The anti-ageing effects of a natural peptide discovered by artificial intelligence.

OBJECTIVE: As skin ages, impaired extracellular matrix (ECM) protein synthesis and increased action of degradative enzymes manifest as atrophy, wrinkling and laxity. There is mounting evidence for the functional role of exogenous peptides across many areas, including in offsetting the effects of cutaneous ageing. Here, using an artificial intelligence (AI) approach, we identified peptide RTE62G (pep_RTE62G), a naturally occurring, unmodified peptide with ECM stimulatory properties. The AI-predicted anti-ageing properties of pep_RTE62G were then validated through in vitro, ex vivo and proof of concept clinical testing. METHODS: A deep learning approach was applied to unlock pep_RTE62G from a plant source, Pisum sativum (pea). Cell culture assays of human dermal fibroblasts (HDFs) and keratinocytes (HaCaTs) were subsequently used to evaluate the in vitro effect of pep_RTE62G. Distinct activities such as cell proliferation and ECM protein production properties were determined by ELISA assays. Cell migration was assessed using a wound healing assay, while ECM protein synthesis and gene expression were analysed, respectively, by immunofluorescence microscopy and PCR. Immunohistochemistry of human skin explants was employed to further investigate the induction of ECM proteins by pep_RTE62G ex vivo. Finally, the clinical effect of pep_RTE626 was evaluated in a proof of concept 28-day pilot study. RESULTS: In vitro testing confirmed that pep_RTE62G is an effective multi-functional anti-ageing ingredient. In HaCaTs, pep_RTE62G treatment significantly increases both cellular proliferation and migration. Similarly, in HDFs, pep_RTE62G consistently induced the neosynthesis of ECM protein elastin and collagen, effects that are upheld in human skin explants. Lastly, in our proof of concept clinical study, application of pep_RTE626 over 28 days demonstrated anti-wrinkle and collagen stimulatory potential. CONCLUSION: pep_RTE62G represents a natural, unmodified peptide with AI-predicted and experimentally validated anti-ageing properties. Our results affirm the utility of AI in the discovery of novel, functional topical ingredients.

OBJECTIF: À mesure que la peau vieillit, une altération de la synthèse des protéines de la matrice extracellulaire (ECM) et une action accrue des enzymes dégradantes se manifestent par une atrophie, des rides et un laxisme. Il existe de plus en plus de preuves du rôle fonctionnel des peptides exogènes dans de nombreux domaines, y compris pour compenser les effets du vieillissement cutané. Ici, en utilisant une approche d'intelligence artificielle (AI), nous avons identifié le peptide RTE62G (pep_RTE62G), un peptide naturel non modifié avec des propriétés de stimulation ECM. Les propriétés anti-âge prédites par l'IA de pep_RTE62G ont ensuite été validées par des tests cliniques in vitro, ex vivo et de validation de principe. LES MÉTHODES: Une approche d'apprentissage en profondeur a été appliquée pour déverrouiller pep_RTE62G à partir d'une source végétale, Pisum sativum (pois). Des tests de culture cellulaire de fibroblastes dermiques humains (HDF) et de kératinocytes (HaCaTs) ont ensuite été utilisés pour évaluer l'effet in vitro de pep_RTE62G. Des activités distinctes telles que la prolifération cellulaire et les propriétés de production de protéines ECM ont été déterminées par des tests ELISA. La migration cellulaire a été évaluée à l'aide d'un test de cicatrisation des plaies, tandis que la synthèse des protéines ECM et l'expression des gènes ont été analysées, respectivement, par microscopie à immunofluorescence et PCR. L'immunohistochimie des explants de peau humaine a été utilisée pour approfondir l'induction des protéines ECM par pep_RTE62G ex vivo. Enfin, l'effet clinique de pep_RTE626 a été évalué dans une étude pilote de 28 jours de validation de principe. RÉSULTATS: Les tests in vitro ont confirmé que pep_RTE62G est un ingrédient anti-âge multifonctionnel efficace. Dans HaCaTs, le traitement pep_RTE62G augmente de manière significative à la fois la prolifération et la migration cellulaire. De même, dans les HDF, pep_RTE62G a induit de manière cohérente la néosynthèse de la protéine ECM élastine et collagène, effets qui sont maintenus dans les explants de peau humaine. Enfin, dans notre étude clinique de preuve de concept, l'application de pep_RTE626 sur 28 jours a démontré un potentiel stimulant anti-rides et collagène. CONCLUSION: pep_RTE62G représente un peptide naturel, non modifié avec des propriétés anti-âge prédites par l'IA et validées expérimentalement. Nos résultats confirment l'utilité de l'IA dans la découverte de nouveaux ingrédients topiques fonctionnels.

