Search

Background: Chronic urticaria (CU), in both inducible and spontaneous forms, is associated with a substantial burden in the Asia-Pacific region (APAC). Patient-centred care recognises patients desire to be involved in decisions regarding their health. Although patient-centred approaches have previously not been studied in the context of CU management, they have demonstrated benefits in the management of other chronic conditions. Methods: Information and opinions regarding the barriers and solutions to the implementation of patient-centred approaches to the management of CU were gathered from a group of 13 expert dermatologists and allergist/immunologists from APAC through surveys and a face-to-face meeting. Results: Barriers identified there included a lack of awareness of CU amongst patients, delays in consulting healthcare providers, financial constraints, and low adherence. Particular issues raised included a lack of suitable online information for patients (83% of experts), and patients accessing oral corticosteroids without a prescription. Compliance issues were also identified as key reasons for inadequate responses to treatments (67% of experts). Solutions proposed by the authors were improving patients' knowledge about their condition (92% strongly agree, 8% agree), physicians’ consideration of patient characteristics when choosing treatments (92% strongly agree, 8% agree), implementing shared decision-making (85% strongly agree, 15% agree), and using patient-reported outcome measures (70% strongly agree, 23% agree). Conclusion: Expert opinion within APAC supports the use of patient-centred approaches to improve the management of CU. We provide several recommendations focusing on patient education and involvement in disease management as well as disease monitoring methods that can be implemented by physicians in APAC.

IntroductionThe nematode, Caenorhabditis elegans (C. elegans), is an advantageous model for studying developmental toxicology due to its well-defined developmental stages and homology to humans. It has been established that across species, dopaminergic neurons are highly vulnerable to neurotoxicant exposure, resulting in developmental neuronal dysfunction and age-induced degeneration. C. elegans, with genetic perturbations in dopamine system proteins, can provide insight into the mechanisms of dopaminergic neurotoxicants. In this study, we present a comprehensive analysis on the effect of gene mutations in dopamine-related proteins on body size, development, and behavior in C. elegans.MethodsWe studied C. elegans that lack the ability to sequester dopamine (OK411) and that overproduce dopamine (UA57) and a novel strain (MBIA) generated by the genetic crossing of OK411 and UA57, which both lack the ability to sequester dopamine into vesicles and, additionally, endogenously overproduce dopamine. The MBIA strain was generated to address the hypothesis that an endogenous increase in the production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. These strains were analyzed for body size, developmental stage, reproduction, egg laying, motor behaviors, and neuronal health utilizing multiple methods.ResultsOur results further implicate proper dopamine synthesis and sequestration in the regulation of C. elegans body size, development through larval stages into gravid adulthood, and motor functioning. Furthermore, our analyses demonstrate that body size in terms of length is distinct from the developmental stage as fully developed gravid adult C. elegans with disruptions in the dopamine system have decreased body lengths. Thus, body size should not be used as a proxy for the developmental stage when designing experiments.DiscussionOur results provide additional evidence that the dopamine system impacts the development, growth, and reproduction in C. elegans. Furthermore, our data suggest that endogenously increasing the production of dopamine mitigates deficits in C. elegans lacking the ability to package dopamine into synaptic vesicles. The novel strain, MBIA, and novel analyses of development and reproduction presented here can be utilized in developmental neurotoxicity experiments.

Abstract Protease activated receptors (PARs) are among the first receptors shown to transactivate other receptors: noticeably, these interactions are not limited to members of the same family, but involve receptors as diverse as receptor kinases, prostanoid receptors, purinergic receptors and ionic channels among others. In this review, we will focus on the evidence for PAR interactions with members of their own family, as well as with other types of receptors. We will discuss recent evidence as well as what we consider as emerging areas to explore; from the signalling pathways triggered, to the physiological and pathological relevance of these interactions, since this additional level of molecular cross-talk between receptors and signaling pathways is only beginning to be explored and represents a novel mechanism providing diversity to receptor function and play important roles in physiology and disease.

