What is the effect of systemic anticancer treatment on cognitive function?

Treatment regimens for solid tumours have been extensively investigated for their physical toxic effects, but far less is known about the potential impairment of cognitive function by anticancer treatment regimens. Here, we review published studies that examined cognitive function in adult patients receiving systemic therapy for solid tumours. Our review suggests that patients can experience cognitive changes related to their treatment. However, several studies had methodological limitations, such as use of a limited sample size, lack of baseline assessment, and lack of control for potential confounding factors. Better designed clinical trials are required so that the difficulties patients face in terms of reduced cognitive function as a result of anticancer treatment can be fully elucidated. These trials should have sufficient statistical power and, importantly, should also be prospective.

Multi-touch and keyboard/mouse devices comparison in an information search task: influence on cognitive load and task engagement

Nowadays multi-touch devices (MTD) can be found in all kind of contexts. In the learning context, MTD availability leads many teachers to use them in their class room, to support the use of the devices by students, or to assume that it will enhance the learning processes. Despite the raising interest for MTD, few researches studying the impact in term of performance or the suitability of the technology for the learning context exist. However, even if the use of touch-sensitive screens rather than a mouse and keyboard seems to be the easiest and fastest way to realize common learning tasks (as for instance web surfing behaviour), we notice that the use of MTD may lead to a less favourable outcome. The complexity to generate an accurate fingers gesture and the split attention it requires (multi-tasking effect) make the use of gestures to interact with a touch-sensitive screen more difficult compared to the traditional laptop use. More precisely, it is hypothesized that efficacy and efficiency decreases, as well as the available cognitive resources making the users’ task engagement more difficult. Furthermore, the presented study takes into account the moderator effect of previous experiences with MTD. Two key factors of technology adoption theories were included in the study: familiarity and self-efficacy with the technology.Sixty university students, invited to a usability lab, are asked to perform information search tasks on an online encyclopaedia. The different tasks were created in order to execute the most commonly used mouse actions (e.g. right click, left click, scrolling, zooming, key words encoding…). Two different conditions were created: (1) MTD use and (2) laptop use (with keyboard and mouse). The cognitive load, self-efficacy, familiarity and task engagement scales were adapted to the MTD context. Furthermore, the eye-tracking measurement would offer additional information about user behaviours and their cognitive load.Our study aims to clarify some important aspects towards the usage of MTD and the added value compared to a laptop in a student learning context. More precisely, the outcomes will enhance the suitability of MTD with the processes at stakes, the role of previous knowledge in the adoption process, as well as some interesting insights into the user experience with such devices.

ERM transactivation is up-regulated by the repression of DNA binding after the PKA phosphorylation of a consensus site at the edge of the ETS domain

The final step of the transduction pathway is the activation of gene transcription, which is driven by kinase cascades leading to changes in the activity of many transcription factors. Among these latter, PEA3/E1AF, ER81/ETV1, and ERM, members of the well conserved PEA3 group from the Ets family are involved in these processes. We show here that protein kinase A (PKA) increases the transcriptional activity of human ERM and human ETV1, through a Ser residue situated at the edge of the ETS DNA-binding domain. PKA phosphorylation does not directly affect the ERM transactivation domains but does affect DNA binding activity. Unphosphorylated wild-type ERM bound DNA avidly, whereas after PKA phosphorylation it did so very weakly. Interestingly, S367A mutation significantly reduced the ERM-mediated transcription in the presence of the kinase, and the DNA binding of this mutant, although similar to that of unphosphorylated wild-type protein, was insensitive to PKA treatment. Mutations, which may mimic a phosphorylated serine, converted ERM from an efficient DNA-binding protein to a poor DNA binding one, with inefficiency of PKA phosphorylation. The present data clearly demonstrate a close correlation between the capacity of PKA to increase the transactivation of ERM and the drastic down-regulation of the binding of the ETS domain to the targeted DNA. What we thus demonstrate here is a relatively rare transcription activation mechanism through a decrease in DNA binding, probably by the shift of a non-active form of an Ets protein to a PKA-phosphorylated active one, which should be in a conformation permitting a transactivation domain to be active.

Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATPBinding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds. The transport of these drugs across the membrane is coincident with changes in the size and shape of this pocket during the course of the transport cycle. Here, we present the crystal structures of three inward-facing conformations of mouse P-gp derived from two different crystal forms. One structure has a nanobody bound to the C-terminal side of the first nucleotide-binding domain. This nanobody strongly inhibits the ATP hydrolysis activity of mouse Pgp by hindering the formation of a dimeric complex between the ATP-binding domains, which is essential for nucleotide hydrolysis. Together, these inward-facing conformational snapshots of P-gp demonstrate a range of flexibility exhibited by this transporter, which is likely an essential feature for the binding and transport of large, diverse substrates. The nanobody-bound structure also reveals a unique epitope on P-gp.