Toward optimisation of water use efficiency in dryland pastures using carbon isotope discrimination as a tool to select plant species mixtures.

Pastoral agriculture is important for supplying global demand for animal products but pasture productivity is often water limited. Increased plant diversity has been shown to increase water use efficiency (ω) and productivity under water limitation but the optimal mix of species varies spatially, dependent on climate, soil type, and plant water requirements. Consequently, a cost-effective method to screen for high ω plant species and mixes in situ at farm scale is needed. Using carbon isotope discrimination (∆13C) to examine ω is attractive because the method integrates over useful time scales, does not modify the measurement environment, and is cost-effective. Field scale ω was measured using eddy covariance (EC) at two sites with contrasting plant diversity (2 species, 7 species) and compared to the seasonal progression of ω calculated from foliage ∆13C (ω∆). Soil water evaporation (ES) was removed from EC measured total ecosystem evaporation using a modelling approach and canopy ω (ωC) was calculated as gross primary production (GPP) divided by canopy evaporation. Mixed species foliage samples were harvested pre-grazing, dried, sub-sampled, ground, and the ratio of 13C to 12C was measured. A strong positive correlation was found between ω∆ and ωC at both study sites (r2 > 0.83, p < 0.01). In addition to bulk biomass samples, individual species were also harvested seasonally. Relative increases in both ω∆ and production for some species showed that manipulation of pasture species mixtures may lead to increased ω. Combined with production monitoring, ∆13C could be developed as a tool to optimise species selection for site specific climate and soil conditions to maximise ω and farm production and profit.

Examining alcohol outcome expectancies in laboratory and naturalistic bar settings: a within-subject experimental analysis.

Using a within-subject design, this study investigated the situational-specificity hypothesis, namely that alcohol outcome expectancies (AOEs), subjective evaluations of AOEs, and the speed with which AOEs are accessed from memory vary as a function of environmental setting. Thirty-nine undergraduates (20 women), of legal drinking age, responded to the Comprehensive Effects of Alcohol questionnaire (K. Fromme, E. Stroot, & D. Kaplan, 1993) that was presented on a laptop computer in 2 counterbalanced contexts: a laboratory setting and an on-campus bar. Response latencies served as dependent measures for memory accessibility. Consistent with previous research (A.-M. Wall, S. A. McKee, & R. E. Hinson, 2000), evidence in support of the situational-specificity hypothesis was found. Specifically, environmental context influenced undergraduates' expectations concerning alcohol's effects and subjective evaluations of AOEs, as well as the speed with which specific AOEs were accessed from memory. Overall, these findings suggest the need for greater attention to situational variation in AOEs.

Assessing variation in alcohol outcome expectancies across environmental context: an examination of the situational-specificity hypothesis.

Using an in vivo manipulation, this study examined whether alcohol outcome expectancies (AOEs) vary across environmental settings. Two hundred twenty-one undergraduates were randomly assigned to 1 of 4 conditions in which environmental context (an on-campus bar vs. a laboratory) and instructed phase of intoxication ("just enough to begin to feel intoxicated" vs. "too much to drink") were manipulated. AOEs were assessed with a revised version of the Effects of Alcohol Scale (L. Southwick, C. Steele, A. Marlatt, & M. Lindell, 1981). Compared with participants tested in the laboratory, individuals exposed to the on-campus bar expected greater alcohol-related stimulation/perceived dominance and pleasurable disinhibition. Women expected more behavioral impairment during the latter stage of intoxication. These findings highlight the importance of ecologically valid research in this area, as well as cue-exposure assessment and treatment approaches.

