Spatial control of Draper receptor signaling initiates apoptotic cell engulfment.

The engulfment of apoptotic cells is essential for tissue homeostasis and recovering from damage. Engulfment is mediated by receptors that recognize ligands exposed on apoptotic cells such as phosphatidylserine (PS). In this study, we convert Drosophila melanogaster S2 cells into proficient phagocytes by transfecting the Draper engulfment receptor and replacing apoptotic cells with PS-coated beads. Similar to the T cell receptor (TCR), PS-ligated Draper forms dynamic microclusters that recruit cytosolic effector proteins and exclude a bulky transmembrane phosphatase, consistent with a kinetic segregation-based triggering mechanism. However, in contrast with the TCR, localized signaling at Draper microclusters results in time-dependent depletion of actin filaments, which facilitates engulfment. The Draper-PS extracellular module can be replaced with FRB and FKBP, respectively, resulting in a rapamycin-inducible engulfment system that can be programmed toward defined targets. Collectively, our results reveal mechanistic similarities and differences between the receptors involved in apoptotic corpse clearance and mammalian immunity and demonstrate that engulfment can be reprogrammed toward nonnative targets

The role of emotions and physiological arousal in modulating impulsive behaviour.

Impulsivity received considerable attention in the context of drug misuse and certain neuropsychiatric conditions. Because of its great health and well-being importance, it is crucial to understand factors which modulate impulsive behaviour. As a growing body of literature indicates the role of emotional and physiological states in guiding our actions and decisions, we argue that current affective state and physiological arousal exert a significant influence on behavioural impulsivity. As 'impulsivity' is a heterogeneous concept, in this paper, we review key theories of the topic and summarise information about distinct impulsivity subtypes and their methods of assessment, pointing out to the differences between the various components of the construct. Moreover, we review existing literature on the relationship between emotional states, arousal and impulsive behaviour and suggest directions for future research

Deformation analysis of a metropolis from C- to X-band PSI: proof-of-concept with Cosmo-Skymed over Rome, Italy

Stability of monuments and subsidence of residential quarters in Rome (Italy) are depicted based on geospatial analysis of more than 310,000 Persistent Scatterers (PS) obtained from Stanford Method for Persistent Scatterers (StaMPS) processing of 32 COSMO-SkyMed 3m-resolution HH StripMap ascending mode scenes acquired between 21 March 2011 and 10 June 2013. COSMO-SkyMed PS densities and associated displacement velocities are compared with almost 20 years of historical C-band ERS- 1/2, ENVISAT and RADARSAT-1/2 imagery. Accounting for differences in image processing algorithms and satellite acquisition geometries, we assess the feasibility of ground motion monitoring in big cities and metropolitan areas by coupling newly acquired and legacy SAR in full time series. Limitations and operational benefits of the transition from medium resolution C-band to high resolution X-band PS data are discussed, alongside the potential impact on the management of expanding urban environments

Pharmacokinetics and pharmacogenomics of ribociclib in black patients with metastatic breast cancer the LEANORA study.

Underrepresented populations participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve did not significantly differ between PMs (39,230 h*ng/mL) and IM/NMs (43,546 h*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes

Translational Up-Regulation and High-Level Protein Expression from Plasmid Vectors by mTOR Activation via Different Pathways in PC3 and 293T Cells

BACKGROUND: Though 293T cells are widely used for expression of proteins from transfected plasmid vectors, the molecular basis for the high-level expression is yet to be understood. We recently identified the prostate carcinoma cell line PC3 to be as efficient as 293T in protein expression. This study was undertaken to decipher the molecular basis of high-level expression in these two cell lines. METHODOLOGY/PRINCIPAL FINDINGS: In a survey of different cell lines for efficient expression of platelet-derived growth factor-B (PDGF-B), β-galactosidase (β-gal) and green fluorescent protein (GFP) from plasmid vectors, PC3 was found to express at 5-50-fold higher levels compared to the bone metastatic prostate carcinoma cell line PC3BM and many other cell lines. Further, the efficiency of transfection and level of expression of the reporters in PC3 were comparable to that in 293T. Comparative analyses revealed that the high level expression of the reporters in the two cell lines was due to increased translational efficiency. While phosphatidic acid (PA)-mediated activation of mTOR, as revealed by drastic reduction in reporter expression by n-butanol, primarily contributed to the high level expression in PC3, multiple pathways involving PA, PI3K/Akt and ERK1/2 appear to contribute to the abundant reporter expression in 293T. Thus the extent of translational up-regulation attained through the concerted activation of mTOR by multiple pathways in 293T could be achieved through its activation primarily by the PA pathway in PC3. CONCLUSIONS/SIGNIFICANCE: Our studies reveal that the high-level expression of proteins from plasmid vectors is effected by translational up-regulation through mTOR activation via different signaling pathways in the two cell lines and that PC3 is as efficient as 293T for recombinant protein expression. Further, PC3 offers an advantage in that the level of expression of the protein can be regulated by simple addition of n-butanol to the culture medium

