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Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.

Effective communication that encourages patient participation and maximizes rehabilitation outcomes is a primary goal in physical therapy (PT) education. A framework that provides insight into individual conceptualization of rehabilitation goals and strategies is Regulatory Focus Theory, which examines motivation stemming from two self-regulatory systems: promotion (i.e., concerns with nurturance, progress, and attaining gains vs. non-gains) and prevention (i.e., concerns with security, safety, and maintaining non-losses vs. losses). We distributed questionnaires assessing promotion (vs. prevention) predominance both personally and in a rehabilitation context, as well as sociodemographic data, to 116 Doctor of Physical Therapy students. On average, students were promotion (vs. prevention) predominant in their personal lives, with predominance scores varying as a function of sex. Males exhibited a predominant personal promotion focus, while females showed a relative balance between personal promotion versus prevention concerns. In contrast, when framed as working with patients in a rehabilitation context, females demonstrated a promotion focus, whereas promotion and prevention concerns were balanced in males. As suggested by these differences, we found that males and females demonstrated significant shifts in regulatory focus in a goal-setting rehabilitation (vs. personal) context in opposing directions, with females becoming more promotion-predominant and males becoming more prevention-predominant. Additionally, regulatory focus in a rehabilitation context varied as a function of students’ race/ethnicity, reason for choosing PT, and student year. Further studies are needed to investigate how PT curriculum influences motivational predilections in clinical settings, as well as to identify the impact of these motives on patient rehabilitation outcomes.

As human beings, we are bound by time. It is essential for daily functioning, and yet our ability to keep track of time is influenced by a myriad of factors (Block & Zakay, 1997, Psychonomic Bulletin & Review, 4[2], 184-197). First and foremost, time estimation has been found to depend on whether participants estimate the time prospectively or retrospectively (Hicks et al., 1976, The American Journal of Psychology, 89[4], 719-730). However, there is a paucity of research investigating differences between these two conditions in tasks over two minutes (Tobin et al., 2010, PLOS ONE, 5[2], Article e9271). Moreover, estimates have also been shown to be influenced by cognitive load. We thus investigated participants' ability to keep track of time during a visual and memory search task and manipulated its difficulty and duration. Two hundred and ninety-two participants performed the task for 8 or 58 minutes. Participants in the prospective time judgment condition were forewarned of an impending time estimate, whereas participants in the retrospective condition were not. Cognitive load was manipulated and assessed by altering the task's difficulty. The results revealed a higher overestimation of time in the prospective condition compared with the retrospective condition. However, this was found in the 8-minute task only. Overall, participants significantly overestimated the duration of the 8-minute task and underestimated the 58-minute task. Finally, cognitive load had no effect on participants' time estimates. Thus, the well-known cross-over interaction between cognitive load and estimation paradigm (Block et al., 2010, Acta Psychologica, 134[3], 330-343) did not extend to a longer duration in this experiment.

Developing valid tools that assess key determinants of canine healthspan such as frailty and health-related quality of life (HRQL) is essential to characterizing and understanding aging in dogs. Additionally, because the companion dog is an excellent translational model for humans, such tools can be applied to evaluate gerotherapeutics and investigate mechanisms underlying longevity in both dogs and humans. In this multi-center, cross sectional study, we investigated the use of a clinical questionnaire (Canine Frailty Index; CFI; Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs. Results demonstrated validity of the tools by confirming expectations that frailty and HRQL deteriorate with age. CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (≥ 7 years of age) compared to young dogs (≥ 2 and < 6 years of age). Body size (small < 25lbs or large > 50lbs) was not associated with CFI or total HRQL score. However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort. Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL are useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life. Establishing validated tools that operationalize the assessment of canine healthspan is critical for the advancement of geroscience and the development of gerotherapeutics that benefit both human and veterinary medicine.Graphical abstractGraphical summary of the design, results, and conclusions of the study.

