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Most empirical research on the effects of the economic downturns has been a-spatial and overlooked the location choices of creative industries (CIs). The present study addresses an open debate on whether economic downturns have pushed a change in the relative importance of resilience-based versus traditional CIs location factors. Considering the location choices of 6332 CIs Portuguese start-ups in the period 2005–2012, we found that: (1) the crisis brought changes in the relative importance of location factors, enhancing traditional CI location factors such as technology and diminishing the relevance of resilience-based factors related to regions industrial specialisation; (2) resilience-based factors, such as industrial diversity, higher education, cultural and social networking and traditional CI factors, namely lower social inequality and life quality, were robust drivers for the emergence of new start-ups all over the period; and (3) although cultural policy significantly and positively support the emergence of new CIs start-ups in the crisis period, the austerity period reversed that role. Our results suggest that the sustainable development of regions implies encompassing public stimulus to the generation of a diversified, interdependent network of creative activities, able to enhance innovation through their own synergies and linkages with the rest of the economy.

Key Points Despite knowing that overeating is harmful, many people who are overweight are unable to control their food intake The satisfaction, or hedonic response, gained from eating overcomes satiety feedback mechanisms Hormones produced in taste cells in the tongue modify the intensity of taste perception; leptin modifies neurological hedonic responses to eating and the intensity of sweet perception Localization of taste receptors is not restricted to taste cells and the roles of these receptors in other physiological functions are being investigated Obesity and/or overnutrition (chronic excess energy states) might affect taste perception; individuals with obesity require increased amounts of tastants to elicit the same intensity of hedonic response as healthy individuals Insight into how metabolic surgery results in weight loss and understanding of the role of gut microbiota in taste perception might reveal how taste perception and obesity are related In contemporary society, the ready availability of calorie-dense, highly palatable foods has contributed to the global obesity epidemic. Individuals with obesity often consume an excess of food, despite knowledge of the associated adverse consequences. In this Review, Santa-Cruz Calvo and Egan explore the physiology of taste perception with regard to taste receptors, neuronal signalling and hormonal control of food intake. Levels of obesity have reached epidemic proportions on a global scale, which has led to considerable increases in health problems and increased risk of several diseases, including cardiovascular and pulmonary diseases, cancer and diabetes mellitus. People with obesity consume more food than is needed to maintain an ideal body weight, despite the discrimination that accompanies being overweight and the wealth of available information that overconsumption is detrimental to health. The relationship between energy expenditure and energy intake throughout an individual's lifetime is far more complicated than previously thought. An improved comprehension of the relationships between taste, palatability, taste receptors and hedonic responses to food might lead to increased understanding of the biological underpinnings of energy acquisition, as well as why humans sometimes eat more than is needed and more than we know is healthy. This Review discusses the role of taste receptors in the tongue, gut, pancreas and brain and their hormonal involvement in taste perception, as well as the relationship between taste perception, overeating and the development of obesity.

Nowadays, the elderly tend to make more trips: Health benefits resulting from their daily walking routines are an important topic in the context of urban renewal processes. Many health organizations and researchers have demonstrated the influence of the urban environment on walkability levels. This article aims to design a multifactor Walkability Index for Elderly Health (WIEH), capable of associating both the adequacy level of public spaces to elderly walkability, and physical exercise benefits while walking. The methodological approach comprised two main parts: Firstly, a literature review of main reports, legislation, and scientific articles was conducted at the intersection of ‘gerontology and physical exercise’ with ‘urban design and mobility’, leading to the selection of four aging-related studies as main contributors to the design of the WIEH; and, secondly, the development of the WIEH was undertaken, based on two premises and designed according to four steps. The first premise defined three systematic areas (urban tissue, urban scene, and safety), variables, and criteria to classify the pedestrian network; and the second premise focused on slopes and stairs in public spaces. The WIEH is divided in four steps: (1) Analyzing public spaces and characterizing their quality for walking, (2) considering the existence of slopes and stairs, (3) calculating different routes for the elderly in their daily routines, or when going to points of interest, and (4) selecting the “heart-friendly route” for elderly people. Adequate walking paths for the elderly can be identified through this innovative approach, with the aim of achieving direct health benefits during their daily routines. Ultimately, the WIEH is capable of supporting decision makers and designers in creating inclusive and age-friendly spaces.

CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene–enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions. Genetic manipulation of poised enhancers (PEs) shows that orphan CpG islands promote physical and functional communication between PEs and distally located developmental genes.