Superior Inhibitory Control and Resistance to Mental Fatigue in Professional Road Cyclists

Purpose: Given the important role of the brain in regulating endurance performance, this comparative study sought to determine whether professional road cyclists have superior inhibitory control and resistance to mental fatigue compared to recreational road cyclists. Methods: After preliminary testing and familiarization, eleven professional and nine recreational road cyclists visited the lab on two occasions to complete a modified incongruent colour-word Stroop task (a cognitive task requiring inhibitory control) for 30 min (mental exertion condition), or an easy cognitive task for 10 min (control condition) in a randomized, counterbalanced cross-over order. After each cognitive task, participants completed a 20-min time trial on a cycle ergometer. During the time trial, heart rate, blood lactate concentration, and rating of perceived exertion (RPE) were recorded. Results: The professional cyclists completed more correct responses during the Stroop task than the recreational cyclists (705±68 vs 576±74, p = 0.001). During the time trial, the recreational cyclists produced a lower mean power output in the mental exertion condition compared to the control condition (216±33 vs 226±25 W, p = 0.014). There was no difference between conditions for the professional cyclists (323±42 vs 326±35 W, p = 0.502). Heart rate, blood lactate concentration, and RPE were not significantly different between the mental exertion and control conditions in both groups. Conclusion: The professional cyclists exhibited superior performance during the Stroop task which is indicative of stronger inhibitory control than the recreational cyclists. The professional cyclists also displayed a greater resistance to the negative effects of mental fatigue as demonstrated by no significant differences in perception of effort and time trial performance between the mental exertion and control conditions. These findings suggest that inhibitory control and resistance to mental fatigue may contribute to successful road cycling performance. These psychobiological characteristics may be either genetic and/or developed through the training and lifestyle of professional road cyclists

Effect of linguistic acculturation on self-efficacy and anxiety in caregivers of Latina breast cancer survivors.

12121 Background: Latina breast cancer survivors and their caregivers face unique challenges. Acculturation is the acquisition of the cultural elements of a dominant society. Higher acculturation in Latino survivors is positively correlated with self-efficacy in patient-provider communication and improved patient-reported outcomes. There is a paucity of research on how language acculturation affects caregiver and patient outcomes. We examined associations over time between linguistic acculturation among caregivers of Latina survivors and outcomes of caregiver self-efficacy and anxiety. Methods: We partnered with four community-based organizations that serve Latino families facing cancer. We enrolled 136 Latina breast cancer survivors and their caregivers for a randomized trial comparing a dyadic coping intervention to usual care (e.g., support groups). Participants completed surveys including demographic and clinical information, the short acculturation scale for Hispanics, caregiver inventory to assess self-efficacy and PROMIS domains of anxiety at baseline and 6-months after the intervention. Results: In multivariate linear regressions models, we examined the effect of acculturation on caregiver self-efficacy and anxiety, controlling for demographics (patient and caregiver age, caregiver education, employment), patient treatment history (chemotherapy and surgery) patient and caregiver language preference (Spanish or English) and intervention arm (intervention vs. usual care). Greater caregiver self-efficacy at 6-months was associated with younger patient age (t=-2.93, p=.004), older caregiver age (t=2.63, p = .01), female caregiver gender (t=2.79, p = .006) and higher acculturation (t=2.01, p=.04), controlling for baseline self-efficacy, patient language and randomization group. Caregiver anxiety was not related to caregiver acculturation or patient language preferences. Conclusions: Caregivers’ language acculturation was significantly associated with their self-efficacy over time, suggesting that caregivers with lower acculturation experience lower confidence in their provision of care for Latina survivors. These findings are particularly salient because participants for this study were enrolled from organizations with bilingual services. Caregivers of Latina survivors without access to these community resources may face even more striking challenges. Future work can explore how caregivers’ confidence relates to survivors’ adherence to care and patient outcomes over time. </jats:p