Generative Artificial Intelligence (AI) approaches open up new avenues of digital creation, and are simultaneously accompanied by societal and ethical implications such as the creation of Deepfakes and spread of misinformation, renewing our understanding of technical AI systems as socio-technical systems. Applications of, and media generated by generative AI techniques are abundantly present on social media platforms frequented by children, who are not yet aware of the existence of AI-manipulated media. Previous work has highlighted the importance of digital media literacy and AI literacy for children. In this work, we introduce middle school students to generative AI techniques as a tool for creation, while also focusing on critical discussion about their societal and ethical implications, and encouraging pro-activeness in being responsible consumers, creators and stakeholders of technology. We present learning activities that introduce 38 middle-school students to generative modeling, how it is used to generate Deepfakes, cues that help to recognize Deepfakes, and the spread and effects of misinformation. Students demonstrated an understanding that generative media may be believable, but not necessarily true, and can contribute to the spread of misinformation. They were also able to identify why misinformation may be harmful or lasting, drawing specific examples to social settings that indicate human-centered implications. Finally, students expressed opinions about policies surrounding the presence of Deepfakes on social media. This approach can be adopted to introduce students to other technical systems that constitute both productive applications and potential negative implications of technology. CCS concepts: ⋅Applied computing → Interactive learning environments; ⋅Human-centered computing → Social media; Social networks; ⋅Social and professional topics → Computing literacy; K-12 education; Additional key words and phrases: Misinformation, Deepfakes, digital literacy, media literacy, social media.

Abstract Introduction: The COVID-19 pandemic has impacted millions of lives globally. To learn more about this disease and find potential diagnostic, therapeutic, and preventative products, the healthcare community has initiated a staggering number of clinical trials. Methods: ClinicalTrials.gov was reviewed to determine if trial sponsor type had a relationship to time to COVID-19 response, which was defined as the date from disease discovery in Wuhan, China to ClinicalTrials.gov study “First Posted” date. Results: A total of 673 United States (US) sponsored, interventional study listings were retrieved, of which 293 (43.5%) were Industry-sponsored, 349 (51.9%) were Academic sponsored, and 31 (4.6%) were Other sponsor types. Of the Academic studies, 181 (51.9%) were Clinical and Translational Science Award (CTSA) hubs. The average response time for all sponsor types was 189 days, with Academic sponsors having the shortest average response time of 172.6 days (P < 0.001). CTSA hubs had a significantly (P < 0.001) shorter average response time (168.1 days) compared to all other sponsor types (197.4 days). However, while shorter in duration by 9.4 days, response time was not significantly different from non-CTSA sponsors (177.5 days; P = 0.238). Additionally, ANOVA indicated significant relationships (P < 0.001) between funding type, study phase, number of sites, and enrollment size on response time. Conclusions: Studies posted with the shortest response time were Academic-sponsored trials and included smaller sized investigations of repurposed approved or investigational drugs for the treatment of COVID-19 symptoms. A small second wave of study postings occurred approximately 4 months later, and included small, unique therapies targeting prevention or treatment of COVID-19.

Background: Coronavirus disease 2019 (COVID-19) has spread throughout the world since late 2019. Symptoms appear after a two-week incubation period and commonly include fever, cough, myalgia or fatigue, and shortness of breath. Case Report: A 32-year-old male with a history of opiate abuse presented to the emergency department with altered mental status. The patient was lethargic and hypoxic with improvement from naloxone. Official chest radiograph was read as normal; however, the treating clinicians noted bilateral interstitial opacities, raising concern for underlying infectious etiology. Opiates and cocaine were positive on drug screen, and an arterial blood gas on room air showed hypoxemia with respiratory acidosis. The patient was intubated during the treatment course due to persistent hypoxemia and for airway protection after resuscitation. The COVID-19 test was positive on admission, and later computed tomography showed ground-glass opacities. The patient was extubated and discharged after one week on the ventilator. Conclusion: When screening patients at and during evaluation, physicans should consider a broad differential as patients with atypical presentations may be overlooked as candidates for COVID-19 testing. As screening and evaluation protocols evolve, we emphasize maintaining a high index of suspicion for COVID-19 in patients with atypical symptoms or presenting with other chief complaints in order to avoid spreading the disease.