Exploring the benefits of using multi-touch devices in performing information search tasks: An analysis in terms of performance, cognitive load and task engagement

Over the last decade, multi-touch devices (MTD) have spread in a range of contexts. In the learning context, MTD accessibility leads more and more teachers to use them in their classroom, assuming that it will improve the learning activities. Despite a growing interest, only few studies have focused on the impacts of MTD use in terms of performance and suitability in a learning context.However, even if the use of touch-sensitive screens rather than a mouse and keyboard seems to be the easiest and fastest way to realize common learning tasks (as for instance web surfing), we notice that the use of MTD may lead to a less favorable outcome. More precisely, tasks that require users to generate complex and/or less common gestures may increase extrinsic cognitive load and impair performance, especially for intrinsically complex tasks. It is hypothesized that task and gesture complexity will affect users’ cognitive resources and decrease task efficacy and efficiency. Because MTD are supposed to be more appealing, it is assumed that it will also impact cognitive absorption. The present study also takes into account user’s prior knowledge concerning MTD use and gestures by using experience with MTD as a moderator. Sixty university students were asked to perform information search tasks on an online encyclopedia. Tasks were set up so that users had to generate the most commonly used mouse actions (e.g. left/right click, scrolling, zooming, text encoding…). Two conditions were created: MTD use and laptop use (with mouse and keyboard) in order to make a comparison between the two devices. An eye tracking device was used to measure user’s attention and cognitive load. Our study sheds light on some important aspects towards the use of MTD and the added value compared to a laptop in a student learning context.

15N NMR relaxation data reveal significant chemical exchange broadening in the alpha-domain of human α-lactalbumin

Human alpha-lactalbumin (alpha-LA), a 123-residue calcium-binding protein, has been studied using (15)N NMR relaxation methods in order to characterize backbone dynamics of the native state at the level of individual residues. Relaxation data were collected at three magnetic field strengths and analyzed using the model-free formalism of Lipari and Szabo. The order parameters derived from this analysis are generally high, indicating a rigid backbone. A total of 46 residues required an exchange contribution to T(2); 43 of these residues are located in the alpha-domain of the protein. The largest exchange contributions are observed in the A-, B-, D-, and C-terminal 3(10)-helices of the alpha-domain; these residues have been shown previously to form a highly stable core in the alpha-LA molten globule. The observed exchange broadening, along with previous hydrogen/deuterium amide exchange data, suggests that this part of the alpha-domain may undergo a local structural transition between the well-ordered native structure and a less-ordered molten-globule-like structure.

Solution structure of the N-terminal transactivation domain of ERM modified by SUMO-1.

ERM is a member of the PEA3 group of the Ets transcription factor family that plays important roles in development and tumorigenesis. The PEA3s share an N-terminal transactivation domain (TADn) whose activity is inhibited by small ubiquitin-like modifier (SUMO). However, the consequences of sumoylation and its underlying molecular mechanism remain unclear. The domain structure of ERM TADn alone or modified by SUMO-1 was analyzed using small-angle X-ray scattering (SAXS). Low resolution shapes determined ab initio from the scattering data indicated an elongated shape and an unstructured conformation of TADn in solution. Covalent attachment of SUMO-1 does not perturb the structure of TADn as indicated by the linear arrangement of the SUMO moiety with respect to TADn. Thus, ERM belongs to the growing family of proteins that contain intrinsically unstructured regions. The flexible nature of TADn may be instrumental for ERM recognition and binding to diverse molecular partners.

Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation.

Immunoglobulin superfamily (IgSF) domains are conserved structures present in many proteins in eukaryotes and prokaryotes. These domains are well-capable of facilitating sequence variation, which is most clearly illustrated by the variable regions in immunoglobulins (Igs) and T cell receptors (TRs). We studied an antibody-deficient patient suffering from recurrent respiratory infections and with impaired antibody responses to vaccinations. Patient's B cells showed impaired Ca(2+) influx upon stimulation with anti-IgM and lacked detectable CD19 membrane expression. CD19 sequence analysis revealed a homozygous missense mutation resulting in a tryptophan to cystein (W52C) amino acid change. The affected tryptophan is CONSERVED-TRP 41 located on the C-strand of the first extracellular IgSF domain of CD19 and was found to be highly conserved, not only in mammalian CD19 proteins, but in nearly all characterized IgSF domains. Furthermore, the tryptophan is present in all variable domains in Ig and TR and was not mutated in 117 Ig class-switched transcripts of B cells from controls, despite an overall 10% amino acid change frequency. In vitro complementation studies and CD19 western blotting of patient's B cells demonstrated that the mutated protein remained immaturely glycosylated. This first missense mutation resulting in a CD19 deficiency demonstrates the crucial role of a highly conserved tryptophan in proper folding or stability of IgSF domains.