Converse Barrier Certificates for Finite-time Safety Verification of Continuous-time Perturbed Deterministic Systems

In this paper, we investigate the problem of verifying the finite-time safety of continuous-time perturbed deterministic systems represented by ordinary differential equations in the presence of measurable disturbances. Given a finite time horizon, if the system is safe, it, starting from a compact initial set, will remain within an open and bounded safe region throughout the specified time horizon, regardless of the disturbances. The main contribution of this work is to uncover that there exists a time-dependent barrier certificate if and only if the system is safe. This barrier certificate satisfies the following conditions: negativity over the initial set at the initial time instant, non-negativity over the boundary of the safe set, and non-increasing behavior along the system dynamics over the specified finite time horizon. The existence problem is explored using a Hamilton-Jacobi differential equation, which has a unique Lipschitz viscosity solution

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases

Multi-Context Interaction Network for Few-Shot Segmentation

Few-Shot Segmentation (FSS) is challenging for limited support images and large intra-class appearance discrepancies. Due to the huge difference between support and query samples, most existing approaches focus on extracting high-level representations of the same layers for support-query correlations but neglect the shift issue between different layers and scales. In this paper, we propose a Multi-Context Interaction Network (MCINet) to remedy this issue by fully exploiting and interacting with the multi-scale contextual information contained in the support-query pairs. Specifically, MCINet improves FSS from the perspectives of boosting the query representations by incorporating the low-level structural information from another query branch into the high-level semantic features, enhancing the support-query correlations by exploiting both the same-layer and adjacent-layer features, and refining the predicted results by a multi-scale mask prediction strategy, with which the different scale contents have bidirectionally interacted. Experiments on two benchmarks demonstrate that our approach reaches SOTA performances and outperforms the best competitors with many desirable advantages, especially on the challenging COCO dataset

Glycine in the prevention of neonatal necrotizing enterocolitis lesions: experimental study in rats

Objetivo: Avaliar o efeito da glicina no intestino e em órgãos à distância num modelo experimental de enterocolite necrosante neonatal em ratos recém-nascidos. Métodos: Foram utilizados ratos Wistar recém-nascidos distribuídos em três grupos: G1: controle, G2: animais submetidos a hipóxia-reoxigenação (H-R), G3: animais submetidos a hipóxia-reoxigenação após uma infusão intraperitoneal de glicina 5%.Segmentos intestinais foram preparados para análise histológica, imunohistoquímica com caspase 3 clivada e lamina A clivada, como marcadores para apoptose e dosagem tecidual de Malondialdeído (MDA). O fígado foi preparado para avaliação imunohistoquímica e dosagem de malondialdeído tecidual, e os rins foram preparados para avaliação imunohistoquímica. Resultados: A dosagem de MDA tecidual mostrou que o grupo de animais submetido a H-R apresentou valores maiores do que o grupo previamente submetido à injeção intraperitoneal de glicina (p < 0,05). O índice apoptótico pela avaliação da caspase 3 clivada e lamina A clivada foi maior nos animais submetidos à H-R do que nos animais que receberam previamente glicina em todos os órgãos examinados, porém nos rins a avaliação pela lamina A clivada não foi significante, quando da avaliação estatística. A análise histológica não mostrou diferença estatística entre o grupo H-R e o previamente submetido à injeção de glicina. Conclusões: A glicina foi capaz de reduzir os efeitos deletérios da hipóxiareoxigenação, quando se considerou como critério de avaliação a dosagem de MDA e os índices de apoptose celular e não influenciou, estatisticamente, as alterações histológicas.Objective: To evaluate the effect of glycine on the intestine and in distant organs, in an experimental model of neonatal necrotizing enterocolitis in rats. Methods: Newborn Wistar rats were utilized, distributed into three groups: G1: control, G2: animals subjected to hypoxia-reoxygenation (H-R), G3: animals subjected to hypoxia-reoxygenation after intraperitoneal infusion of 5% glycine. Intestinal segments were prepared for histological analysis, immunohistochemistry using cleaved caspase-3 and cleaved lamina-A as markers for apoptosis, and tissue assaying for malonaldehyde (MDA). The liver and kidneys were prepared for immunohistochemical evaluation and the liver alone for tissue MDA assaying. Results: Tissue MDA assaying showed that the animals subjected to H-R alone presented higher values than did those previously subjected to glycine infusion (p < 0.05). The apoptosis index from evaluation of cleaved caspase-3 and cleaved lamina-A was greater in the animals subjected to H-R alone than in those previously subjected to glycine infusion, in all the organs examined. However, in the kidneys the findings from cleaved lamina-A did not present any statistical difference. The histological analysis did not show any statistical difference between the group with H-R alone and the group previously subjected to glycine infusion. Conclusions: Glycine was capable of reducing the deleterious effects from hypoxiareoxygenation, when the MDA assay and cell apoptosis index were considered as the evaluation criteria.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)BV UNIFESP: Teses e dissertaçõe

