United States higher education prioritizes independence as the cultural ideal. As a result, first-generation students (neither parent has a four-year degree) often confront an initial cultural ...mismatch early on in college settings: they endorse relatively interdependent cultural norms that diverge from the independent cultural ideal. This initial cultural mismatch can lead first-generation students to perform less well academically compared with continuing-generation students (one or more parents have a four-year degree) early in college. Yet, what happens as first-generation students experience the university culture throughout their time in college? Using cross-sectional and longitudinal approaches, we find that initial cultural mismatch is associated with psychological and academic costs that persist until graduation. First, at college entry, we find social class differences in cultural norms: first-generation students endorse more interdependent cultural norms than their continuing-generation peers. Second, endorsing interdependence at college entry predicts reduced subjective sense of fit in college four years later. Third, lower subjective sense of fit predicts lower grade point average and subjective social status upon graduation. Together, these results suggest that initial cultural mismatch contributes to worse experiences and academic outcomes among first-generation students, and that these disparities persist even until graduation. Further, we find that social class differences in cultural norms remain stable throughout college: first-generation students continue to endorse more interdependence than do continuing-generation students. We suggest providing access is not sufficient to reduce social class inequity; colleges need to create more inclusive environments to ensure that students from diverse backgrounds can reap similar rewards.
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards ...can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control.
Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The ...two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'
Immobility is major contributor to poor outcomes for older people during hospitalisation with an acute medical illness. Yet currently there is no specific mobility guidance for this population, to ...facilitate sustainable changes in practice. This study aimed to generate draft physical activity (PA) and sedentary behaviour (SB) recommendations for older adults' during hospitalisation for an acute medical illness.
A 4-Round online Delphi consensus survey was conducted. International researchers, medical/nursing/physiotherapy clinicians, academics from national PA/SB guideline development teams, and patients were invited to participate. Round 1 sought responses to open-ended questions. In Rounds 2-3, participants rated the importance of items using a Likert scale (1-9); consensus was defined a priori as: ≥70% of respondents rating an item as "critical" (score ≥ 7) and ≤ 15% of respondents rating an item as "not important" (score ≤ 3). Round 4 invited participants to comment on draft statements derived from responses to Rounds 1-3; Round 4 responses subsequently informed final drafting of recommendations.
Forty-nine people from nine countries were invited to each Round; response rates were 94, 90, 85 and 81% from Rounds 1-4 respectively. 43 concepts (items) from Rounds 2 and 3 were incorporated into 29 statements under themes of PA, SB, people and organisational factors in Round 4. Examples of the final draft recommendations (being the revised version of statements with highest participant endorsement under each theme) were: "some PA is better than none", "older adults should aim to minimise long periods of uninterrupted SB during waking hours while hospitalised", "when encouraging PA and minimising SB, people should be culturally responsive and mindful of older adults' physical and mental capabilities" and "opportunities for PA and minimising SB should be incorporated into the daily care of older adults with a focus on function, independence and activities of daily living".
These world-first consensus-based statements from expert and stakeholder consultation provide the starting point for recommendations to address PA and SB for older adults hospitalised with an acute medical illness. Further consultation and evidence review will enable validation of these draft recommendations with examples to improve their specificity and translation to clinical practice.
Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with ...epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized 1-(13)C α-KG to hyperpolarized 1-(13)C glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized 1-(13)C α-KG, hyperpolarized 1-(13)C glutamate production was detected both in cells and in vivo, and the level of hyperpolarized 1-(13)C glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized 1-(13)C glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized 1-(13)C glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.
To determine the impact of comorbid migraine on quality of life (QOL) in chronic rhinosinusitis (CRS).
A total of 213 adult patients with CRS were recruited. All participants completed the 22-item ...Sinonasal Outcome Test (SNOT-22), from which total and validated nasal, ear/facial pain, sleep, and emotional subdomain scores were calculated, and the 5-dimension EuroQol general health questionnaire (EQ-5D), from which the visual analogue scale (VAS) and health utility value (HUV) were calculated. The presence of comorbid migraine was determined by a score of ≥4 on the 5-item Migraine Screen Questionnaire (MS-Q).