Subjective confidence reports are used in numerous research paradigms to examine the extent to which participants are aware of their performance in a task. By examining the discrepancy between objective performance and subjective confidence ratings, inferences can be made about the conditions in which participants have greater explicit knowledge of the representations and processes used to complete a task. In the current study, we examined the effects of prior knowledge on subjective assessments of performance using a categorisation task wherein lists of features that defined exemplars shared latent feature associations on the basis of prior knowledge or had no prior associations. Using 2 methods for computing confidence, we demonstrate the strengths and limitations of these measures of subjective awareness. Whereas our findings replicated the effect of prior knowledge on learning, our results challenge the role of explicit and implicit knowledge suggested by previous research using a similar paradigm. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The establishment of clinically relevant models for tumor metastasis and drug testing is a major challenge in cancer research. Here we report a physiologically relevant assay enabling quantitative analysis of metastatic capacity of tumor cells following implantation into the chorioallantoic membrane (CAM). Engraftment of as few as 103 non-small cell lung cancer (NSCLC) and prostate cancer (PCa) cell lines was sufficient for both primary tumor and metastasis formation. Standard 2D-imaging as well as 3D optical tomography imaging were used for the detection of fluorescent metastatic foci in the chick embryo. H2228- and H1975-initiated metastases were confirmed by genomic analysis. We quantified the inhibitory effect of docetaxel on LNCaP, and that of cisplatin on A549- and H1299-initiated metastatic growths. The CAM assay also mimicked the sensitivity of ALK-rearranged H2228 and EGFR-mutated H1975 NSCLC cells to tyrosine kinase inhibitors crizotinib and gefitinib respectively, as well as sensitivity of LNCaP cells to androgen-dependent enzalutamide therapy. The assay was suggested to reconstitute the bone metastatic tropism of PCa cells. We show that the CAM chick embryo model may be a powerful preclinical platform for testing and targeting of the metastatic capacity of cancer cells.

Research has shown that undergraduate courses in psychology often fail to make students accept the discipline as a science. It may be that explicit instruction is not sufficient to modify students’ conceptualization of psychology as something other than science. The goal of this study was to examine introductory psychology students’ conceptualizations of psychology and science. Five hundred and seventy participants completed a free association task for disciplines that included psychology and other sciences. They also provided ratings for these disciplines on relevant dimensions (e.g., important and scientific) and were asked “Is psychology a science?” Students tended to agree that psychology was a science but rated it to be less scientific than the natural sciences. Moreover, the free association results suggested that psychology was semantically distant from the other sciences. Thus, successful pedagogy will need to focus on conceptual change if students are to accept psychology as a science.

International audience; Background: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinibresistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. Patients and methods: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. Results: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n ¼ 2 FGFR3-TACC3, n ¼ 1 KIF5B-RET, n ¼ 1 STRN-ALK fusions; n ¼ 2 BRAF V600E , n ¼ 1 KRAS G12V , n ¼ 1 KRAS G12R , n ¼ 1 KRAS G12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. Conclusions: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

Western literature as we know it begins with a mythic war: the anger of Achilles that “brought thousandfold pain upon the Achaeans.” Many non-Western literary traditions are built on similar origin stories: the Indian epic Mahabharata is, like the Iliad, a war story, and one could find many other examples in other traditions, both oral and written....

Alison LaCroix and William Birdthistle examine two works: Sebastian Barry’s A Long Long Way (2005) and Michael Ondaatje’s The English Patient (1992), which was made into a film, directed by Anthony Minghella, in 1996. Both novels challenge traditional notions of loyalty in wartime. Although they focus on different wars—Barry on World War I, Ondaatje on World War II—the novels raise a pair of related, crucial questions: Loyalty to what and to whom? The books interrogate the meaning of national sovereignty in an age of empire or imperial decline, as their characters confront law in personal ways. Barry’s novel holds out a slim hope that the birth of the Irish Republic might make comprehensible, even if not justify, the bloodbaths of the Western Front. Ondaatje, however, challenges the primacy of nations, suggesting instead that personal loyalties or regional ties provide the only meaningful connections for individuals uprooted by modern global warfare. Both novels thus force their characters to negotiate an overlapping series of boundaries: local and national political lines, as well as ethnic, familial, and emotional borders.