Effects of acute administration of different doses of methylphenidate on cognition in healthy young

Os chamados ampliadores cognitivos têm sido ampla e crescentemente utilizados por indivíduos saudáveis, que apesar de não apresentarem nenhum tipo de patologia, buscam por melhoras no desempenho cognitivo. Um fármaco utilizado para este fim é o metilfenidato, droga de primeira escolha para tratamento do transtorno de déficit de atenção e hiperatividade (TDAH). O presente estudo visou verificar o efeito da administração aguda de diferentes doses de metilfenidato (10, 20 e 40 mg e placebo) sobre uma ampla gama de funções cognitivas em jovens saudáveis. Participaram do estudo 36 jovens universitários ou graduados, tendo sido realizados testes de atenção, memória operacional, episódica e semântica. Não foram observadas diferenças no desempenho dos sujeitos em nenhum dos testes. Houve efeito na auto-avaliação de bem estar, sendo este efeito dose dependente – 40 mg > placebo. De acordo com a literatura recente, medicações psicoestimulantes, como o metilfenidato, produzem melhoras no desempenho quando os processos cognitivos estão abaixo de um nível ótimo o que não era o caso dos sujeitos do presente estudo. Sendo assim, a impressão que o metilfenidato melhora o desempenho cognitivo em pessoas jovens e saudáveis se deve provavelmente ao efeito subjetivo de bem estar.The so called cognitive enhancers have been widely and increasingly used by healthy individuals, who despite not having any kind of pathology, seek improvements in cognitive performance. A drug used for this purpose is methylphenidate, a first choice drug for the treatment of the attention deficit and hyperactivity disorder (ADHD). This study aimed to evaluate the effect of acute administration of different doses of methylphenidate (10, 20 and 40 mg and placebo) in a wide range of cognitive functions in healthy young subjects. Participated in the study 36 university students or graduates, and were applied tests of attention, working memory, episodic and semantic memory. There were no differences among the groups in any of the tests. Significant effect on self-assessment of well being was observed, and this effect was dose dependent - 40 mg> placebo. According to recent literature, psychostimulant medications such as methylphenidate, produce improvements in performance when cognitive processes are below an optimal level which was not the case of the subjects of this study. Thus, the impression that methylphenidate improves cognitive performance in healthy young people is probably due to the effect of subjective well-being.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Associação Fundo de Incentivo à Psicofarmacologia (AFIP)BV UNIFESP: Teses e dissertaçõe

Bioactivities of EF24, a Novel Curcumin Analog: A Review

Curcumin is an attractive agent due to its multiple bioactivities. However, the low oral bioavailability and efficacy profile hinders its clinical application. To improve the bioavailability, many analogs of curcumin have been developed, among which EF24 is an excellent representative. EF24 has enhanced bioavailability over curcumin and shows more potent bioactivity, including anti-cancer, anti-inflammatory, and anti-bacterial. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through its inhibitory effect on the nuclear factor kappa B (NF-κB) pathway and by regulating key genes through microRNA (miRNA) or the proteosomal pathway. Based on the current structure, more potent EF24 analogs have been designed and synthesized. However, some roles of EF24 remain unclear, such as whether it induces or inhibits reactive oxygen species (ROS) production and whether it stimulates or inhibits the mitogen activated kinase-like protein (MAPK) pathway. This review summarizes the known biological and pharmacological activities and mechanisms of action of EF24

Dietary Calcium but Not Elemental Calcium from Supplements Is Associated with Body Composition and Obesity in Chinese Women