In this work, we adopt the integration of the L-system fractal tree generation, 3D printed wind tunnel modeling, and computational fluid dynamics (CFD) simulation approach to model the wind effect on a single tree. We compare the agreement between CFD simulations and wind tunnel measurements of rigid branched structures resembling trees. First, fractal tree mesh models based on species growth and branching patterns are developed to represent tree species for wind–tree modeling. Subsequently, a scaled-down fractal tree is generated with 3D-printing and subjected to tunnel testing with load cell and particle image velocimetry measurement data under the wind speed of 10 m/s and 15 m/s. Finally, CFD based on Reynolds-Average Navier–Stokes (RANS) simulation with a full closure model and Large Eddy Simulation (LES) using appropriate momentum sink and turbulence source terms for the volumetric tree is carried out. We use both the volume-average porous media and the volume-splitting discretized zones (split number 10 × 10 × 10) to reproduce the momentum sink effect in the numerical simulation. Three tree species, namely, Peltophorum pterocarpum (yellow flame), Khaya senegalensis (African mahogany), and Hopea odorata (ironwood), are tested, and a reasonable agreement of drag force prediction and velocity profiles is obtained when comparing the CFD simulation results with wind tunnel data. The RANS modeled drag force results exhibit 20% of over-prediction, while the normalized velocity profiles display a good match of velocity decay at the tree leeward sides. On the other hand, LES produces much better results with only 3% discrepancy with the experimental results. A comparison of experimental results among the tree species is also carried out. Due to the actual random wind direction, tree slenderness representation, and structural flexibility issues, the current methodology still has the limitation for validation with urban on-site measurement. Nonetheless, this integrated approach is the first step in establishing modeling tool applicability to examine the effect of the forest structure and composition on wind loads.

Abstract Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK)-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.

ABSTRACT IMPACT: Increase understanding of the types of sponsors responding to the COVID-19 pandemic. OBJECTIVES/GOALS: The COVID-19 pandemic has impacted millions of lives globally. To learn more about this disease and find potential diagnostic, treatment, and preventative products, the healthcare community has initiated a staggering number of clinical trials. Clinicaltrials.gov was reviewed to determine the types of sponsors who are conducting COVID-19 studies. METHODS/STUDY POPULATION: Clinicaltrials.gov was searched using terms ‘COVID-19’ and ‘SARS-Cov-2’. Search results were further defined to include only ‘Interventional’ studies. Of these, only studies with sites located in the United States were selected and for which the ‘Condition’ included at least one of the following terms: ‘COVID’, ‘COVID-19’, ‘Coronavirus’, ‘SARS-Cov-2’, ‘SARS’, or ‘2019-nCoV'. Study sponsors were then categorized as: (1) commercial, (2) academic, or (3) other, based on ‘Sponsor’ information within each study listing. A Google search was conducted for any sponsor that was not easily categorized to obtain additional information to support the proper assessment of sponsor type. The types of sponsors were analyzed over time using the ‘First Posted’ date of each study listing. RESULTS/ANTICIPATED RESULTS: A total of 3662 studies were retrieved, of which 2075 were ‘Interventional’ studies. The studies were further reduced to 681 studies by including only United States sites and the desired ‘Condition’. The percentage of studies from this refined dataset, by sponsor type, were found to be 63% academic, 34% commercial, and 3% other. The relationship between time and sponsor type demonstrated that academic sponsors had the highest percentage of study postings in the first month (March) of the COVID-19 pandemic compared to commercial and other sponsors. Following this first month, academic study postings gradually declined, while commercial sponsors had an increase in postings per month into July, followed by a gradual decline. Few other sponsor type postings were made and occurred primarily in August. DISCUSSION/SIGNIFICANCE OF FINDINGS: The number and timing of listings may be a reflection of study intention and regulatory pathway requirements. Additional variables, such as inconsistent terminology, collaborators, funding, and study start date may influence results. Further analysis may reveal how modification of listing information may result in expedited pandemic response.

