Search Results (44)

Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [³⁵S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED₅₀ value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article

Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of early-stage pancreatic ductal adenocarcinoma (PDAC) that performs well in high-risk controls. Methods: Enzyme-linked immunosorbent assays were used to measure 10 previously identified serum protein biomarker candidates in Stage I and II PDAC cases (n = 128), high-risk controls (n = 465), and normal-risk controls (n = 30). Various combinations of biomarker candidates (models) were trained using machine learning and tested for robustness in differentiating cases from controls on the full cohort and in clinically relevant sub-types including those with diabetes, those ≥65 years of age, and low producers of carbohydrate antigen 19-9 (CA 19-9). Results: At 98% specificity, the top performing model, which was comprised of tissue inhibitor of metalloproteinase 1 (TIMP1), intracellular adhesion molecule 1 (ICAM1), thrombospondin 1 (THBS1), cathepsin D (CTSD), and CA 19-9, achieved 85% sensitivity in the full cohort and sensitivities of 91% in diabetics, 90% in ≥65 years of age, and 60% in low CA 19-9 producers. This model demonstrated significantly higher sensitivity in detecting PDAC in the full cohort and all sub-populations compared to CA 19-9 alone (p < 0.001). Conclusions: Our findings demonstrate the feasibility of a blood-based assay for detecting early-stage PDAC in high-risk individuals and key sub-populations, representing an important step towards improving diagnostic success for early-stage disease. Full article

Objectives: The purpose of the present study was to investigate the relationship between acute and chronic loads, and the fatigue response within male elite professional football players. Design: 40-week longitudinal study across the 2021–2022 season in the English Championship. Methods: Twenty-three outfield football players had workload measured using global positioning system (Distance, High-Intensity Distance and Sprint Distance) and perceived exertion. Load-response was measured via a perceived wellbeing questionnaire, counter-movement jump (CMJ) and salivary immunoglobulin A. Results: General estimating equation models identified 18 significant interactions between workload and load-response markers. Thirteen significant interactions were found between acute and chronic workloads and CMJ variables, jump height, eccentric duration and flight contraction time. A poor CMJ was observed when acute sprint workload was >+1 standard deviation and chronic distance increased. However, when chronic perceived exertion increased, and acute sprint workload was >+1 standard deviation an advantageous response was detected on counter movement jump variables. The S-IgA response to acute and chronic workload was more variable; when chronic loads were >+1 standard deviation above mean values and acute workload increased, salivary immunoglobulin A was both suppressed and elevated depending on the interacting acute variable. Higher chronic workload was associated with better perceived wellbeing, even when acute workload was >+1 standard deviation above the mean. Conclusion: In general, low chronic workloads and acute spikes in workload were associated with poorer neuromuscular and immune function. Furthermore, CMJ performance and perceived wellbeing improved when chronic workloads were higher, despite the occurrence of acute spikes in workload. Full article

This article uses the English Gothic’s eighteenth-century dismantling of male lineage and Enlightenment certainty in Horace Walpole’s The Castle Otranto as a lens for understanding the twenty-first-century commercial popularity of director Mike Flanagan’s Gothic films, particularly Doctor Sleep. Building on Stephen King’s 2013 novel and Stanley Kubrick’s 1980 film The Shining, Flanagan’s Doctor Sleep establishes a new lineage of male writers who value how the Gothic traditions of irrational emotion and doubt can inspire new realms of knowledge to lessen psychological suffering caused by traumatic lineage. By “traumatic lineage” I mean the threat and violence some find necessary to maintain the patrilineal claim that it is “naturally” the only way to organize society. Like Walpole’s mythopoeic Gothic novel, Flanagan’s Gothic films demonstrate how patrilineal lineage damages other men, not just women; thus, Flanagan’s films offer psychological workbooks for practicing a type of reparative masculinity that involves exposure-exercises of cognitive behavior therapy (Doctor Sleep’s “boxing” intrusive, traumatic memories), male communities of care, and interdependent empathy. I support this argument by closely reading how Flanagan’s filmic tools of domestic metaphor, uncanny casting, and repurposed sets from Kubrick’s The Shining not only tell how to exorcise the inherited stills of the Overlook Hotel but also show viewers how to do so. We experience Dan Torrance’s reparative masculinity in real-time, communally sharing and recasting Dan’s horrific images of 40 years ago, but we now relate to them in psychologically helpful ways that enable community. In this way, I illustrate and encourage future study of how Gothic texts not only point to marginalized, repressed problems, but more importantly, how they help us relate differently to a traumatic past and innovate strategies for immediate relief from inherited suffering. Full article