We assessed whether dietary calcium intake or calcium supplements associated with body composition and obesity in a Chinese population.A cross-sectional survey was performed in a population of 8940, aged 20 to 74 y. 8127 participants responded (90.9%). Height, weight, fat mass (FM), waist circumference (WC) and hip circumference were measured. Obesity definition: body mass index (BMI) ≥28 kg/m(2) (overall obesity); WC ≥85 cm for men or ≥80 cm for women (abdominal obesity І) and waist hip ratio (WHR) ≥0.90 for men or ≥0.85 for women (abdominal obesity П). The data on dietary calcium and calcium supplements were collected using food-frequency questionnaire and self-report questionnaire. Multivariate linear and multivariable logistic regressions were used to examine the associations between dietary calcium intake or calcium supplements and body composition and obesity.The average dietary calcium intake of all subjects was 430 mg/d. After adjusting for potential confounding factors, among women only, negative associations were observed between habitual dietary calcium intake and four measures of body composition (β, -0.086, P<0.001 for BMI; β, -0.072, P<0.001 for WC; β, -0.044, P<0.05 for WHR; and β, -0.058, P<0.01 for FM, respectively) and both measures of abdominal obesity (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI], 0.80-0.93; P<0.001, for abdominal obesity I; OR = 0.92, 95% CI, 0.86-0.99; P = 0.026, for abdominal obesity II). These associations were not observed among men (P>0.05). Similarly, among both men and women, we did not observe significant associations between calcium supplements and any measures of body composition or abdominal obesity (P>0.05).Dietary calcium from food rather than elemental calcium from calcium supplements has beneficial effects on the maintenance of body composition and preventing abdominal obesity in Chinese women

Vitamin D and suicidality: a Chinese early adolescent cohort and Mendelian randomization study

Abstract Aims Previous cross-sectional and case–control studies have proposed that decreased vitamin D levels are positively correlated with the risk of suicidality in adults. However, limited studies have examined the association between vitamin D and suicidality in adolescents. This study aimed to investigate the relationship between serum vitamin D and suicidality risk among early adolescents. Methods Data were obtained from a Chinese early adolescent cohort. In this cohort, seventh-grade students from a middle school in Anhui Province were invited to voluntarily participate in the baseline assessments and provide peripheral blood samples (in September 2019). The participants were followed up annually (in September 2020 and September 2021). Serum 25-hydroxyvitamin D [25(OH)D] and vitamin D–related single-nucleotide polymorphisms at baseline were measured in November 2021. Traditional observational and Mendelian randomization (MR) analyses were performed to examine the relationship between serum 25(OH)D at baseline and the risk of baseline and incident suicidality (i.e., suicidal ideation [SI], plans and attempts). Results Traditional observational analysis did not reveal a significant linear or non-linear association of serum 25(OH)D concentration with the risks of baseline and 2-year incident suicidality in the total sample (P > .05 for all). Sex-stratified analysis revealed a non-linear association between the 25(OH)D concentration and the risk of baseline SI in women (Poverall = .002; Pnon-linear = .001). Moreover, the risk of baseline SI in the 25(OH) insufficiency group was lower than that in the 25(OH) deficiency group in the total sample (odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.51–0.92, P = .012). This difference remained significant in women (OR = 0.59, 95% CI = 0.40–0.87, P = .008) but not in men (OR = 0.78, 95% CI = 0.53–1.15, P = .205). Additionally, both linear and non-linear MR analyses did not support the causal effect of serum 25(OH)D concentration on the risk of baseline, 1-year and 2-year incident suicidality (P > .05 for all). Conclusions This study could not confirm the causal effect of vitamin D on suicidality risk among Chinese early adolescents. Future studies must confirm these findings with a large sample size

Drivers of vegetation and soil determine natural regeneration of a single plantation at different slope positions

Promoting natural regeneration in artificial forest ecosystems is crucial for sustainable management. Understanding the fundamental mechanisms and drivers of tree regeneration is the prerequisite for promoting it effectively. This study worked with Larix principis-rupprechtii, a species considered difficult to regenerate. Twenty-four sample plots measuring 30 m × 30 m were established, with eight plots at each of the lower, middle, and upper slope positions, respectively. Field investigation and multivariate analysis were performed to uncover the regeneration traits in the plantations with abundant seedlings on the continuous slope. The results revealed that ground diameter and height of the regeneration (RGD and RH) were larger at the lower slope, with significant positive correlations to available nitrogen (contribution rate, CR: 0.858) and slope (CR: 0.652). In contrast, regeneration density (RD), representing the quantity of regeneration, was greater at the middle slope. Its significant impact factors were slope position (CR: −0.648) and herb diversity, represented by Pielou index (CR: 0.961). Stand density had a significant negative effect on regeneration, particularly at the upper slope, with CRs of −0.842 and −0.764 to RGD/RH and RD, respectively. Common contribution was found among the factors, with the largest contribution groups being the topographical and soil factors (CR: 0.358). These findings provide valuable insights into the single species regeneration progress on northern mountainous slopes and offer essential information for developing facilitation methods for the natural regeneration in artificial forests

OsPIE1, the Rice Ortholog of Arabidopsis PHOTOPERIOD-INDEPENDENT EARLY FLOWERING1, Is Essential for Embryo Development

orthologs in monocots remains unknown., respectively).Taken together, our results suggest that OsPIE1 is the rice ortholog of Arabidopsis PIE1 and plays an essential role in rice embryo development