A monoclonal antibody-based immunoassay to measure the antibody response against the repeat region of the circumsporozoite protein of Plasmodium falciparum

Background: The malaria vaccine candidate RTS, S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS, S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients and study their possible contribution to protection against infection. Results: MAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS, S/AS01 vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS, S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection. Conclusions: The competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS, S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection

Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay.

Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis

Fiat: Deductive Synthesis of Abstract Data Types in a Proof Assistant

We present Fiat, a library for the Coq proof assistant supporting refinement of declarative specifications into efficient functional programs with a high degree of automation. Each refinement process leaves a proof trail, checkable by the normal Coq kernel, justifying its soundness. We focus on the synthesis of abstract data types that package methods with private data. We demonstrate the utility of our framework by applying it to the synthesis of query structures--abstract data types with SQL-like query and insert operations. Fiat includes a library for writing specifications of query structures in SQL-inspired notation, expressing operations over relations (tables) in terms of mathematical sets. This library includes a suite of tactics for automating the refinement of specifications into efficient, correct- by-construction OCaml code. Using these tactics, a programmer can generate such an implementation completely automatically by only specifying the equivalent of SQL indexes, data structures capturing useful views of the abstract data. Throughout we speculate on the new programming modularity possibilities enabled by an automated refinement system with proved-correct rules. “Every block of stone has a statue inside it and it is the task of the sculptor to discover it.”--MichelangeloNational Science Foundation (U.S.) (NSF grant CCF-1253229)United States. Defense Advanced Research Projects Agency (DARPA, agreement number FA8750-12-2- 0293

What affects the magnitude of age-related dual-task costs in working memory? The role of stimulus domain and access to semantic representations

International audienceAlthough there is evidence that the effect of including a concurrent processing demand onthe storage of information in working memory is disproportionately larger for older thanyounger adults, not all studies show this age-related impairment, and the critical factorsresponsible for any such impairment remain elusive. Here we assess whether domain overlapbetween storage and processing activities, and access to semantic representations, areimportant determinants of performance in a sample of younger and older adults (N = 119).We developed four versions of a processing task by manipulating the type of stimuli involved(either verbal or non-verbal) and the decision that participants had to make about the stimulipresented on the screen. Participants either had to perform a spatial judgment, in decidingwhether the verbal or non-verbal item was presented above or below the centre of the screen,or a semantic judgment, in deciding whether the stimulus refers to something living or notliving. The memory task was serial-ordered recall of visually presented letters. The studyrevealed a large increase in age-related memory differences when concurrent processing wasrequired. These differences were smaller when storage and processing activities both usedverbal materials. Dual-task effects on processing were also disproportionate for older adults.Age differences in processing performance appeared larger for tasks requiring spatialdecisions rather than semantic decisions. We discuss these findings in relation to threecompeting frameworks of working memory and the extant literature on cognitive ageing

Measurement of the Free-Floating Planet Mass Function with Simultaneous Euclid and WFIRST Microlensing Parallax Observations

Free-floating planets are the remnants of violent dynamical rearrangements of planetary systems. It is possible that even our own solar system ejected a large planet early in its evolution. WFIRST will have the ability to detect free-floating planets over a wide range of masses, but it will not be able to directly measure their masses. Microlensing parallax observations can be used to measure the masses of isolated objects, including free-floating planets, by observing their microlensing events from two locations. The intra-L2 separation between WFIRST and Euclid is large enough to enable microlensing parallax measurements, especially given the exquisite photometric precision that both spacecraft are capable of over wide fields. In this white paper we describe how a modest investment of observing time could yield hundreds of parallax measurements for WFIRST's bound and free-floating planets. We also describe how a short observing campaign of precursor observations by Euclid can improve WFIRST's bound planet and host star mass measurements.Comment: Astro2020 White Pape

Delusions in frontotemporal lobar degeneration

We assessed the significance and nature of delusions in frontotemporal lobar degeneration (FTLD), an important cause of young-onset dementia with prominent neuropsychiatric features that remain incompletely characterised. The case notes of all patients meeting diagnostic criteria for FTLD attending a tertiary level cognitive disorders clinic over a three year period were retrospectively reviewed and eight patients with a history of delusions were identified. All patients underwent detailed clinical and neuropsychological evaluation and brain MRI. The diagnosis was confirmed pathologically in two cases. The estimated prevalence of delusions was 14 %. Delusions were an early, prominent and persistent feature. They were phenomenologically diverse; however paranoid and somatic delusions were prominent. Behavioural variant FTLD was the most frequently associated clinical subtype and cerebral atrophy was bilateral or predominantly right-sided in most cases. We conclude that delusions may be a clinical issue in FTLD, and this should be explored further in future work