In Melbourne, Australia, strict ‘lockdowns’ were implemented in 2020 to suppress COVID-19, significantly disrupting daily life. Young people (<18 years) with medical conditions have an elevated risk of mental health problems and may have been disproportionately affected by the distress associated with the COVID-19 restrictions. To investigate this, we conducted a single-site, longitudinal cohort study involving the parents of 135 children and adolescents with medical conditions. Using an adapted version of the CoRonavIruS Health Impact Survey (CRISIS), parents rated their child’s mental health, activities and healthcare experiences pre-COVID-19 (retrospectively), during lockdown and 6 months post-lockdown. General linear mixed models revealed that mental health symptoms, including anxiety, fatigue, distractibility, sadness, irritability, loneliness and worry, were higher during lockdown compared to pre-COVID-19. Notably, anxiety, sadness and loneliness remained elevated 6 months post-lockdown. Covariates such as older child age, increased parent stress and child screen time contributed to greater mental health difficulties. While most mental health symptoms resolved post-lockdown, the persistence of anxiety, sadness and loneliness highlights the need for ongoing clinical monitoring for young people with medical conditions during periods of community stress and restrictions. Full article

Background: The global COVID-19 pandemic has resulted in approximately 7 million deaths and a historic vaccination effort, with over 13.6 billion doses administered. Despite this, understanding of immune responses in vulnerable populations, such as transplant recipients (TR) and hemodialysis patients (HD), remains limited, especially outside the US and Europe. Methods: To address this gap, we analyzed blood samples and deidentified data from the Instituto Nacional de Coordinación de Trasplante (INCORT) in The Dominican Republic, measuring antibody levels to SARS-CoV-2 post-infection and vaccination with BNT162b2 (Pfizer-BioNTech) and Sinovac-CoronaVac (Sinovac) in TR, HD, and healthy controls (CO). Using a fluorescent multiplex assay (mPlex-CoV) and mixed-effects modeling, we assessed variations in anti-S, anti-RBD, and anti-N IgG antibodies. Results: The results indicate that the CO group experienced an early peak in anti-S and anti-RBD antibodies, followed by stabilization. In contrast, the TR and HD groups showed a slower, gradual increase in antibodies. Despite fluctuations in the HD group, both the TR and HD groups maintained high anti-S and anti-RBD IgG levels, indicating a back-boosting effect from vaccination. However, elevated anti-N IgG levels in the TR and HD groups suggest potential reinfections. Additionally, prior SARS-CoV-2 infection led to higher anti-S IgG levels, with BNT162b2 associated with higher anti-S IgG and CoronaVac associated with higher anti-N IgG levels. Conclusion: These findings highlight the variability in antibody responses and the need for targeted public health strategies to diverse immunological profiles. Full article

Background: The COVID-19 pandemic has exacerbated existing healthcare disparities among American Indian/Alaska Native (AI/AN) populations rooted in historical traumas and systemic marginalization. Methods: This study conducted at a single Indian Health Service (IHS) clinic in central Michigan evaluates two educational interventions for enhancing COVID-19 knowledge and attitudes in a sample AI/AN population. Utilizing a pre/post-intervention prospective study design, participants received either a video or infographic educational intervention, followed by a survey assessing their COVID-19 knowledge and attitudes. Results: The results indicate significant improvements in knowledge and attitudes post-intervention, with both modalities proving effective. However, specific factors such as gender, political affiliation, and place of residence influenced COVID-19 attitudes and knowledge, emphasizing the importance of tailored interventions. Conclusions: Despite limitations, this study highlights the critical role of educational interventions in addressing vaccine hesitancy and promoting health equity within AI/AN communities. Moving forward, comprehensive strategies involving increased Indian Health Service funding, culturally relevant interventions, and policy advocacy are crucial in mitigating healthcare disparities and promoting health equity within AI/AN communities. Full article