The push for greater urban sustainability has increased the urgency of the search for noise mitigation solutions that allow for natural ventilation into buildings. Although a viable active noise control (ANC) solution with up to 10 dB of global attenuation between 100 Hz and 1000 Hz was previously developed for an open window, it had limited low-frequency performance below 300 Hz, owing to the small loudspeakers used. To improve the low-frequency attenuation, four passive radiator-based speakers were affixed around the opening of a top-hung ventilation window. The active control performance between 100 Hz and 700 Hz on a single top-hung window in a full-sized mock-up apartment room was examined. Active attenuation came close to the performance of the passive insulation provided by fully closing the window for expressway traffic and motorbike passing noise types. For a jet aircraft flyby, the performance of active attenuation with the window fully opened was similar to that of passive insulation with fully closed windows. In the case of low-frequency compressor noise, active attenuation’s performance was significantly better than the passive insulation. Overall, between 8 dB and 12 dB of active attenuation was achieved directly in front of the window opening, and up to 10.5 dB of attenuation was achieved across the entire room.

Lon, also known as Protease La, is one of the simplest ATP-dependent proteases. It is a homooligomeric enzyme comprised of an ATPase domain and a proteolytic domain in each enzyme subunit. Despite sharing about 40% sequence identity, human and Escherichia coli Lon proteases utilize a highly conserved ATPase domain found in the AAA+ family to catalyze ATP hydrolysis, which is needed to activate protein degradation. In this study, we utilized mechanistic enzymology techniques to show that despite comparable kcat and Km parameters found in the ATPase activity, human and E. coli Lon exhibit significantly different susceptibility to ADP inhibition. Due to the low affinity of human Lon for ADP, the conformational changes in human Lon generated from the ATPase cycle are also different. The relatively low affinity of human Lon for ADP cannot be accounted for by reversibility in ATP hydrolysis, as a positional isotope exchange experiment demonstrated both E. coli Lon and human Lon catalyzed ATP hydrolysis irreversibly. A limited tryptic digestion study however indicated that human and E. coli Lon bind to ADP differently. Taken together, the findings reported in this research article suggest that human Lon is not regulated by a substrate-promoted ADP/ATP exchange mechanism as found in the bacterial enzyme homolog. The drastic difference in structural changes associated with ADP interaction with the two protease homologs offer potential for selective inhibitor design and development through targeting the ATPase sites. In addition to revealing unique mechanistic differences that distinguish human vs. bacterial Lon, this article underscores the benefit of mechanistic enzymology in deciphering the physiological mechanism of action of Lon proteases and perhaps other closely related ATP-dependent proteases in the future.

The serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1–4. The activation of Protease-Activated Receptor 1(PAR1), the prototype of this receptor family, leads to an increase in intracellular Ca+2 concentration ([Ca+2]i) mediated by Gq11α coupling and phospholipase C (PLC) activation. We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness. Within this context, the elucidation of the mechanisms involved in PAR1 inactivation is of utmost importance. Due to the irreversible nature of PAR1 activation, its inactivation must be efficiently regulated in order to terminate signaling. Using ARPE-19 human RPE cell line, we characterized thrombin-induced [Ca+2]i increase and demonstrated the calcium-dependent activation of μ-calpain mediated by PAR1. Calpains are a family of calcium-activated cysteine proteases involved in multiple cellular processes including the internalization of membrane proteins through clathrin-coated vesicles. We demonstrated that PAR1-induced calpain activation results in the degradation of α-spectrin by calpain, essential for receptor endocytosis, and the consequent decrease in PAR1 membrane expression. Collectively, the present results identify a novel μ-calpain-dependent mechanism for PAR1 inactivation following exposure to thrombin.

