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Covering: 2017.01 to 2023.11Natural products biosynthesized by myxobacteria are appealing due to their sophisticated chemical skeletons, remarkable biological activities, and intriguing biosynthetic enzymology. This review aims to systematically summarize the advances in the discovery methods, new structures, and bioactivities of myxobacterial NPs reported in the period of 2017-2023. In addition, the peculiar biosynthetic pathways of several structural families are also highlighted.
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Produtos Biológicos , Myxococcales , Produtos Biológicos/metabolismo , Produtos Biológicos/química , Myxococcales/metabolismo , Myxococcales/química , Estrutura Molecular , Vias Biossintéticas , Descoberta de DrogasRESUMO
Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.
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Imunofenotipagem , Transtornos Linfoproliferativos , Humanos , Transtornos Linfoproliferativos/imunologia , Masculino , Feminino , Criança , Pré-Escolar , Adolescente , Lactente , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/imunologia , Linfócitos/imunologiaRESUMO
BACKGROUND AND AIMS: Niche differentiation is a crucial issue in speciation. Although it has a well-known role in adaptive processes of hybrid angiosperms, it is less understood in hybrid ferns. Here, we investigate whether an intermediate ecological niche of a fern hybrid is a novel adaptation that provides insights into fern hybrid speciation. METHODS: Pteris fauriei (Pteridaceae) is a natural hybrid fern, occurring in environments between its parent species. The maternal Pteris minor is found in sunny areas, but the habitat of the paternal Pteris latipinna is shady. We combined data from morphology, leaf anatomy and photosynthetic traits to explore adaptation and differentiation, along with measuring the environmental features of their niches. We also performed experiments in a common garden to understand ecological plasticity. KEY RESULTS: The hybrid P. fauriei was intermediate between the parent species in stomatal density, leaf anatomical features and photosynthetic characteristics in both natural habitats and a common garden. Interestingly, the maternal P. minor showed significant environmental plasticity and was more similar to the hybrid P. fauriei in the common garden, suggesting that the maternal species experiences stress in its natural habitats but thrives in environments similar to those of the hybrid. CONCLUSIONS: Based on the similar niche preferences of the hybrid and parents, we propose hybrid superiority. Our results indicate that the hybrid P. fauriei exhibits greater fitness and can compete with and occupy the initial niches of the maternal P. minor. Consequently, we suggest that the maternal P. minor has experienced a niche shift, elucidating the pattern of niche differentiation in this hybrid group. These findings offer a potential explanation for the frequent occurrence of hybridization in ferns and provide new insights into fern hybrid speciation, enhancing our understanding of fern diversity.
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Ecossistema , Hibridização Genética , Fenótipo , Pteris , Pteris/fisiologia , Pteris/anatomia & histologia , Pteris/genética , Folhas de Planta/anatomia & histologia , Folhas de Planta/fisiologia , Folhas de Planta/crescimento & desenvolvimento , Especiação Genética , Fotossíntese/fisiologia , Gleiquênias/fisiologia , Gleiquênias/anatomia & histologia , Adaptação FisiológicaRESUMO
The phenomenon of polymorphism is ubiquitous in nature, the controlled manipulation of which not only increases our ontological understanding of nature but also facilitates the conceptualization and realization of novel functional materials. However, achieving targeted polymorphism in supramolecular assemblies (SAs) remains a formidable challenge, largely because of the constraints inherent in controlling the specific binding motifs of noncovalent interactions. Herein, we propose self-adaptive aromatic cation-π binding motifs to construct polymorphic SAs in both the solid and solution states. Using distinct discrete cation-π-cation and long-range cation-π binding motifs enables control of the self-assembly directionality of a C2h-symmetric bifunctional monomer, resulting in the successful formation of both two-dimensional and three-dimensional crystalline SAs (2D-CSA and 3D-CSA). The differences in the molecular packing of 3D-CSA compared with that of 2D-CSA significantly improve the charge separation and carrier mobility, leading to enhanced photocatalytic activity for the aerobic oxidation of thioanisole to methyl phenyl sulfoxide (yield of 99 % vs 57 %). 2D-CSA, which has a vertical extended structure with favorable stronger interaction with toluene though face-to-face cation-π interactions than methylcyclohexane, shows higher toluene/methylcyclohexane separation efficiency than 3D-CSA (96.9 % for 2D-CSA vs 56.3 % for 3D-CSA).
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The first enantioselective vinylogous Mannich reaction is developed using 2-methoxyfuran under chiral spirophosphoric acid catalysis. The strategy involves 4-isoxazoline derivatives as cyclic ketimine surrogates and provides γ-butenolide scaffolds (up to 97% ee and >20:1 dr). The mechanistic investigations suggest that an in situ generated water molecule plays a crucial role in delivering γ-butenolide, while the use of molecular sieves delivers aza-Friedel-Crafts products. The synthetic utility of γ-butenolide is shown toward obtaining piperidone skeleton via a lactone-lactam rearrangement.
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Fatigue is believed to increase the risk of anterior cruciate ligament (ACL) injury by directly promoting high-risk biomechanics in the lower limbs. Studies have shown that dynamic taping can help normalize inadequate biomechanics during landings. This study aims to examine the effects of dynamic taping on landing biomechanics in fatigued football athletes. Twenty-seven high-school football athletes were recruited and randomly allocated to groups of either active taping or sham taping, with a crossover allocation two weeks later. In each group, the participants underwent a functional agility short-term fatigue protocol and were evaluated using the landing error scoring system before and after the fatigue protocol. The landing error scoring system (LESS) scores in the sham taping group increased from 4.24 ± 1.83 to 5.36 ± 2.00 (t = -2.07, p = 0.04, effect size = 0.61). In contrast, the pre-post difference did not reach statistical significance in the active taping group (from 4.24 ± 1.69 to 4.52 ± 1.69, t = -1.50, p = 0.15, effect size 0.46). Furthermore, the pre-post changes between the sham and active taping groups were statistically significant (sham taping: 1.12 ± 1.20; active taping: 0.28 ± 0.94, p = 0.007). Dynamic taping, particularly using the spiral technique, appeared to mitigate faulty landing biomechanics in the fatigued athletes by reducing hip and knee flexion and increasing hip internal rotation during landing. These results suggest that dynamic taping can potentially offer protective benefits in landing mechanics, which could further be applied to prevent ACL injuries in fatigued athletes.
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Three widths of manufacturing S-ribs carbon-fiber filaments acting as turbulence promoters were implemented into the flow channel of direct contact membrane distillation (DCMD) modules to augment the permeate flux improvement in the present study. Attempts to reduce the disadvantageous temperature polarization effect were made by inserting S-ribs turbulence promoters in improving pure water productivity, in which both heat- and mass-transfer boundary layers were diminished due to creating vortices in the flow pattern and increasing turbulence intensity. The temperature polarization coefficient ttemp was studied and found to enhance device performance (less thermal resistance) under inserting various S-ribs carbon-fiber thicknesses and operating both cocurrent- and countercurrent-flow patterns. The permeate fluxes in the DCMD modules with inserted S-ribs carbon-fiber turbulence promoters were investigated theoretically by developing the mathematical modeling equations and were conducted experimentally with various design and operating parameters. The theoretical predictions and experimental results exhibited a great potential to considerably achieve permeate flux enhancement in the new design of the DCMD system. The DCMD module with inserted S-ribs carbon-fiber turbulence promoters in the flow channel could provide a relative permeate flux enhancement up to 37.77% under countercurrent-flow operations in comparisons with the module of using the empty channel. An economic consideration on both permeate flux enhancement and power consumption increment for the module with inserted S-ribs carbon-fiber filaments was also delineated.
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Background In a population, when a disease is causing a symptom, the overall symptom incidence can be determined by proportions diseased, baseline symptom incidence, and risk ratios of developing the symptom due to the disease. There are various measures of association, including risk ratios. How risk ratios are linked to other measures of association, such as correlation coefficients and chi-squared statistics, has not been explicitly discussed. This study aims to demonstrate their connection via equations and simulations, assuming one disease causes symptoms. Methods The equations for correlation coefficients and chi-square statistics were rewritten using epidemiological measures: proportions diseased, baseline symptom incidence, and risk ratios. Simulations were conducted to test the accuracy of the equations. The baseline symptom incidence and the proportions diseased were assumed to be 0.05, 0.1, 0.2, 0.4, or 0.8. The risk ratios were assumed to be 0.5, 1, 2, 5, 10, and 25. Another disease that correlates with this disease was created (correlation = 0, 0.3, or 0.7). For each combination of symptom incidence, proportions diseased, risk ratios, and between-disease correlations, 10,000 subjects were simulated. The correlation coefficients and chi-squared statistics were approximated with epidemiologic measures and their interaction terms. R-squared was used to assess the importance of the epidemiologic measures. Results In the simulations, the overall symptom incidence, correlation coefficients, and chi-squared statistics between the disease and symptoms could be fully explained by the epidemiologic measures in the equations (R-squared = 1). When approximating correlation coefficients and chi-squared statistics with individual measures or their interaction terms, the importance of these measures depended on whether the at-risk incidence reached 1 or not. The numbers in the four cells in the contingency table predicted correlation coefficients, or chi-squared statistics, with different R-squared. Conclusion To our knowledge, this is the first study to translate the three epidemiologic measures (risk ratios, baseline symptom incidence, and proportions diseased) into correlation coefficients and chi-squared statistics. However, chi-squared statistics also depend on sample sizes. This study also provides a platform for developing teaching cases for students to investigate the causal relationship between diseases and symptoms or exposure and outcomes.