Cilia are microtubule-based cellular projections that act as motile, sensory, and secretory organelles. These structures receive information from the environment and transmit downstream signals to the cell body. Cilia also release vesicular ectosomes that bud from the ciliary membrane and carry an array of bioactive enzymes and peptide products. Peptidergic signals represent an ancient mode of intercellular communication, and in metazoans are involved in the maintenance of cellular homeostasis and various other physiological processes and responses. Numerous peptide receptors, subtilisin-like proteases, the peptide-amidating enzyme, and bioactive amidated peptide products have been localized to these organelles. In this review, we detail how cilia serve as specialized signaling organelles and act as a platform for the regulated processing and secretion of peptidergic signals. We especially focus on the processing and trafficking pathways by which a peptide precursor from the green alga Chlamydomonas reinhardtii is converted into an amidated bioactive product—a chemotactic modulator—and released from cilia in ectosomes. Biochemical dissection of this complex ciliary secretory pathway provides a paradigm for understanding cilia-based peptidergic signaling in mammals and other eukaryotes. Full article

Psoriasis is a chronic immune-mediated inflammatory disease affecting the skin and other systems. Gastrointestinal disease was found to be correlated with psoriasis in previous studies and it can significantly affect the quality of life of psoriasis patients. Despite the importance of the gut microbiome in gut and skin health having already been demonstrated in many research studies, the potential effect of probiotics on GI comorbidities in psoriasis patients is unclear. To investigate the effects of probiotics on functional GI comorbidities including irritable bowel syndrome, functional constipation, and functional diarrhea in psoriasis patients, we conducted a targeted 16S rRNA sequencing and comprehensive bioinformatic analysis among southern Chinese patients to compare the gut microbiome profiles of 45 psoriasis patients over an 8-week course of novel oral probiotics. All the participants were stratified into responders and non-responders according to their improvement in GI comorbidities, which were based on their Bristol Stool Form Scale (BSFS) scores after intervention. The Dermatological Life Quality Index (DLQI) score revealed a significant improvement in quality of life within the responder group (DLQI: mean 10.4 at week 0 vs. mean 15.9 at week 8, p = 0.0366). The proportion of psoriasis patients without GI comorbidity manifestation at week 8 was significantly higher than that at week 0 (week 0: Normal 53.33%, Constipation/Diarrhea 46.67%; week 8: Normal 75.56%, Constipation/Diarrhea 24.44%, p = 0.0467). In addition, a significant difference in the gut microbiome composition between the responders and non-responders was observed according to alpha and beta diversities. Differential abundance analysis revealed that the psoriasis patients exhibited (1) an elevated relative abundance of Lactobacillus acidophilus, Parabacteroides distasonis, and Ruminococcus bromii and (2) a reduced relative abundance of Oscillibacter, Bacteroides vulgatus, Escherichia sp., and Biophila wadsworthia after the 8-week intervention. The responders also exhibited a higher relative abundance of Fusicatenibacter saccharivorans when compared to the non-responders. In summary, our study discovers the potential clinical improvement effects of the novel probiotic formula in improving GI comorbidities and quality of life in psoriasis patients. We also revealed the different gut microbiome composition as well as the gut microbial signatures in the patients who responded to probiotics. These findings could provide insight into the use of probiotics in the management of psoriasis symptoms. Full article

