Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug\'s safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Indonesia is often regarded as a country with a strong inclination toward prosocial behavior, with both public and anonymous acts of kindness being commonplace. However, there is a notable gap in related research regarding the predictors of such behaviors. Previous studies have highlighted how individuals with diverse motives for wellbeing are inclined to either assist or hinder others. The present study explored the role of eudaimonic, hedonic, and extrinsic motives for wellbeing in predicting public and anonymous prosocial behavior. Using convenience sampling, 254 Indonesian undergraduate students (18-25 years old) from a private university participated in an online survey. The data were analyzed with correlational design and structural equation modelling. The findings revealed that the eudaimonic motive for wellbeing positively predicted anonymous prosocial behavior. Interestingly, no significant impact of hedonic motives on either public or anonymous prosocial behavior was observed. On the other hand, the extrinsic motive for wellbeing emerged as a positive predictor of public prosocial behavior. The absence of a discernible effect of the hedonic motive on either form of prosocial behavior highlights the need for further research into the complex interplay between motives for well-being and altruistic actions. This research represents a pioneering exploration into the distinct impacts of individuals\' pursuit of wellbeing on their approaches to altruistic actions, providing valuable insights for understanding and promoting prosocial behavior in society.

Migratory divides, hybrid zones between populations that use different seasonal migration routes, are hypothesised to contribute to speciation. Specifically, relative to parental species, hybrids at divides are predicted to exhibit (1) intermediate migratory behaviour and (2) reduced fitness as a result. We provide the first direct test of the second prediction here with one of the largest existing avian tracking datasets, leveraging a divide between Swainson\'s thrushes where the first prediction is supported. Using detection rates as a proxy for survival, our results supported the migratory divide hypothesis with lower survival rates for hybrids than parental forms. This finding was juvenile-specific (vs. adults), suggesting selection against hybrids is stronger earlier in life. Reduced hybrid survival was not explained by selection against intermediate phenotypes or negative interactions among phenotypes. Additional work connecting specific features of migration is needed, but these patterns provide strong support for migration as an ecological driver of speciation.

Extrinsic and intrinsic factors contribute to skin aging; nonetheless, they are intertwined. Moreover, intrinsic skin aging mirrors age-related declines in the entire human body\'s internal organs. There is evidence that skin appearance is an indicator of the general health of somebody. Earlier, it was apparent that the intrinsic factors are unalterable, but the sparkling of skin aging gene therapy on the horizon is changing this narrative. Skin aging gene therapy offers tools for skin rejuvenation and, natural beauty restoration, and therapy for diseases affecting the entire skin. However, skin aging gene therapy is an arduous and sophisticated task relying on precise interim stimulation of telomerase to extend telomeres and wend back the biological clock in the hopes to find the fountain of youth, while preserving cells innate biological features. Finding the hidden fountain of youth will be a remarkable discovery for promoting aesthetics medicine, genecosmetics, and healthy aging. Caloric restriction offers ultimate health benefits and a reproducible way to promote longevity in mammals, while delaying age-related diseases. Moreover, exercise further enhances these health benefits. This article highlights the potential of skin aging gene therapy and foretells the emerging dawn of the genecosmetics era.

Apoptosis is a programmed cell death comprising two signaling cascades including the intrinsic and extrinsic pathways. This process has been shown to be involved in the therapy response of different cancer types, making it an effective target for treating cancer. Cancer has been considered a challenging issue in global health. Cancer cells possess six biological characteristics during their developmental process known as cancer hallmarks. Hallmarks of cancer include continuous growth signals, unlimited proliferation, resistance to proliferation inhibitors, apoptosis escaping, active angiogenesis, and metastasis. Sesquiterpene lactones are one of the large and diverse groups of planet-derived phytochemicals that can be used as sources for a variety of drugs. Some sesquiterpene lactones possess many biological activities such as anti-inflammatory, anti-viral, anti-microbial, anti-malarial, anticancer, anti-diabetic, and analgesic. This review article briefly overviews the intrinsic and extrinsic pathways of apoptosis and the interactions between the modulators of both pathways. Also, the present review summarizes the potential effects of sesquiterpene lactones on different modulators of the intrinsic and extrinsic pathways of apoptosis in a variety of cancer cell lines and animal models. The main purpose of the present review is to give a clear picture of the current knowledge about the pro-apoptotic effects of sesquiterpene lactones on various cancers to provide future direction in cancer therapeutics.

