse, Item Nonresponse, and Misreporting

Paper-and-pencil surveys are a widely used method for gaining data. Numeric codes printed on the questionnaire are often a prerequisite for the use of scan software, which, in turn, permits a fast and efficient entering of the data from such surveys. However, printed numbers used for optical mark recognition on a questionnaire can provoke concerns about anonymity that may lead to unit nonresponse, item nonresponse, and misreporting. To test this, we conducted an experiment in a mail survey on group-focused enmity, printing a scanner code on half of the questionnaires. Our results show no significant deviation concerning unit nonresponse. We find a higher item nonresponse and misreporting bias towards socially desirable answers in sensitive questions if the questionnaire is marked with a code. The influence of biased responses on regression results is minor. If the numeric code is brought to the respondents’ attention in the cover letter, regression coefficients might be affected. Therefore we conclude that researchers should trade off these small biases against the usefulness of the code. From a methodological perspective, we recommend not to make a statement concerning the numeric code in the cover letter. Our results are of relevance for researchers conducting paper-and-pencil surveys as well as for those analyzing data sets from these surveys. While this article analyzes biases caused by scanner codes, the results are potentially transferable to printed identification numbers used in panel studies, in survey experiments, or to match paradata or context data

Quality control concept and recent developments of the light climatic observatory at Arosa: Ozone measuring station of the Swiss Meteorological Institute (LKO)

Total ozone observations of two Dobson instruments (D15 and D101, C- and AD wavelength pair observations) and of two Brewer instruments (Br40 and Br72) are currently performed at the LKO at Arosa. A quality control concept is presented in order to make best use of the large number of quasi-simultaneous measurements. The longest ozone series of the world is mainly based on the measurements of the Dobson instrument D15 (wavelength pair C). Since the last years D15 has suffered from instrumental problems. The transformation of the longterm series to the measurements of D101(AD) is described

Articulating User Preferences in Many-Objective Problems by Sampling the Weighted Hypervolume

International audienceThe hypervolume indicator has become popular in recent years both for performance assessment and to guide the search of evolutionary multiobjective optimizers. Two critical research topics can be emphasized with respect to hyper\-volume-based search: (i) the hypervolume indicator inherently introduces a specific preference and the question is how arbitrary user preferences can be incorporated; (ii) the exact calculation of the hypervolume indicator is expensive and efficient approaches to tackle many-objective problems are needed. In two previous studies, we addressed both issues independently: a study proposed the weighted hypervolume indicator with which user-defined preferences can be articulated; other studies exist that propose to estimate the hypervolume indicator by Monte-Carlo sampling. Here, we combine these two approaches for the first time and extend them, i.e., we present an approach of sampling the weighted hypervolume to incorporate user-defined preferences into the search for problems with many objectives. In particular, we propose weight distribution functions to stress extreme solutions and to define preferred regions of the objective space in terms of so-called preference points; sampling them allows to tackle problems with many objectives. Experiments on several test functions with up to 25 objectives show the usefulness of the approach in terms of decision making and search

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

Background: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. Methods: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. Results: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe3+ induced asyn129E oligomers and markedly reduced in Al3+ induced oligomers. Conclusion: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase