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Background: Antimicrobial resistance (AMR) is associated with significant human and financial costs, particularly among vulnerable populations like older adults living in long-term care homes (LTCHs). Urinary tract infection (UTI) is the leading indication for antibiotic use in this population, with some estimates suggesting that up to 70% of these prescriptions may be avoidable. Objective: The purpose of this study is to develop and test novel behavioural science-informed antimicrobial stewardship (AMS) quality improvement strategies in Canadian LTCHs, which aim to decrease unnecessary testing and treatment for residents who lack the minimum clinical signs and symptoms of UTI. Intervention: The quality improvement strategy is a two-pronged approach that includes 1) targeted education for essential care providers (family and friends of LTCH residents) about UTI and benefits of AMS, which strives to outline a positive role for this group in UTI management, and 2) monthly feedback to LTCH staff on their facility's urine culture ordering rates. Outcomes: The protocol was piloted in a single LTCH; a process evaluation of the pilot implementation served to refine the research protocol, which is being implemented in eight LTCHs across Canada using an eight-month stepped wedge randomized cluster design. Conclusion: This protocol represents a behavioural science-informed intervention to improve AMS across LTCHs. If successful, this model of care could be scalable across Canadian LTCHs, offering an inclusive approach that aims to empower clinicians, non-regulated healthcare staff, residents and their family and friends to improve health outcomes as antibiotic stewards. [ABSTRACT FROM AUTHOR]

Advancements in genomics and machine learning have significantly enhanced the study of Salmonella epidemiology. Whole-genome sequencing has revolutionized bacterial genomics, allowing for detailed analysis of genetic variation and aiding in outbreak investigations and source tracking. Short-read sequencing technologies, such as those provided by Illumina, have been instrumental in generating draft genomes that facilitate serotyping and the detection of antimicrobial resistance. Long-read sequencing technologies, including those from Pacific Biosciences and Oxford Nanopore Technologies, offer the potential for more complete genome assemblies and better insights into genetic diversity. In addition to these sequencing approaches, machine learning techniques like decision trees and random forests provide powerful tools for pattern recognition and predictive modeling. Importantly, the study of bacteriophages, which interact with Salmonella, offers additional layers of understanding. Phages can impact Salmonella population dynamics and evolution, and their integration into Salmonella genomics research holds promise for novel insights into pathogen control and epidemiology. This review revisits the history of Salmonella and its pathogenesis and highlights the integration of these modern methodologies in advancing our understanding of Salmonella. [ABSTRACT FROM AUTHOR]

Diverse research programs employing complementary strategies have been uncovering cellular, molecular, and genetic mechanisms essential to avian beak development and evolution. In reviewing these discoveries, I offer an interdisciplinary perspective on bird beaks that spans their derivation from jaws of dinosaurian reptiles, their anatomical and ecological diversification across major taxonomic groups, their common embryonic origins, their intrinsic patterning processes, and their structural integration. I describe how descriptive and experimental approaches, including gene expression and cell lineage analyses, tissue recombinations, surgical transplants, gain- and loss-of-function methods, geometric morphometrics, comparative genomics, and genome-wide association studies, have identified key constituent parts and putative genes regulating beak morphogenesis and evolution. I focus throughout on neural crest mesenchyme, which generates the beak skeleton and other components, and describe how these embryonic progenitor cells mediate species-specific pattern and link form and function as revealed by 20 years of research using chimeras between quail and duck embryos. [ABSTRACT FROM AUTHOR]

Dragon fruit (Hylocereus spp.), renowned for its aesthetic appeal and rich antioxidant content, has gained global popularity due to its numerous health benefits. In Australia, despite growing commercial interest in cultivating dragon fruit, there is uncertainty for local growers stemming from competition with imported varieties. Notably, there is a lack of comparative research on the shelf-life, antioxidant activity, and phytochemical contents of Australian-grown versus imported dragon fruit, which is crucial for enhancing market competitiveness and consumer perception. This study compares the shelf-life, antioxidant activity, and phytochemical content of Australian-grown and imported dragon fruits under ambient conditions, addressing the competitive challenges faced by local growers. Freshly harvested white-flesh (Hylocereus undatus) and red-flesh (H. polyrhizus) dragon fruit were sourced from Queensland and the Northern Territory and imported fruit were sourced from an importer in Queensland. All fruit were assessed for key quality parameters including peel color, firmness, weight loss, total soluble solids (TSS), pH, titratable acidity (TA), total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), total betalain content (TBC), and total anthocyanin content (TAC). The results indicate that Australian-grown white dragon fruits exhibited average one day longer shelf-life with less color degradation, better firmness retention, and less decline in weight loss, TSS, and acidity compared to imported fruits. Australian-grown red dragon fruits showed similar shelf-life compared to fruits from overseas. Antioxidant activities and phytochemicals were consistently higher in Australian-grown fruits throughout their shelf-life. These findings indicate that Australian-grown dragon fruits offer better physical quality and retain more nutritional value, which could enhance their marketability. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) formed by neutrophils are netlike scaffolds that mainly contain DNA and a variety of granule proteins. Many stimuli can lead to the NET formation through independent molecular pathways. Clinically, the abundance of NETs is correlated with poor tumor prognosis. The biological actions of NETs are complex and diverse, including promoting tumor progression, awakening the dormant cancer cells, and resulting in immunosuppression in support of tumor growth and metastasis. Therefore, NET‐associated pathological processes provide an important clue for both diagnostic imaging and alternative therapies for many kinds of cancers. In recent years, scientists' efforts have focused on developing novel imaging probes to visualize NETs and therapeutic strategies by degrading NETs or inhibiting its formation to block their pro‐tumoral functions. In this review, the development and evaluation of NETs‐targeted imaging and intervention progress for tumor therapy are focused on. [ABSTRACT FROM AUTHOR]

Acetochlor is frequently applied to various food crops in agriculture sector, and long-term exposure can cause significant endocrine-disrupting effects in exposed animals including impacts on human health. This study aimed to evaluate the effects of acetochlor on the growth, hematology, serum biochemistry, and histopathological alterations in Japanese quail. Eighty male quail were obtained and divided into four groups (A-D) and given acetochlor orally for the period of 45 days. Group A was served as the control, while groups B, C, and D received 20mg/kg, 30mg/kg, and 40mg/kg acetochlor, respectively. The study found that Japanese quail administered higher doses of acetochlor exhibited reduced frequency of crowing and foam production. The results showed that increased concentrations of acetochlor led to adverse effects on the growth parameters of Japanese quail. Hematology analysis indicated that birds exposed to higher concentrations of acetochlor experienced a significant decrease in red blood cell count, hemoglobin concentration, hematocrit (HCT), mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), along with a significant increase in white blood cell count compared to the control group. Additionally, higher concentrations of acetochlor led to a significant increase in various serological indices including urea, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), while the values of total proteins, albumin, and plasma proteins declined. The histopathology results of treated Japanese quail exposed to higher concentrations of acetochlor showed a range of pathological lesions in the testes, heart, and brain. The study concluded that even low concentrations of acetochlor can cause slight to significant changes in Japanese quail, affecting their physical, hematological, histopathological and serum biochemical parameters. [ABSTRACT FROM AUTHOR]

Background: Ireland's Smoking Ban reduced health inequalities known to be associated with smoking but some groups may not have benefitted. Mental ill-health and smoking are known to be associated with health inequalities. Whether similar patterns exist for e-cigarette use is less clear, as few data exist. Objectives: To examine: (1) self-reported doctor-diagnosed mental ill-health in Irish 20-year-olds; (2) smoking, e-cigarette, and dual use in those with and without mental ill-health; and (3) protective and risk factors for smoking and e-cigarette use in these groups. Methods: We use cross-sectional data from 20 year-olds in Wave 4 of Growing Up in Ireland Child Cohort. They were asked to self-report mental ill-health which had been diagnosed by a clinician, and their smoking and e-cigarette use. All analyses were performed using SPSS v27. Results: 19.4% (n = 1008) of the total sample (n = 4729) reported a mental ill-health diagnosis. Comparing those with and without, those with mental ill-health had significantly higher prevalence of current smoking (47%, n = 419 vs 36%, n = 1361; OR 1.57, CI: 1.36, 1.82), e-cigarette use (17%, n = 152 vs 13%, n = 485; OR 1.40, CI:1.15, 1.70), and dual use (12%, n = 109 vs 9%, n = 328; OR 1.46, CI:1.16, 1.84). Risk factors for smoking and e-cigarette use were, earlier smoking initiation, peers or primary caregivers who smoked, being in paid employment, one-parent family background, and social media use. Being female was protective. Most risk factors were significantly higher in young adults with mental ill-health but, after adjusting for these variables, respondents with mental ill-health still have significantly higher adjusted higher odds of smoking (aOR 1.28, CI:1.05, 1.56). Conclusions: Inequalities in smoking and e-cigarette use in young adults with mental ill-health are evident 20 years after Ireland's National Smoking Ban. Despite extensive Tobacco Control interventions in the past 20 years, there is still need in Ireland for new targeted interventions to reduce health inequalities for left-behind young smokers with mental ill-health. [ABSTRACT FROM AUTHOR]

Fungal secondary metabolites (SMs) represent an invaluable source of therapeutic drugs. Genomics-based approaches to SM discovery have revealed a vast and largely untapped biosynthetic potential within fungal genomes. Here, we used the publicly available fungal genome sequences from the NCBI public database, as well as tools such as antiSMASH, BIG-SLiCE, etc., to analyze a total of 11,598 fungal genomes, identifying 293,926 biosynthetic gene clusters (BGCs), which were subsequently categorized into 26,825 gene cluster families (GCFs). It was discovered that only a tiny fraction, less than 1%, of these GCFs could be mapped to known natural products (NPs). Some GCFs that only contain a single BGC internally are crucial for the biodiversity of fungal biosynthesis. Evident patterns emerged from our analysis, revealing popular taxa as prominent sources of both actual and potential biosynthetic diversity. Our study also suggests that the genus rank distribution of GCF is generally consistent with NP diversity. It is noteworthy that genera Xylaria, Hypoxylon, Colletotrichum, Diaporthe, Nemania, and Calonectria appear to possess a higher potential for SM synthesis. In addition, 7213 BGCs match possible known compound structures, and homologous gene clusters of well-known drugs can be located in different genera, facilitating the development of derivatives that share structural similarity to these drugs and may potentially possess similar biological activity. Our study demonstrated the various types of fungi with mining potential, assisting researchers in prioritizing their research efforts and avoiding duplicate mining of known resources to further explore fungal NP producers. [ABSTRACT FROM AUTHOR]

Purpose: To explore the association between lifelong learning (LL) and successful aging and discover ways that primary care nurses (PCNs) may facilitate successful aging by promoting LL. Method: A narrative review of international evidence from Google Scholar, PubMed, CINAHL Plus, Ovid, and ProQuest was conducted. Twenty-one articles were reviewed. A theoretical framework supported by Troutman-Jordan's theory of successful aging and Baltes and Baltes' model of selection, optimization, and compensation were implemented to examine and illustrate findings. Results: Evidence consistently showed a positive correlation between LL and successful aging. Conclusion: Promotion of successful aging is an important consideration in PCN practice. This study brings awareness to the value of LL in achieving that goal. Incorporating strategies, such as encouraging creative activities and healthy behaviors, cultivating positive perceptions about aging, and helping patients meet their perceived needs, fosters coping with growing older. [Journal of Gerontological Nursing, 50(8), 11–17.] [ABSTRACT FROM AUTHOR]

When stressed, cells need to adapt their proteome to maintain protein homeostasis. This requires increased proteasome assembly. Increased proteasome assembly is dependent on increased production of proteasome assembly chaperones. In Saccharomyces cerevisiae, inhibition of the growth-promoting kinase complex TORC1 causes increased proteasome assembly chaperone translation, including that of Adc17. This is dependent upon activation of the mitogen-activated protein kinase (MAPK) Mpk1 and relocalisation of assembly chaperone mRNA to patches of dense actin. We show here that TORC1 inhibition alters cell wall properties to induce these changes by activating the cell wall integrity pathway through the Wsc1, Wsc3 and Wsc4 sensor proteins. We demonstrate that, in isolation, these signals are insufficient to drive protein expression. We identify that the TORC1-activated S6 kinase Sch9 must be inhibited as well. This work expands our knowledge on the signalling pathways that regulate proteasome assembly chaperone production. [ABSTRACT FROM AUTHOR]

A large-eddy simulation was implemented for the flow around a cylindrical observation tower to investigate the effects of the tower structure on wind speed and drag coefficient. The mean wind velocity accelerates above the tower because flow separation occurs at the leading edge of the top of the tower. The drag coefficient is strongly linked to the Reynolds shear stress. Above the tower, the Reynolds shear stresses change from negative to positive within the recirculation zone and return to a negative value in the latter half of the tower because of the steep velocity gradients near the top of the tower. The change in the Reynolds shear stress results in an inaccurate drag coefficient. When one anemometer is used, a location at over 10 m above the top of the tower is suitable for measuring the drag coefficient accurately. When two anemometers are used, the Reynolds shear stress can be measured more accurately. Although the effects of the tower on the drag coefficient are not entirely removed, the use of two anemometers is a promising approach to estimate the drag coefficient in a tower. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the potential mechanisms involved in the therapeutic effects of daitongxiao (DTX) on hyperuricemia (HUA). DTX was administered to two animal models of HUA via gavage feeding: HUA quail model (a uricotelic animal with urate oxidase deficiency), treated continuously for 35 days post-HUA induction, and HUA rats (an animal with active urate oxidase), treated continuously for 28 days post-HUA induction. HUA was induced in quail by administering a solution of sterile dry yeast powder via gavage feeding, while in rats, it was induced by intragastric gavage feeding of a solution of adenine and ethambutol hydrochloride. DTX improved overall health; increased bodyweight; reduced renal index, serum urate levels, serum xanthine oxidase activity, blood urea nitrogen, and creatinine; and enhanced urinary and fecal uric acid (UA) excretion in these two animal models. The results of hematoxylin and eosin and hexamine silver staining of kidney sections revealed that DTX significantly mitigated HUA-induced renal structural damage and inflammatory response. The results of quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence analyses revealed that DTX downregulated the renal expression levels of glucose transporter 9 (GLUT9) and upregulated the renal expression levels of organic anion transporters (OAT1 and OAT3) in both HUA models. Thus, the findings of this study suggest that DTX suppresses the progression of HUA by modulating the expression of the UA transporter group members. [ABSTRACT FROM AUTHOR]

Conventional immunization methods such as intramuscular injections lack effective mucosal protection against pathogens that enter through the mucosal surfaces. Moreover, conventional therapy often leads to adverse events and compromised immunity, followed by complicated outcomes, leading to the need to switch to other options. Thus, a need to develop safe and effective treatment with long-term beneficial outcomes to reduce the risk of relapse is mandatory. Mucosal vaccines administered across mucosal surfaces, such as the respiratory or intestinal mucosa, to prompt robust localized and systemic immune responses to prevent the public from acquiring pathogenic diseases. Mucosal immunity contains a unique immune cell milieu that selectively identify pathogens and limits the transmission and progression of mucosal diseases, such as allergic dermatitis and inflammatory bowel disease (IBD). It also offers protection from localized infection at the site of entry, enables the clearance of pathogens on mucosal surfaces, and leads to the induction of long-term immunity with the ability to shape regulatory responses. Regulatory T (Treg) cells have been a promising strategy to suppress mucosal diseases. To find advances in mucosal treatment, we investigated the therapeutic effects of intranasal pep27 mutant immunization. Nasal immunization protects mucosal surfaces, but nasal antigen presentation appears to entail the need for an adjuvant to stimulate immunogenicity. Here, a novel method is developed to induce Tregs via intranasal immunization without an adjuvant to potentially overcome allergic diseases and gut and lung inflammation using lung–gut axis communication in animal models. The implementation of the pep27 mutant for these therapies should be preceded by studies on Treg resilience through clinical translational studies on dietary changes. [ABSTRACT FROM AUTHOR]