This paper explores theories of motivation, including instinct theory, arousal theory, incentive theory, intrinsic theory, extrinsic theory, the ARCS model, self-determination theory, expectancy-value theory, and goal-orientation theory. Each theory is described in detail, along with its key concepts, assumptions, and implications for behavior. Intrinsic theory suggests that individuals are motivated by internal factors like enjoyment and satisfaction, while extrinsic theory suggests that external factors like rewards and social pressure drive behavior. Arousal theory says that to feel motivated, people try to keep an optimal level of activation or excitement. Incentive theory suggests that behavior is driven by the promise of rewards or the threat of punishment. The ARCS model, designed to motivate learners, incorporates elements of attention, relevance, confidence, and satisfaction. Self-determination theory proposes that individuals are motivated by their needs for autonomy, competence, and relatedness. The expectation-value theory suggests that behavior is influenced by individuals\' beliefs about their ability to succeed and the value they place on the task. The goal-orientation theory suggests that individuals have different goals for engaging in a behavior. By understanding these different theories of motivation, educators, coaches, managers, and individuals may analyze what drives behavior and how to harness it to achieve their goals. In essence, a nuanced comprehension of these diverse motivation theories equips individuals across varied domains with a strategic toolkit to navigate the complex landscape of human behavior, fostering a more profound understanding of what propels actions and how to channel these insights toward the attainment of overarching goals.

OBJECTIVE: Further investigate the application of self-determination theory (SDT) to experiences of solitude by examining the effects of recalling intrinsic versus non-intrinsic memories.
BACKGROUND: SDT research indicates that recalling memories associated with intrinsic goals (e.g., personal growth, relationships, altruism) enhances present moment wellness by satisfying basic psychological needs.
METHODS: Two studies were conducted with American adults. Study 1 included 465 participants (age = 49.49 [SD = 19.01], 49.46% female) and Study 2 comprised 490 participants (age = 54.16 [SD = 18.89], 51.84% female). Both studies assessed the impact of recalling intrinsic versus non-intrinsic memories prior to a five-minute solitude session.
RESULTS: Study 1 found intrinsic memories were linked to more basic psychological need satisfaction than non-intrinsic memories, but both memory types resulted in similar wellness improvements. Contrary to expectations, Study 2 revealed extrinsic memories (e.g., wealth, fame, image) led to the highest basic psychological need satisfaction and least need frustration compared to intrinsic and neutral memories, with all memory conditions showing similar wellness gains.
CONCLUSIONS: Solitude appears beneficial regardless of memory content. While different memories vary in need satisfying quality, this does not seem to impact the benefits of solitude. These findings suggest further exploration is needed before developing a \"solitude skill set\" for use during inevitable periods of solitude.

Self-healing polymeric materials, engineered to autonomously self-restore damages from external stimuli, are at the forefront of sustainable materials research. Their ability to maintain product quality and functionality and prolong product life plays a crucial role in mitigating the environmental burden of plastic waste. Historically, initial research on the development of self-healing materials has focused on extrinsic self-healing systems characterized by the integration of embedded healing agents. These studies have primarily focused on optimizing the release of healing agents and ensuring rapid self-healing capabilities. In contrast, recent advancements have shifted the focus towards intrinsic self-healing systems that utilize their inherent reactivity and interactions within the matrix. These systems offer the advantage of repeated self-healing over the same damaged zone, which is attributed to reversible chemical reactions and supramolecular interactions. This review offers a comprehensive perspective on extrinsic and intrinsic self-healing approaches and elucidates their unique properties and characteristics. Furthermore, various self-healing mechanisms are surveyed, and insights from cutting-edge studies are integrated.

Soft robots are becoming more popular because they can solve issues stiff robots cannot. Soft component and system design have seen several innovations recently. Next-generation robot-human interactions will depend on soft robotics. Soft material technologies integrate safety at the material level, speeding its integration with biological systems. Soft robotic systems must be as resilient as biological systems in unexpected, uncontrolled situations. Self-healing materials, especially polymeric and elastomeric ones, are widely studied. Since most currently under-development soft robotic systems are composed of polymeric or elastomeric materials, this finding may provide immediate assistance to the community developing soft robots. Self-healing and damage-resilient systems are making their way into actuators, structures, and sensors, even if soft robotics remains in its infancy. In the future, self-repairing soft robotic systems composed of polymers might save both money and the environment. Over the last decade, academics and businesses have grown interested in soft robotics. Despite several literature evaluations of the soft robotics subject, there seems to be a lack of systematic research on its intellectual structure and development despite the rising number of articles. This article gives an in-depth overview of the existing knowledge base on damage resistance and self-healing materials\' fundamental structure and classifications. Current uses, problems with future implementation, and solutions to those problems are all included in this overview. Also discussed are potential applications and future directions for self-repairing soft robots.

Elevated serum level of total and (or) allergen-specific IgE is one of the key features of atopic dermatitis (AD). Previous studies have shown that the gut microbiome mediates interactions between external exposures and the immune system in AD; however, the relationship between the gut microbiota and IgE remains unclear. In the present study, analyses of environmental exposures for 250 AD patients and 138 healthy volunteers revealed an association between hygiene levels in the residential environment and the occurrence of AD and the IgE level. Metagenomic sequencing of the gut microbiota from 68 AD patients and 77 healthy controls showed that AD patients had a distinct gut microbiota composition; moreover, while L-histidine degradation was enriched in healthy controls, L-histidine biosynthesis was enriched in AD patients. Extrinsic and intrinsic AD showed different enrichment patterns of specific microbes and differential associations of functional pathways. Our study indicated that elevated levels of IgE in AD were related to specific microbes in the gut microbiota, which showed extensive interactions with environmental factors.