Mental health issues have emerged as a significant concern in public health, given their association with physical and psychological comorbidities and the resultant socioeconomic burdens. Recent studies have highlighted the interplay between gut microbes and brain functions through the gut–brain axis. To investigate this further, we conducted a targeted 16S rRNA sequencing and comprehensive bioinformatic analysis among Southern Chinese individuals to explore the role of the gut microbiome in depression, anxiety, and sleep disturbance. We analyzed the differences in the gut microbiome profile of 68 participants with sleep disturbance and mood symptoms before and after an 8-week course of a novel oral E3 multi-strain probiotics formula. The results revealed a significant improvement in subjective sleep quality (PSQI: mean 8.79 at baseline vs. 7.10 at week 8, p < 0.001), depressive symptoms (PHQ9: mean 6.17 at baseline vs. 4.76 at week 8, p < 0.001), and anxious symptoms (GAD7: mean 4.90 at baseline vs. 3.76 at week 8, p < 0.001). Additionally, there were notable differences in beta diversity (weighted UniFrac; p = 0.045) and increased Firmicutes/Bacteroidetes (F/B) ratio (p = 4 × 10⁻⁴) were observed in the gut microbiome analysis. Furthermore, the relative abundance of Bifidobacterium bifidum (p < 0.001), Lactobacillus acidophilus (p < 0.001), Lactobacillus helveticus (p < 0.001) and Lactobacillus plantarum (p < 0.001) were significantly increased after the 8-week probiotic supplementation. Our study suggests that the gut microbial landscape varies between responders and non-responders at multiple levels, including genera, species, functional, and network interaction. Notably, the use of probiotics in populations with depressive or anxious symptoms and poor sleeping quality remodeled the gut microbiome and demonstrated improved mood and sleep quality. Full article

In this work, we study the neutrino mixing sum rules arising from discrete symmetries and the class of Littlest Seesaw (LS) neutrino models. These symmetry-based approaches all offer predictions for the cosine of the leptonic CP phase $cos\delta$ in terms of the mixing angles, ${\theta }_{13}$, ${\theta }_{12}$, ${\theta }_{23}$, while the LS models also predict the sine of the leptonic CP phase $sin\delta$, as well as making other predictions. In particular, we study the solar neutrino mixing sum rules, arising from charged lepton corrections to tri-bimaximal (TB), bimaximal (BM), golden ratio (GR) and hexagonal (HEX) neutrino mixing, and the atmospheric neutrino mixing sum rules, arising from preserving one of the columns of these types of mixing—for example, the first or second column of the TB mixing matrix (TM1 or TM2)—and we confront them with an up-to-date global fit of the neutrino oscillation data. We show that some mixing sum rules, such as an atmospheric neutrino mixing sum rule arising from a version of neutrino golden ratio mixing (GRa1), are already excluded at 3$\sigma$, and we determine the remaining models allowed by the data. We also consider the more predictive LS models (which obey the TM1 sum rules and offer further predictions) based on constrained sequential dominance CSD(n) with $n\approx 3$. We compare for the first time the three cases $n=2.5$, $n=3$ and $n=1+\sqrt{6}\approx 3.45$, which are favored by theoretical models, using a new type of analysis to accurately predict the observables ${\theta }_{12}$, ${\theta }_{23}$ and $\delta$. We study all the above approaches, solar and atmospheric mixing sum rules and LS models, together so that they may be compared and to give an up-to-date analysis of the predictions of all of these possibilities, when confronted with the most recent global fits. Full article

Axonemal dyneins are highly complex microtubule motors that power ciliary motility. These multi-subunit enzymes are assembled at dedicated sites within the cytoplasm. At least nineteen cytosolic factors are specifically needed to generate dynein holoenzymes and/or for their trafficking to the growing cilium. Many proteins are subject to N-terminal processing and acetylation, which can generate degrons subject to the ^AcN-end rule, alter N-terminal electrostatics, generate new binding interfaces, and affect subunit stoichiometry through targeted degradation. Here, we have used mass spectrometry of cilia samples and electrophoretically purified dynein heavy chains from Chlamydomonas to define their N-terminal processing; we also detail the N-terminal acetylase complexes present in this organism. We identify four classes of dynein heavy chain based on their processing pathways by two distinct acetylases, one of which is dependent on methionine aminopeptidase activity. In addition, we find that one component of both the outer dynein arm intermediate/light chain subcomplex and the docking complex is processed to yield an unmodified Pro residue, which may provide a setpoint to direct the cytosolic stoichiometry of other dynein complex subunits that contain N-terminal degrons. Thus, we identify and describe an additional level of processing and complexity in the pathways leading to axonemal dynein formation in cytoplasm. Full article