Despite success in the treatment of some blood cancers and melanoma, positive response to immunotherapies remains disappointingly low in the treatment of solid tumors. The context of the molecular crosstalk within the tumor microenvironment can result in dysfunctional immune cell activation, leading to tumor tolerance and progression. Although modulating these protein–protein interactions (PPIs) is vital for appropriate immune cell activation and recognition, targeting nonenzymatic PPIs has proven to be fraught with challenges. To address this, a synthetic, multivalent molecular modality comprised of small interfering peptides precisely hybridized to a semirigid DNA scaffold is introduced. Herein, a prototype of this modality that targets the IL‐33/ST2 signaling axis, which is associated with tumor tolerance and immunotherapy treatment failure is described. Using peptides that mimic the specific high‐energy "hotspot" residues with which the IL‐33/ST2 coreceptor, IL‐1RAcP, interacts with the initial binary complex, this platform is shown to effectively bind IL‐33/ST2 with a KD of 110 nm. Additionally, this molecule effectively abrogates signal transduction in cell models at high nanomolar concentrations and is exquisitely selective for this complex over structurally similar PPIs within the same cytokine superfamily. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases are a major challenge for patients with HER2+ breast cancer. Traditional treatments, like radiotherapy, can help but often cause severe side effects and may not provide lasting control. Researchers are exploring new, more precise treatments, including antibodies, drug-antibody combinations, and small molecule drugs that can better penetrate the brain. These new therapies have shown promise in clinical trials, helping to control brain tumors more effectively and with fewer side effects than radiotherapy. The goal of this review is to improve treatments for HER2+ breast cancer patients who develop brain metastases, enhancing their survival rates and quality of life. The findings from this research could significantly impact the medical community by offering better alternatives to radiotherapy and improving how brain metastases are managed. This progress could provide new hope for patients facing this challenging condition and potentially transform treatment strategies in the future. Brain metastases (BM) pose a significant challenge in the management of HER2+ breast cancer since almost 50% of patients with HER2+ breast cancer develop brain tumors. The complex process of brain metastases involves genetic mutations, adaptations and mechanisms to overcome the blood–brain barrier. While radiotherapy is still fundamental in local therapy, its use is associated with cognitive adverse effects and limited long-term control, necessitating the exploration of alternative treatments. Targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates, offer promising options for HER2+ breast cancer patients with BM. Clinical trials have demonstrated the efficacy of these agents in controlling tumor growth and improving patient outcomes, posing the question of whether radiotherapy is always the unique choice in treating this cancer. Ongoing research into novel anti-HER2 antibodies and innovative combination therapies holds promise for advancing treatment outcomes and enhancing patient care in this clinical scenario. This narrative review provides a comprehensive overview of traditional medical treatments, molecularly targeted therapy and investigational agents in the management of HER2+ breast cancer with BM, highlighting the evolving landscape and potential future directions in treatment strategies to improve patient survival and quality of life. [ABSTRACT FROM AUTHOR]

The relationship between individual phytochemical constituents and overall antioxidant capacity or total phenolic content (TPC) is poorly understood in faba bean. This study used a range of linear and nonlinear regression techniques to investigate whether the antioxidant capacity and TPC of 60 faba bean samples (flour and methanolic extracts) could be predicted from 12 individual compounds (10 common polyphenols and 2 alkaloid glycosides) measured in the same samples. Nonlinear regression using machine learning with a Radial Basis Function showed the best performance for antioxidant and TPC prediction across all sample types, while multiple linear regression allowed moderately accurate predictions in most sample matrices. Improved performance metrics were seen for the methanolic extracts compared to the flour samples. The strongest predictors of antioxidant activity in the multiple linear regression models were protocatechuic acid, p-hydroxybenzoic acid, and ferulic acid, suggesting that these compounds are particularly important contributors to the high antioxidant activity of faba bean. Understanding the relationship between individual constituents and the antioxidant capacity may help food technologists and plant breeders develop faba bean products with maximal health benefits. [ABSTRACT FROM AUTHOR]

Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation to the yolk of maturing oocytes, 2) the IgY deposited in yolk is transported to the circulation of the embryo via the yolk sac membrane. An IgY-Fc receptor, FcRY, is involved in the second step, but the mechanism of the first step is still unclear. We determined whether FcRY was also the basis for maternal blood IgY transfer to the yolk in the first step during egg development. Immunohistochemistry revealed that FcRY was expressed in the capillary endothelial cells in the internal theca layer of the ovarian follicle. Substitution of the amino acid residue in Fc region of IgY substantially changed the transport efficiency of IgY into egg yolks when intravenously-injected into laying quail; the G365A mutant had a high transport efficiency, but the Y363A mutant lacked transport ability. Binding analyses of IgY mutants to FcRY indicated that the mutant with a high transport efficiency (G365A) had a strong binding activity to FcRY; the mutants with a low transport efficiency (G365D, N408A) had a weak binding activity to FcRY. One exception, the Y363A mutant had a remarkably strong binding affinity to FcRY, with a small dissociation rate. The injection of neutralizing FcRY antibodies in laying quail markedly reduced IgY uptake into egg yolks. The neutralization also showed that FcRY was engaged in prolongation of half-life of IgY in the blood; FcRY is therefore a multifunctional receptor that controls avian immunity. The pattern of the transport of the IgY mutants from the maternal blood to the egg yolk was found to be identical to that from the fertilized egg yolk to the newly-hatched chick blood circulation, via the yolk sac membrane. FcRY is therefore a critical IgY receptor that regulates the IgY uptake from the maternal blood circulation into the yolk of avian species, further indicating that the two steps of maternal--newly-hatched IgY transfer are controlled by a single receptor. [ABSTRACT FROM AUTHOR]