Leishmaniasis remains an important neglected tropical disease, and current treatments are limited by toxicity, resistance, and low bioavailability. In this study, novel guanidine derivatives were evaluated through an integrated approach, combining in silico physicochemical profiling with in vitro biological assays using Leishmania (Viannia) braziliensis, the etiological agent of American Tegumentary Leishmaniasis (ATL). Most compounds exhibited favorable drug-like properties, though variations in lipophilicity and solubility influenced biological performance. Among the tested molecules, FURL-G5 emerged as the most promising candidate, showing potent activity against promastigote forms and low cytotoxicity in murine macrophages, resulting in high selectivity indices (SI > 10), comparable to those of LQOF-G1, a compound with previously established leishmanicidal effects. These compounds were also tested on intracellular amastigotes, drastically reducing the infection rate of macrophages. The integration of an in silico approach and biological validation enabled rational compound prioritization and supports the early-stage development of these scaffolds. Overall, this study reinforces the potential of guanidine-based compounds as leads for innovative ATL drug discovery and demonstrates the value of multidisciplinary strategies for identifying selective and safe therapeutic candidates.

The closure of schools during the COVID-19 pandemic affected adolescents’ social withdrawal and social anxiety. Yet, self-esteem may have acted as a protective factor during this period. This study aimed to compare the trajectories of social withdrawal and social anxiety before (Year 1), during (Year 2 and 3), and after (Year 4) the closure of schools imposed by the COVID-19-related lockdowns, and to investigate the association of self-esteem with these trajectories. Participants were 844 (50.6% boys) Portuguese adolescents (mean age 12.70 years, SD  = 1.14). The Social and Emotional Competencies Evaluation Questionnaire (QACSE) was used to assess social withdrawal and social anxiety, while The Global Self-Esteem scale of the Self-Description Questionnaire II was used to measure self-esteem. Growth curve analysis showed that social withdrawal and social anxiety had more negative trajectories during the year in which the school closures occurred. In addition, adolescents reported higher social withdrawal after the lockdowns than before the pandemic. Higher self-esteem was associated with a more positive trajectory in social withdrawal. Therefore, the results showed the negative of impact of the closure of schools on adolescents’ social anxiety and social withdrawal, and that self-esteem was a protective factor during these challenging and adverse events.

Climate change and rapid population ageing pose challenges for communities and public policies. This systematic review aims to gather data from studies that present health indicators establishing the connection between climate change and the physical and mental health of the older population (≥ 65 years), who experience a heightened vulnerability to the impacts of climate change when compared to other age cohorts. This review was conducted according to the PICO strategy and following Cochrane and PRISMA guidelines. Three databases (PubMed, Scopus and Greenfile) were searched for articles from 2015 to 2022. After applying inclusion and exclusion criteria,nineteen studies were included. The findings indicated that various climate change phenomena are associated with an elevated risk of mortality and morbidity outcomes in older adults. These included cardiovascular, respiratory, renal, and mental diseases, along with physical injuries. Notably, the impact of climate change was influenced by gender, socioeconomic status, education level, and age—vulnerability factors. Climate change directly affected the health of older adults through ambient temperature variability, extreme and abnormal temperatures, strong winds, sea temperature variability, extreme El Niño-southern Oscillation (ENSO) conditions and droughts, and indirectly by air pollution resulting from wildfires. This review presents further evidence confirming that climate change significantly impacts the health and well-being of older adults. It highlights the urgency for implementing effective strategies to facilitate adaptation and mitigation, enhancing the overall quality of life for all individuals.

Objectives Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes. We performed a meta-analysis to assess tirzepatide’s weight reduction efficacy and safety. Methods We searched PubMed, Embase, and Cochrane for randomized controlled trials published from inception to July 2022, comparing tirzepatide with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratio (OR) were calculated for continuous and binary outcomes, respectively. Review Manager 5.4.1 and RStudio were used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. Results Of 397 search results, 6 studies (4036 participants) ranging from 12 to 72 weeks were included. Pooled analysis showed that tirzepatide 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight of −7.7 kg (95% CI −11.0, −4.4; p  < 0.001), −11.6 kg (95% CI −18.8, −4.3; p  = 0.002), and −11.8 kg (95% CI −17.4, -6.2; p  < 0.001), respectively, and MD in percent change in weight of −8.1% (95% CI −11.0, −5.2; p  < 0.001), −11.9% (95% CI −18.1, −5.6; p  < 0.001), and -12.4% (95% CI −17.2, −7.5; p  < 0.001), respectively. Tirzepatide also reduced BMI and waist circumference. Adverse events were more common with tirzepatide with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p  < 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p  < 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p  < 0.001) (15 mg dose), when compared with placebo. Conclusions The results support that tirzepatide leads to substantial weight reduction and constitutes a valuable therapeutic option for weight management, despite an increase in gastrointestinal symptoms. Protocol registration CRD42022348576.

The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node-derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue-based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs.

We present a novel approach to generate Bessel–Gauss modes of arbitrary integer order and well-defined optical angular momentum in a gradient index medium of transverse parabolic profile. The propagation and coherence properties, as well as the quality factor, are studied using algebraic techniques that are widely used in quantum mechanics. It is found that imposing the well-defined optical angular momentum condition, the Lie group SU(1,1) comes to light as a characteristic symmetry of the Bessel–Gauss beams.