Mitochondrial permeability transition pore (mPTP) formation is well documented in isolated mitochondria. However, convincing detection of mPTP in whole cells remains elusive. In this study, we describe a high-throughput assay for Ca2+-activated mPTP opening in platelets using HyperCyt flow cytometry. In addition, we demonstrate that in several nucleated cells, using multiple approaches, the detection of cyclophilin D-dependent mPTP opening is highly challenging. Results with the mitochondrial-targeted Ca2+-sensing green fluorescent protein (mito-Case12) suggest the involvement of protein phosphatase 2B (PP2B; calcineurin) in regulating mitochondrial dynamics. Our results highlight the danger of relying on cyclosporine A alone as a pharmacological tool, and the need for comprehensive studies of mPTP in the cell.

Function learning research has shown that people tend to underestimate positive linear functions when extrapolating Y for X-values below the training range. Kwantes and Neal (2006) proposed that this underestimation occurs because people anchor their Y-estimates at zero. It is equally plausible, however, that people are biased to make Y-estimates similar to the presented X-value. To differentiate these 2 explanations, 135 participants extrapolated positive linear functions with a y-intercept either greater than or less than zero. In line with the anchoring hypothesis, participants underestimated in the lower extrapolation region when the y-intercept was positive, but overestimated when the y-intercept was negative. These results are consistent with a version of the extrapolation association model (EXAM; Delosh, Busemeyer, & McDaniel, 1997), which proposes that people interpolate linearly between the training exemplars and zero in the lower extrapolation region. (PsycINFO Database Record

Although high-throughput sequencing is revolutionising medicine, data on the actual cost of whole exome sequencing (WES) applications are needed. We aimed at assessing the cost of WES at a French cancer institute in 2015 and 2018.Actual costs of WES application in oncology research were determined using both micro-costing and gross-costing for the years 2015 and 2018, before and after the acquisition of a new sequencer. The entire workflow process of a WES test was tracked, and the number and unit price of each resource were identified at the most detailed level, from library preparation to bioinformatics analyses. In addition, we conducted an ad hoc analysis of the bioinformatics storage costs of data issued from WES analyses.The cost of WES has decreased substantially, from €1921 per sample (i.e. cost of €3842 per patient) in 2015 to €804 per sample (i.e. cost of €1,608 per patient) in 2018, representing a decrease of 58%. In the meantime, the cost of bioinformatics storage has increased from €19,836 to €200,711.This study suggests that WES cost has decreased significantly in recent years. WES has become affordable, even though clinical utility and efficiency still need to be confirmed.

The 1840s and 1850s witnessed the publication of three great “condition of England” novels: Charlotte Brontë’s Shirley (1849) and Elizabeth Gaskell’s Mary Barton (1848) and North and South (1855). All three novels examine the consequences of the Industrial Revolution in England, and all are critical in their appraisal of its effects on individuals, society, and the national—and even the international—realm. All three focus on the world of commerce and manufacturing, but the realm of law is never far away. Yet there are differences: in Shirley, Brontë delves into the interior lives of two very different female protagonists, while Gaskell’s narratives are more concerned with economic and social injustice. Brontë set Shirley during the Napoleonic Wars of the early 1800s, a period of British imperial struggle and ultimate triumph. Gaskell placed the action of Mary Barton a decade prior to its writing, but in North and South she depicted her current moment, with a consequent sharpening of her critique. This essay examines the novels’ treatment of a set of interconnected themes: commerce, law, and revolution, with reference to related questions of politics, gender, and time.