La función del glutamato en la retina, como neurotransmisor, factor trófico o neurotoxina, se relaciona directamente con la diversidad y la composición heteromérica de sus receptores. Los receptores de glutamato de tipo NMDA (NMDARs) son tetrámeros integrados por dos subunidades NR1, que forman un canal iónico permeable al calcio, y subunidades NR2 y NR3, que modulan su actividad. Los NMDARs de la retina incluyen subunidades NR2, así como variantes postranscripcionales de NR1 específicas, tanto en el tejido diferenciado como el embrionario, cuya estructura determina diferencias funcionales significativas entre el cerebro y la retina. Consecuentemente, fármacos que protegen a las neuronas de la excitotoxicidad del glutamato en el cerebro, no tienen efecto en la retina. La repercusión clínica de estos resultados es evidente, ya que permitirá, en el futuro, el diseño de compuestos protectores de la muerte neuronal en la retina en padecimientos relacionados con la elevación de la concentración extracelular del glutamato, como el glaucoma, la oclusión vascular, la neuropatía óptica y la isquemia, entre otros.

Introduction: While abnormal responses to threat, including overgeneralization to conditioned fear, have been postulated to play a critical role in pathological anxiety, the relevance of previous findings to social anxiety disorder (SAD) is unclear. We investigated conditioned and generalized fear responses in patients with SAD using socially relevant stimuli. Methods: A total of 26 patients with SAD and 25 healthy controls participated in a fear conditioning and generalization paradigm consisting of two neutral faces as conditioned stimuli (CS+ or CS-) and an angry face with contemptuous comments as unconditioned stimuli. Eight morphed faces of two conditioned stimuli in each continuum were given to test generalization. Behavioral data and physiological responses were acquired. Results: Successful conditioning was observed in the risk ratings for both groups, while only a marginal indication of conditioning was noted in physiological measures. During the generalization phase, patients rated the risk higher than CS-when the stimuli close to CS- contained a portion of CS+ features. Larger skin conductance responses to this stimulus were linked to higher fear of negative evaluation. In addition, patients spent a longer time evaluating safe and ambiguous stimuli than healthy controls and exhibited consistently high levels of subjective arousal. Discussion: Taken together, our findings suggest that SAD patients may exhibit a tendency towards overgeneralization of fear responses and show distinct patterns in processing generalized threat stimuli compared to healthy controls. Even though overgeneralization was not evident in physiological measures, it is necessary to consider this behavioral characteristic in the clinical management of patients with SAD. [ABSTRACT FROM AUTHOR]

Background: Tuvalu is a Pacific Island country within the small island developing states that has observed a significant and alarming increase in obesity rates over the past 40 years, affecting ~60 %-70 % of the current population. Objectives: This study aimed to investigate the association between food patterns and the proportion of obesity in a Pacific Island country. Methods: The 2022 COMmunity-based Behavior and Attitude survey in Tuvalu (COMBAT) included 985 adults with complete data on sociodemographic information and the frequency of consumption of 25 common foods. A latent class analysis determined 4 food patterns. Bayesian multilevel logistic and linear regression models estimated the association between food patterns and the proportion of obesity [body mass index (BMI) -30 kg/m2], severe obesity (BMI -40 kg/m2), and weight (kg), adjusting for potential confounders and accounting for clustering by region. Results: The latent class analysis revealed 4 food patterns with an entropy of 0.94 and an average posterior probability of class assignment for each individual of 0.97, described as follows: 1) local: locally produced foods with moderate food diversity (proportion of individuals = 28 %); 2) diverse-local: local with greater food diversity (17 %); 3) restricted-imported: more imported with restricted diversity (29 %); and 4) imported: heavily imported with high diversity (26 %). Compared to those following the diverse-local pattern, the odds of having obesity were greater for those classified with the imported pattern [odds ratio (OR): 2.52; 95 % credible interval (CrI): 1.59, 3.99], restricted-imported pattern (OR: 1.89; 95 % CrI: 1.59, 3.99), and local pattern (OR: 1.54; 95 % CrI: 0.94, 2.50). Similar trends were observed for severe obesity while body weight was positively associated with both restricted-imported and imported food patterns. Conclusions: The high consumption of imported foods, together with the low consumption of plant-based foods and protein-rich foods, could be a relevant modifiable lifestyle factor explaining the high levels of obesity and severe obesity in Tuvalu, a Pacific Island country. [ABSTRACT FROM AUTHOR]