Climate-smart and sustainable crops are needed for the future. Engineering crops for tolerance of both abiotic and biotic stress is one approach. The accumulation of trehalose, controlled through trehalose-6-phosphate synthase (TPS) or OtsA and trehalose-6-phosphate phosphatase (TPP) or OtsB genes in microbes, is known to provide protection for many microbial and fungal species against abiotic stress. The effect of trehalose accumulation in plant species is less understood. Here, we studied the heterologous expression of Escherichia coli OtsB in potato (Solanum tuberosum var. ‘Desiree’) with regards to stress tolerance. The performance of transgenic lines was assessed in both growth chambers and greenhouse mesocosms. Overexpressing potato OtsB lines significantly increased resilience to heat, photoperiod, herbivory, and competition when compared with wildtype plants. Most strikingly, when subjected to high temperatures, transgenic lines exhibited a significantly lower reduction in tuber yield ranging from 40% to 77%, while wildtype plants experienced a 95% decrease in tuber yield. When exposed to competitors in a selected StSP3D::OtsB line, tuber yield was 1.6 times higher than wildtype. Furthermore, transgenic lines performed significantly better under low-nutrient regimes: under competition, yield increased by 1.5-fold. Together, these results demonstrate that increased trehalose has the potential to create more resistant and stable crop plants. Full article

Representations of play abound in Stephen King’s 1983 novel Pet Sematary and its 1989 and 2019 subsequent film adaptations. However, play in Pet Sematary is not representative of the innocent actions designed to create functioning adults who meaningfully contribute to society. In the 1989 film, for example, “play” for a newly resurrected Gage is a version of hide-and-go-seek resulting in the death of neighbour Jud. Meanwhile, the 2019 adaptation sees a newly resurrected Ellie “playing” in her dirt-stained white funereal dress. These dirt stains become markers of lost innocence and transform her dance into an uncanny performance. Since Gage and Ellie are both somewhat monstrous child figures, their play, like their bodies, is transformed into something unsettling and ventures into the realm of the uncanny. However, play itself is also performed differently between the adaptations because the central child figure also changes. In the 1989 film, it is a male toddler, and in the 2019 film, it is a pre-pubescent female. Both adaptations focus on ideal, socially acceptable forms of play according to the time in which the film was made as well as how children diverge from these behaviours. Play is often rendered dangerous when not performed properly according to the paradigms of age and gender, resulting in what I call ‘uncanny play’. When children engage with ‘uncanny play’, the adults in the narrative are permitted to execute the children for the sake of preserving the memory of them as innocent beings, or what I call the ‘Save the Child’ discourse. Linda Hutcheon argues that ‘when we adapt […] we actualize or concretize ideas’, so that the socially acceptable play put forth in King’s novel becomes more realised and thus more at risk to transgression in each successive filmic adaptation. Full article

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a significant association with various type-2 inflammation-related comorbidities. Ongoing research suggests the crucial involvement of gut microbiome, especially in childhood onset AD, and hence, probiotics have emerged as a potential non-steroid-based therapeutics option to complement existing AD management plans. In order to delineate the impact of probiotics in the gut microbiome of pediatric AD patients from southern China, targeted 16S rRNA sequencing and thorough bioinformatic analysis were performed to analyze the gut microbiome profiles of 24 AD children after taking an orally administered novel synbiotics formula with triple prebiotics for 8 weeks. A notable improvement in Eczema Area and Severity Index (EASI) (p = 0.008) was observed after taking an 8-week course of probiotics, with no adverse effects observed. The relative abundances of key microbial drivers including Bacteroides fragilis and Lactobacillus acidophilus were significantly increased at week 8. We also found that the positive responsiveness towards an 8-week course of probiotics was associated with improvements in the gut microbiome profile with a higher relative abundance of probiotic species. Over-represented functional abundance pathways related to vitamin B synthesis and peptidoglycan recycling may imply the underlying mechanism. In summary, our study suggests how the gut microbial landscape shifts upon probiotic supplementation in AD children, and provides preliminary evidence to support targeted probiotic supplementation for the management of childhood AD. Full article