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.

Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 microM, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m2 per course. The mean steady-state plasma concentration (Cpss) of 68.0 microM was different (P = 0.025) than the predicted Cpss (mean = 87.4 microM; range 35.7-184 microM) had no adjustment in dose been made. The coefficient of variation in Cpss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (>30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P < 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients.

Alcohol outcome expectancies, attitudes toward drinking and the theory of planned behavior.

OBJECTIVE: The present study investigated whether alcohol outcome expectancies are empirically distinguishable from attitudes toward drinking. Specifically, the contribution of expectancies and attitudes to the Theory of Planned Behavior was assessed. METHOD: Undergraduates (N = 316; 170 male), of legal drinking age, who drank at least once a month participated. Intentions to drink "too much" and self-report excessive consumption episodes served as criterion measures, and attitudes, subjective norm, perceived behavioral control and alcohol outcome expectancies were employed as predictor variables. Stepwise regression analyses were performed separately for men and women. RESULTS: The Theory of Planned Behavior appeared to be a valid framework for predicting excessive alcohol consumption among undergraduates. The predictive power of the model, however, was enhanced through the inclusion of gender-specific alcohol outcome expectancies. Specifically, in addition to attitudes and perceived behavioral control, women's expectancies for sociability enhanced the prediction of intentions to drink "too much." Expectancies for sexual functioning (male) and assertiveness (female) improved the prediction of excessive consumption, over and above intentions and perceived behavioral control. CONCLUSIONS: Alcohol outcome expectancies, unlike attitudes, are proximal predictors of excessive alcohol consumption among undergraduates.

Alcohol outcome expectancies and coping styles as predictors of alcohol use in young adults.

This study was designed to examine the pattern and strength of relationships among coping styles and alcohol outcome expectancies with regard to drinking behavior in young adult social drinkers. Quantity and frequency of weekly consumption were used as criterion measures, and alcohol outcome expectancies/valences (CEOA: Fromme, Stroot & Kaplan, 1993) and coping styles (COPE: Carver, Scheier, & Weintraub, 1989) were used as predictor variables. For males, the expectancy of risk and aggression, and the valence of cognitive and behavioral impairment, were predictive of drinking behavior. For females, sociability valence and the expectancy of negative self-evaluation positively predicted the alcohol-use measures. With regards to coping styles, alcohol and drug disengagement and suppression of competing activities uniquely predicted alcohol use in males, whereas alcohol and drug disengagement, turning to religion, and behavioral disengagement were predictive of female alcohol use. In general, coping styles were more predictive of the alcohol-use measures than were alcohol-outcome expectancies. Practical implications of these results are highlighted.

The effect of the CS-UCS interval and extinction on place conditioning and analgesic tolerance with morphine.

In experiment 1, a CS-UCS interval study of place conditioning and analgesic tolerance with morphine was conducted. Morphine (10 mg/kg i.p.) was administered to separate groups of rats either 2 h prior to, 1 h prior to, immediately prior to, immediately after or 2 h after 30-min confinement in one end compartment of a place conditioning apparatus. A total of three choice tests was given, one after every six morphine injections. A preference for the end compartment contingent upon morphine injection was shown in groups that received morphine prior to end compartment placement. Groups that received morphine after end compartment placement were not different in their preference behavior from groups that received only saline during place conditioning training. A hot-plate test for tolerance to the analgesic effect of morphine was given at the end of all choice testing. All groups that had received morphine during place conditioning training were equally tolerant. These results indicate a dissociation between the analgesic effect of morphine and the effect that produces place preference, since the former was not affected by temporal parameters that did affect the latter. In the second experiment, the effect of extinction on a morphine-induced place preference was studied using extinction procedures that, in contrast to previous studies, equated exposure to both end compartments. Whereas the morphine-induced place preference was undiminished by a 10-day retention period in which animals received saline injections in the home cage, extinction trials during the same period eliminated the place preference. These results provide evidence that morphine-induced place preferences involve associative processes.