Sesame is an emerging crop of interest in Australia and has attracted widespread interest due to the health-benefitting properties of its bioactive compounds, including fatty acids, lignans, and polyphenols. This study aimed to investigate the impact of drought stress on these bioactive compounds, using eleven cultivars of black sesame seeds grown in Australia. Specific varieties responded positively to water deficit (WD) conditions, showing increased levels of TPC, FRAP, CUPRAC, and lignans. Varieties 1, 4, 7, and 12 showed significantly increased FRAP values ranging from 158.02 ± 10.43 to 195.22 ± 9.63 mg TE/100 g DW in the WD treatment compared to the well-watered (WW) treatment, whereas varieties 7, 10, 12, 13, and 18 demonstrated the highest CUPRAC values of all varieties (2584.86 ± 99.68–2969.56 ± 159.72 mg TE/100 g) across both WW and WD conditions, with no significant variations between irrigation regimes. Moreover, lignan contents (sesamin and sesamolin) were higher in varieties 1, 2, 5, and 8 grown in WD conditions. Compared to the optimal unsaturated to saturated fatty acid ratio (Σ UFA/Σ SFA ratio) of 0.45, all sesame genotypes showed superior ratios (ranging between 1.86 and 2.34). Moreover, the ω-6/ω-3 PUFA ratio varied from 33.7–65.5, with lower ratios in varieties 2, 4, 5, 8, and 18 under WD conditions. The high levels of phenolic compounds and healthy fats suggest the potential of black sesame to be incorporated into diets as a functional food. Furthermore, the enhanced phytochemistry of these cultivars in WD conditions is promising for widespread adoption. However, larger trial studies to confirm these findings across different geographic locations and seasons are warranted. [ABSTRACT FROM AUTHOR]

Objective: This article aims to identify individual and community-contextual level factors associated with the wellbeing of older adults (50 years and older) in rural Zambia. Methods: Data from the nationally representative 2015 Living Conditions Monitoring Survey (LCMS) was used. Employing multilevel mixed effects, the individual and community-contextual factors on wellbeing were determined. Results: Overall, 31.7% of rural older adults perceived their wellbeing as good. Both individual and community-contextual level factors are associated with the wellbeing of older adults in rural communities. At the individual level, wellbeing was associated with higher education attainment. Community-contextual factors significantly associated with wellbeing included improved housing, access to piped tap water within the premises, own charcoal or income to purchase firewood. Conclusion: The findings foreground the imperative to analyse both individual and community-contextual level factors of wellbeing to generate and present evidence for investments in education across the life course and for the development of infrastructure towards increasing the wellbeing of rural older adults. Additionally, the results provide a basis for planning by devising policies and programmes for older people to thrive and for no one to be left behind regardless the setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is a lethal primary brain tumor, and so far, immunotherapeutic strategies have not significantly improved patients' prognosis, both in newly diagnosed and recurrent settings. Understanding the features of the immune environment of the central nervous system is crucial to designing new treatment strategies able to counteract site-specific immunosuppressive and pro-tumorigenic factors. Here, we review next-generation immunomodulating therapeutic strategies such as immune check-point blockade, vaccinations, and adoptive cell therapies, aiming to re-shape the tumor microenvironment and restore active anti-tumor immunity. The door for immunotherapeutic strategies in glioblastoma treatment is not completely closed; researchers should test combinatorial treatments and design trials with solid translational analyses to gain more close and deep insight into on-treatment modifications of the tumor microenvironment. Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-β, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment. [ABSTRACT FROM AUTHOR]

Background: Light is essential for kiwifruit development, in which photoresponse factors contributes greatly to the quality formation. 'Light sensitive hypocotyls, also known as light-dependent short hypocotyls' (LSH) gene family can participate in fruit development as photoresponse factor. However, the key LSH gene that determine kiwifruit development remains unclear. This study aim to screen and identify the key gene AaLSH9 in A. arguta. Materials and methods: Genome-wide identification of the LSH gene family was used to analyse LSH genes in kiwifruit. Homologous cloning was used to confirm the sequence of candidate LSH genes. qRT-PCR and cluster analysis of expression pattern were used to screen the key AaLSH9 gene. Subcellular localization of AaLSH9 in tobacco leaves and overexpression of AaLSH9 in Arabidopsis thaliana hy5 mutant plants were used to define the acting place in cell and identify molecular function, respectively. Results: We identified 15 LSH genes, which were divided into two sub-families namely A and B. Domain analysis of A and B showed that they contained different domain organizations, which possibly played key roles in the evolution process. Three LSH genes, AaLSH2, AaLSH9, and AaLSH11, were successfully isolated from Actinidia arguta. The expression pattern and cluster analysis of these three AaLSH genes suggested AaLSH9 might be a key photoresponse gene participating in fruit development in A. arguta. Subcellular localization showed AaLSH9 protein was located in the nucleus. The overexpression of AaLSH9 gene in Arabidopsis thaliana hy5 mutant plants partially complemented the long hypocotyls of hy5 mutant, implying AaLSH9 played a key role as photoresponse factor in cells. In addition, the seed coat color of A. thaliana over-expressing AaLSH9 became lighter than the wide type A.thaliana. Finally, AaCOP1 was confirmed as photoresponse factor to participate in developmental process by stable transgenic A. thaliana. Conclusions: AaLSH9 can be involved in kiwifruit (A. arguta) development as key photoresponse factor. Our results not only identified the photoresponse factors AaLSH9 and AaCOP1 but also provided insights into their key role in fruit quality improvement in the process of light response. [ABSTRACT FROM AUTHOR]