Of the participants, 36.2% were screened positive for having comorbid migraine. The mean SNOT-22 score was 64.9 (SD: 18.7) in participants with migraine and 41.5 (SD: 21.1) in participants without migraine (p < 0.001). The mean EQ-5D VAS and HUV were 60.2 (SD: 21.9) and 0.69 (SD: 0.18), respectively, in participants with migraine and 71.4 (SD: 19.4) and 0.84 (SD: 0.13), respectively, in participants without migraine (p < 0.001 for both). Higher ear/facial pain (OR = 1.22, 95% CI: 1.10-1.36, p < 0.001) and sleep (OR = 1.11, 95% CI: 1.04-1.18, p = 0.002) SNOT-22 subdomain scores were positively associated with migraine. The SNOT-22 item scores related to dizziness, reduced concentration, and facial pain, in descending order, were most associated with migraine. The presence of nasal polyps (OR = 0.24, 95% CI: 0.07 - 0.80, p = 0.020) was negatively associated with migraine.
Comorbid migraine may be relatively common amongst CRS patients, and its presence is associated with significantly worse QOL. Dizziness as a symptom in CRS patients may be particularly indicative of migraine.
3 Laryngoscope, 133:3279-3284, 2023.
Time spent in sedentary behavior is largely due to time spent engaged with electronic screen media. Little is known about the extent to which sedentary behaviors for children with autism spectrum ...disorder differ from typically developing children. We used parental report to assess and compare time spent in sedentary behaviors for 53 children with autism spectrum disorder and 58 typically developing children aged 3–11 years. We also determined how sedentary behavior was related to child weight status (body mass index z-score). Overall, children with autism spectrum disorder spent an hour more in sedentary behaviors on weekdays compared to typically developing children (5.2 vs 4.2 h, p = 0.03), and most of this difference was due to screen time. The age- and sex-adjusted estimate of weekday total daily screen time was 1.6 h (typically developing) compared to 2.5 h (autism spectrum disorder, p = 0.004 for difference). A significant relationship between BMI z-score and total sedentary behavior time on weekend days was observed among young children with ASD, but not among TD children. The modest association between weekend sedentary behaviour time and BMI z-score among children with ASD suggests that sedentary behaiour is linked to relative weight status in these children. Further research is needed to confirm these findings and identify causal pathways.
Although a large body of literature exists on the potential use of nanoparticles for medical applications, the number of probes translated into human clinical trials is remarkably small. A major ...challenge of particle probe development and their translation is the elucidation of safety profiles associated with their structural complexity, not only in terms of size distribution and heterogeneities in particle composition but also their effects on biological activities and the relationship between particle structure and pharmacokinetics. Here, we report on the synthesis, characterization, and long-term stability of ultrasmall (<10 nm diameter) dual-modality (optical and positron emission tomography) and integrin-targeting silica nanoparticles (cRGDY–PEG–Cy5–C′ dots and 124I-(or 131I-) cRGDY–PEG–Cy5–C′dots) and the extent to which their surface ligand density differentially modulates key in vitro and in vivo biological activities in melanoma models over a range of ligand numbers (i.e., ∼6–18). Gel permeation chromatography, established as an important particle characterization tool, revealed a two-year shelf life for cRGDY–PEG–Cy5–C′ dots. Radiochromatography further demonstrated the necessary radiochemical stability for clinical applications. The results of subsequent ligand density-dependent studies elucidate strong modulations in biological response, including statistically significant increases in integrin-specific targeting and particle uptake, cellular migration and adhesion, renal clearance, and tumor-to-blood ratios with increasing ligand number. We anticipate that nanoprobe characteristics and a better understanding of the structure–function relationships determined in this study will help guide identification of other lead nanoparticle candidates for in vitro and in vivo biological assessments and product translation.
AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and ...metabolism
. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy
. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
Objective To assess the mortality experience of participants in the Third Harvard Growth Study (1922-1935) who provided ≥8 years of growth data. Study design A total of 1877 participants provided an ...average of 10.5 body mass index measurements between age 6 and 18 years. Based on these measurements, the participants were classified as ever overweight or ever >85th percentile for height in childhood. Age at peak height velocity was used to indicate timing of overweight relative to puberty. Relative risks of all-cause and cause-specific mortality according to measures of childhood growth were estimated using Cox proportional hazards survival analysis. Results For women, ever being overweight in childhood increased the risks of all-cause and breast cancer death; the risk of death from ischemic heart disease was increased in men. Men with a first incidence of overweight before puberty were significantly more likely to die from ischemic heart disease; women in the same category were more likely to die from all causes and from breast cancer. Conclusion We find evidence of long-term effects of having ever been overweight, with some evidence that incidence before puberty influences the pattern of risk.
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