Programa de actividad física y recreativa para adulto mayor / Program of physical and recreative activity for elderly

Se estudia los efectos de la actividad física y recreativa en el mejoramiento y mantenimiento de la capacidad física, en los rangos de movilidad articular, coordinación, ritmo y equilibrio, y desarrollo de la relaciones interpersonales y psicoafectivas en el adulto mayor

Evaluating cervical cone biopsy specimens with frozen sections at hysterectomy.

Frozen section evaluations of cervical cone biopsy specimens were performed at the time of hysterectomy to exclude invasive cervical cancer. During a two-year period we prospectively evaluated 43 cone biopsy specimens. We found all the diagnoses made with frozen sections to be accurate when compared with prospective permanent sections, and all patients received appropriate therapy. Thirty-eight cases showed no evidence of invasion. Two patients had invasive squamous cell cervical cancer, one had invasive cervical adenocarcinoma extending to the endometrial cavity, and two had microinvasion. All invasive cancers were diagnosed correctly with frozen sections and confirmed with permanent sections. When hysterectomy immediately followed conization, no complications occurred, and no significant increase in blood loss was noted. We found frozen section evaluation of a cone biopsy specimen at the time of hysterectomy to be a reliable procedure that saves time, eliminates the risk of additional anesthesia and decreases patients' costs.

Place avoidance conditioning with D-amphetamine: the effect of screening and the use of preferred and non-preferred sides.

The effect of screening animals to identify unconditioned preferences for stimuli used in subsequent place conditioning, and the effect of pairing drug injections with originally most or least preferred stimuli were investigated in place conditioning with 0.5 and 2.0 mg/kg D-amphetamine. A choice test to identify conditioned approach and avoidance responses was given after every two end compartment drug trials until a total of 10 choice tests had been given. During drug trials, the drug was injected 15 min after the animal was placed in the end compartment and the animal remained in the end compartment for 30 min following drug injection. In confirmation of previous research from our laboratory, during choice tests, animals avoided the end compartment that had been paired with D-amphetamine and this avoidance occurred regardless of whether the animals had been initially screened or not, and regardless of whether the originally most or least preferred stimuli were used as the drug-associated end compartment.

Cue exposure during a period of abstinence reduces the resumption of operant behavior for oral ethanol reinforcement.

The present study examined the prediction made by learning theories of drug addiction that systematic cue exposure (extinction) procedures should reduce ethanol (EtOH) consumption. In 3 experiments, male rats were trained on a variable-interval schedule to press a bar for a sweetened EtOH solution. These procedures established associations between a variety of cues (contextual, response feedback, visual, taste) and EtOH consumption. After performance had stabilized, a period of abstinence was imposed during which no EtOH was available. Groups of rats differed only in the number of EtOH-associated cues experienced during this period. The level of EtOH consumption after abstinence was reduced in proportion to the degree of cue exposure. These findings support the learning hypothesis that drug-associated cues contribute to the resumption of drug-taking behavior and further suggest that extinction procedures may be valuable in preventing relapse.

Diagnosis of ectopic pregnancy using transvaginal ultrasound scanning.

A new technique was developed for transvaginal ultrasound scanning in the routine evaluation of women with suspected early ectopic pregnancy. This approach enables us to detect early pregnancies that could not be visualized previously with routine abdominal ultrasound. Transvaginal scanning shows the location of the gestational sac very clearly, whether it is within or outside the uterus. Our introduction of this technique into the evaluation process has reduced patients' risk by minimizing delays in diagnosis and treatment and also has shortened hospital stays, thereby reducing costs.