Red and far-red light–sensing phytochromes are widespread in nature, occurring in plants, algae, fungi, and prokaryotes. Despite at least a billion years of evolution, their photosensory modules remain structurally and functionally similar. Conversely, nature has found remarkably different ways of transmitting light signals from the photosensor to diverse physiological responses. We summarize key features of phytochrome structure and function and discuss how these are correlated, from how the bilin environment affects the chromophore to how light induces cellular signals. Recent advances in the structural characterization of bacterial and plant phytochromes have resulted in paradigm changes in phytochrome research that we discuss in the context of present-day knowledge. Finally, we highlight questions that remain to be answered and suggest some of the benefits of understanding phytochrome structure and function. [ABSTRACT FROM AUTHOR]

Background: The somatopleure serves as the primordium of the amnion, an extraembryonic membrane surrounding the embryo. Recently, we have reported that amniogenic somatopleural cells (ASCs) not only form the amnion but also migrate into the embryo and differentiate into cardiomyocytes and vascular endothelial cells. However, detailed differentiation processes and final distributions of these intra‐embryonic ASCs (hereafter referred to as iASCs) remain largely unknown. Results: By quail‐chick chimera analysis, we here show that iASCs differentiate into various cell types including cardiomyocytes, smooth muscle cells, cardiac interstitial cells, and vascular endothelial cells. In the pharyngeal region, they distribute selectively into the thyroid gland and differentiate into vascular endothelial cells to form intra‐thyroid vasculature. Explant culture experiments indicated sequential requirement of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) signaling for endothelial differentiation of iASCs. Single‐cell transcriptome analysis further revealed heterogeneity and the presence of hemangioblast‐like cell population within ASCs, with a switch from FGF to VEGF receptor gene expression. Conclusion: The present study demonstrates novel roles of ASCss especially in heart and thyroid development. It will provide a novel clue for understanding the cardiovascular development of amniotes from embryological and evolutionary perspectives. Key Findings: Here, we show that amniogenic somatopleure cells (ASCs) differentiate into various cell types constituting the cardiovascular system, with some populations having a molecular background similar to that of hemangioblasts. Among them, those contributing to the thyroid vascular network were suggested to differentiate into vascular endothelial cells with FGF‐specification and VEGF‐induced maturation. This study will provide a novel clue for understanding the cardiovascular development of amniotes from embryological and evolutionary perspectives. [ABSTRACT FROM AUTHOR]

Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously “undruggable” targets for biologic-based therapy. [ABSTRACT FROM AUTHOR]

Locally advanced and metastatic urothelial carcinoma (UC) remains a challenging malignancy, though several novel therapeutic drugs have been developed in recent years. Over the past decade, immune checkpoint inhibitors (ICI) have shifted the paradigm of therapeutic strategies for UC; however, only a limited number of patients respond to ICI. Since radiotherapy (RT) is widely known to induce systemic immune activation, it may boost the efficacy of ICI. Conversely, RT also causes exhaustion of cytotoxic T cells, and the activation and recruitment of immunosuppressive cells; ICI may help overcome these immunosuppressive effects. Therefore, the combination of ICI and RT has attracted attention in recent years. The therapeutic benefits of this combination therapy and its optimal regimen have not yet been determined through prospective studies. Therefore, this review article aimed to provide an overview of the current preclinical and clinical studies that illustrate the underlying mechanisms and explore the optimization of the RT regimen along with the ICI and RT combination sequence. We also analyzed ongoing prospective studies on ICI and RT combination therapies for metastatic UC. We noted that the tumor response to ICI and RT combination seemingly differs among cancer types. Thus, our findings highlight the need for well-designed prospective trials to determine the optimal combination of ICI and RT for locally advanced and metastatic UC. [ABSTRACT FROM AUTHOR]

Defining the mechanisms that allow cells to adapt to environmental stress is critical for understanding the progression of chronic diseases and identifying relevant drug targets. Among these, activation of the pathway controlled by the eIF2-alpha kinase GCN2 is critical for translational and metabolic reprogramming of the cell in response to various metabolic, proteotoxic, and ribosomal stressors. However, its role has frequently been investigated through the lens of a stress pathway signaling via the eIF2α-activating transcription factor 4 (ATF4) downstream axis, while recent advances in the field have revealed that the GCN2 pathway is more complex than previously thought. Indeed, this kinase can be activated through a variety of mechanisms, phosphorylate substrates other than eIF2α, and regulate cell proliferation in a steady state. This review presents recent findings regarding the fundamental mechanisms underlying GCN2 signaling and function, as well as the development of drugs that modulate its activity. Furthermore, by comparing the literature on GCN2's antagonistic roles in two challenging pathologies, cancer and pulmonary diseases, the benefits, and drawbacks of GCN2 targeting, particularly inhibition, are discussed., (© 2024 Federation of European Biochemical Societies.)

Although socioeconomic disadvantage is linked with academic underachievement, many children from low-income backgrounds perform well in school. Which modifiable factors predict this academic resilience? We examine between- and within-person predictors of one important academic metric - mathematics performance - across adolescence in 1715 (796 male, 919 female) youth living in poverty in Ireland, using data from three waves (9, 13, and 17/18 years) of the Growing Up in Ireland study. Using linear mixed models, math performance was worse when adolescents had more socioemotional and behavioural difficulties, more child-parent relationship conflict, parents had lower expectations of the adolescent's educational achievement, and when primary caregivers had less education. Adolescents who had better intellectual self-concept and attended a non-disadvantaged school had greater math performance. This research adds to the growing body of work suggesting academic resilience is dynamic and multisystemic; it provides potential targets at multiple levels to promote such resilience., (© 2024 The Author(s). British Journal of Developmental Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Highly pathogenic Burkholderia pseudomallei is the causative agent of melioidosis, a neglected tropical disease endemic in Southeast Asian tropical region. This bacterium encompasses diverse virulence factors which further undergo dynamic gene-expression flux as it transits through distinct environmental niches within the host which may lead to manifestation of differential clinical symptoms. B. pseudomallei, is classified as a Tier 1 select agent in the United States and regarded as a risk group 3 organism in India with the potential to be used as bioweapon. Considering these facts, it is vital to uncover both physiological and genetic heterogeneity of B. pseudomallei, particularly to identify any novel virulence factors that may contribute to pathogenicity. B. pseudomallei strain CM000113 was isolated from a clinical case in India, characterized it for its physiological, biochemical, and prominently genetic traits through WGS. It has a type 2 morphotype with faster doubling time and high biofilm producing capacity as compared to Pseudomonas aeruginosa. The genome size is 7.3 Mbp and it is phylogenetically close to B. pseudomallei strain Mahidol 1106a and Burkholderia mallei Turkey 2. We observed genetic heterogeneity, as key virulence factors that were identified shows sequence dissimilarity with reference strains. Additionally, presence of genomic islands, harbouring two virulence factors, GmhA and GmhB2, associated with pathogenesis indicates possibility of horizontal gene transfer. These results emphasize the need for an extensive study focusing the genome of B. pseudomallei and its associated heterogeneity, to identify molecular biomarkers aiding to develop point-of-care diagnostic kits for early diagnosis of melioidosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent advancements in cancer treatment have improved patient prognoses, but chemotherapy induced cardiotoxicity remains a prevalent concern. This study explores the potential of F-base-modified aptamers for targeted drug delivery, focusing on their impact on cardiotoxicity. From the phosphoramidite, F-base-functionalized Sgc8-F23 was prepared in an automated and programmable way, which was further reacted with paclitaxel (PTX) to give the F-base- modified aptamer Sgc8-paclitaxel conjugates (Sgc8-F23-PTX) efficiently. The conjugate exhibited prolonged circulation time and enhanced efficacy as a precision anticancer drug delivery system. Echocardiographic assessments revealed no exacerbation of cardiac dysfunction after myocardial infarction (MI) and no pathological changes or increased apoptosis in non-infarcted cardiac regions. Autophagy pathway analysis showed no discernible differences in Sgc8-F23-PTX-treated cardiomyocytes compared with controls, in contrast to the increased autophagy with nanoparticle albumin-bound-paclitaxel (Nab-PTX). Similarly, apoptosis analysis showed no significant differences. Moreover, Sgc8-F23-PTX exhibited no inhibitory effect on hERG, hNav1.5, or hCav1.2 channels. These findings suggest the safety and efficacy of F-base-modified Sgc8 aptamers for targeted drug delivery with potential clinical applications. Further research is warranted for clinical translation and exploration of other drug carriers., (© 2024 Wiley-VCH GmbH.)

There are growing calls from researchers and policy makers to redefine loneliness and social isolation (SI) as public health issues, and to move towards a transdisciplinary, systems-based approach, due to their association with significant health risks, particularly in older people. Research about loneliness and SI in older people has typically adopted a narrow focus, evaluating effects of individual and inter-personal factors on these experiences. Less is known about the community and societal influences that may be used to inform public health interventions. We conducted a scoping review applying Joanna Briggs Institute methodology and the social-ecological model framework in order to: i) identify the available evidence for the influence of the community and societal factors on loneliness and SI as experienced by older people; ii) examine how quantitative research about community- and societal-level factors of loneliness and SI in the older population is conducted; and iii) identify current knowledge gaps in relation to the use of the social-ecological model in this area. A total of 52 articles from 30 countries met the inclusion criteria, including 33 observational studies, primarily cross-sectional (88%), and 19 interventions, mostly (89%) pre-post evaluations. The majority of included articles measured loneliness only (n = 34, 65%), while 11 measured both loneliness and SI (21%). To measure these outcomes validated scales were frequently used. Eighteen community/societal factors were investigated in relation to loneliness and/or SI, most commonly neighbourhood safety, access to public third-places and cultural practices. Three societal-level interventions were found: two campaigns to reduce ageism and one which explored the impact of free public transport. Community-based interventions were either educational or enlisted volunteers to foster connections. There is a need for longitudinal studies to better understand the mechanisms through which community- and societal- level factors affect loneliness and SI, which in turn will guide interventions that utilise the social-ecological framework for these issues. [ABSTRACT FROM AUTHOR]

Consumers are showing increasing awareness of the concept of 'functional foods': foods that can provide health benefits in addition to their nutritional value. There is particular demand for foods with a high antioxidant and phenolic content, which may improve cardiovascular health, reduce inflammation, and slow or prevent the onset of chronic, non-communicable diseases. However, there is a lack of comprehensive databases using consistent analytical protocols to analyze the antioxidant and phenolic content of different food types, particularly in regional areas such as Australia. Over the past four years, our laboratory has analyzed over 1000 food-related samples using several antioxidant capacity assays (ferric reducing antioxidant power—FRAP—and cupric reducing antioxidant capacity—CUPRAC), as well as the total phenolic content (TPC) using the Folin–Ciocalteu method. Here, we provide a summary of these data by different food types to inform researchers, policy planners, nutritionists, and consumers about the typical levels of antioxidants and total phenolics found across a range of Australian foodstuffs, particularly grains. The highest antioxidant and phenolic contents were typically found in native Australian fruits, while grains, nuts, and non-native fruits showed lower antioxidant and phenolic contents. Spices, processed foodstuffs, and non-fruit native Australian foods showed an intermediate content. Furthermore, medicinally used plants showed a much higher phenolic content and antioxidant capacity compared to non-medicinal plants. Finally, we present correlations between the various analytes. [ABSTRACT FROM AUTHOR]

Chickpea (Cicer arietinum L.) is a significant pulse crop in Australia, with an industry value of over AUD 1.3 billion. However, there are few studies investigating the levels of health-benefiting constituents in desi chickpeas and the impacts of variety, growing location, and season on these constituents. This study aimed to study the levels of health-benefiting constituents in desi chickpeas, including 97 samples of Australian desi chickpeas, comprising 18 varieties, grown in a range of field trials across four Victorian locations and three growing seasons. Various physical characteristics and phytochemical compositions were determined in the samples, including 100-seed weight, colour, moisture content, total phenolic content (TPC), ferric-reducing antioxidant potential (FRAP), cupric-reducing antioxidant potential (CUPRAC), and total monomeric anthocyanin content (TMAC). The screening results showed a significant difference in TPC, TMAC, and FRAP among different desi varieties, suggesting there may be variation in their potential health benefits. Furthermore, the growing location and growing season significantly impacted all analytes. Correlation analysis revealed a number of significant correlations, including a moderate positive correlation between the b* colour and the antioxidant capacity and total phenolic content. This work provides the first detailed insight into the range of phenolic and antioxidant contents found in Australian desi chickpeas and the impact that genotype, location, and season can have. [ABSTRACT FROM AUTHOR]

Chemotherapy and radiotherapy are colossal stress factors for tumor cells. In response to therapy, the entire evolutionarily fixed response of cells to stress is activated. This happens at all levels of cell organization, namely, at the protein level and the DNA level. This response includes the cell proteostasis system, DNA-repair systems, tumor-suppressor genes, and many other cell systems. We will consider the role of the main systems of proteostasis in these processes, namely, macroautophagy and chaperones, which are parts of the integrated cell response to stress. As a result of the cell's response to stress, the tumor cell becomes even less differentiated, activating the genes and intracellular systems necessary for survival. Cells that have responded to stress in this way have a more aggressive phenotype that is significantly more resistant to therapy. Under the influence of stress, the cell evolutionarily simplifies, which gives it additional chances for survival. Autophagy, on one hand, contributes to a decrease in tumor-cell differentiation and its plasticity, and, on the other hand, it maintains a certain stability, being responsible for the integrity of the genome and freeing the cell from damaged organelles and defective proteins. Both autophagy and chaperones contribute to the acquisition of multidrug resistance by the tumor, which further complicates therapy. Understanding these processes, taking into account the multistage nature of carcinogenesis, makes it possible to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

The neurovascular system forms the interface between the tissue of the central nervous system (CNS) and circulating blood. It plays a critical role in regulating movement of ions, small molecules, and cellular regulators into and out of brain tissue and in sustaining brain health. The neurovascular unit (NVU), the cells that form the structural and functional link between cells of the brain and the vasculature, maintains the blood-brain interface (BBI), controls cerebral blood flow, and surveils for injury. The neurovascular system is dynamic; it undergoes tight regulation of biochemical and cellular interactions to balance and support brain function. Development of an intrinsic circadian clock enables the NVU to anticipate rhythmic changes in brain activity and body physiology that occur over the day-night cycle. The development of circadian neurovascular function involves multiple cell types. We address the functional aspects of the circadian clock in the components of the NVU and their effects in regulating neurovascular physiology, including BBI permeability, cerebral blood flow, and inflammation. Disrupting the circadian clock impairs a number of physiological processes associated with the NVU, many of which are correlated with an increased risk of dysfunction and disease. Consequently, understanding the cell biology and physiology of the NVU is critical to diminishing consequences of impaired neurovascular function, including cerebral bleeding and neurodegeneration. [ABSTRACT FROM AUTHOR]

Objectives: Skeletal malocclusions are common, and severe malocclusions are treated by invasive surgeries. Recently, jaw bone length has been shown to be developmentally controlled by osteoclasts. Our objective was to determine the effect of inhibiting osteoclast‐secreted proteolytic enzymes on lower jaw bone length of avian embryos by pharmacologically inhibiting matrix metalloproteinase‐9 (MMP9) or cathepsin K (CTSK). Methods: Quail (Coturnix coturnix japonica) embryos were given a single dose of an inhibitor of MMP9 (iMMP9), an inhibitor CTSK (iCTSK), or vehicle at a developmental stage when bone deposition is beginning to occur. At a developmental stage when the viscerocranium is largely calcified, the heads were scanned via micro‐computed tomography and reproducible landmarks were placed on 3D‐reconstructed skulls; the landmark coordinates were used to quantify facial bone dimensions. Results: Approximately half of the quail given either iMMP9 or iCTSK demonstrated an overt lower jaw phenotype, characterized by longer lower jaw bones and a greater lower to upper jaw ratio than control embryos. Additionally, iMMP9‐treated embryos exhibited a significant change in midface length and iCTSK‐treated embryos had significant change in nasal bone length. Conclusion: MMP9 and CTSK play a role in osteoclast‐mediated determination of lower jaw bone length. Pharmacological inhibition of MMP9 or CTSK may be a promising therapeutic alternative to surgery for treating skeletal jaw malocclusions, but more preclinical research is needed prior to clinical translation. [ABSTRACT FROM AUTHOR]