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Tissue inhibitors of metalloproteinase (TIMPs) play a pivotal role in regulating extracellular matrix (ECM) dynamics and have been extensively studied in vertebrates. However, understanding their evolution across invertebrate phyla is limited. Utilizing the high-quality Pteria penguin genome, we conducted phylogenomic orthology analyses across metazoans, revealing the emergence and distribution of the TIMP gene family. Our findings show that TIMP repertoires originated during eumetazoan radiation, experiencing independent duplication events in different clades, resulting in varied family sizes. Particularly, Pteriomorphia bivalves within Mollusca exhibited the most significant expansion and displayed the most diverse TIMP repertoires among metazoans. These expansions were attributed to multiple gene duplication events, potentially driven by the demands for functional diversification related to multiple adaptive traits, contributing to the adaptation of Pteriomorphia bivalves as stationary filter feeders. In this context, Pteriomorphia bivalves offer a promising model for studying invertebrate TIMP evolution.
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PURPOSE: To evaluate the surface characteristics, accuracy (trueness and precision), and dimensional stability of tooth preparation dies fabricated using conventional gypsum and direct light processing (DLP), stereolithography (SLA), and polymer jetting printing (PJP) techniques. MATERIALS AND METHODS: Gypsum preparation dies were replicated according to the reference data and imported into DLP, SLA, and PJP printers, and the test data were obtained by scanning after 0, 1, 3, 7, 14, 28, and 42 days. After analyzing the surface characteristics, a best-fit algorithm between the test and the reference data was used to evaluate the accuracy and dimensional stability of the preparation dies. The data were analyzed by one-way analysis of variance and Tukey test or Kruskal-Wallis H test (α = .05). RESULTS: Compared with the gypsum group (3.61 ± 0.59 µm), the root mean square error (RMSE) values of the SLA group (5.33 ± 0.48 µm) was rougher (P < .05), the PJP group (2.43 ± 0.37 µm) was smoother (P < .05), and the DLP group (2.92 ± 0.91 µm) had no significant difference (P > .05). For trueness, the RMSE was greater in the PJP (34.90 ± 4.91 µm) and SLA (19.01 ± 0.95 µm) groups than in the gypsum (16.47 ± 0.47 µm) group (P < .05), and no significant difference was found between the DLP (17.10 Å} 1.77 µm) and gypsum groups. Regarding precision, the RMSE ranking was gypsum = DLP = SLA < PJP group. The RMSE ranges in the gypsum, DLP, PJP, and SLA groups at different times were 6.79 to 8.86 µm, 5.44 to 10.17 µm, 10.16 to 11.28 µm, and 10.94 to 32.74 µm, respectively. CONCLUSION: Although gypsum and printed preparation dies showed statistically significant differences in surface characteristics, accuracy, and dimensional stability, all tooth preparation dies were clinically tolerated and used to produce fixed restorations.
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Spider dragline (major ampullate) silk is one of the toughest known fibers in nature and exhibits an excellent combination of high tensile strength and elasticity. Increasing evidence has indicated that preassembly plays a crucial role in facilitating the proper assembly of silk fibers by bridging the mesoscale gap between spidroin molecules and the final strong fibers. However, it remains challenging to control the preassembly of spidroins and investigate its influence on fiber structural and mechanical properties. In this study, we explored to bridge this gap by modulating the polyalanine (polyA) motifs in repetitive region of spidroins to tune their preassemblies in aqueous dope solutions. Three biomimetic silk proteins with varying numbers of alanine residues in polyA motif and comparable molecular weights were designed and biosynthesized, termed as N16C-5A, N15C-8A, and N13C-12A, respectively. It was found that all three proteins could form nanofibril assemblies in the concentrated aqueous dopes, but the size and structural stability of the fibrils were distinct from each other. The silk protein N15C-8A with 8 alanine residues in polyA motif allowed for the formation of stable nanofibril assemblies with a length of approximately 200 nm, which were not prone to disassemble or aggregate as that of N16C-5A and N13C-12A. More interestingly, the stable fibril assembly of N15C-8A enabled spinning of simultaneously strong (623.3 MPa) and tough (107.1 MJ m-3) synthetic fibers with fine molecular orientation and close interface packing of fibril bundles. This work highlights that modulation of polyA motifs is a feasible way to tune the morphology and stability of the spidroin preassemblies in dope solutions, thus controlling the structural and mechanical properties of the resulting fibers.
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Fibroínas , Peptídeos , Animais , Motivos de Aminoácidos , Fibroínas/química , Fibroínas/genética , Nanofibras/química , Peptídeos/química , Seda/química , Aranhas/química , Resistência à TraçãoRESUMO
Formoterol, a ß2-adrenergic receptor (ß2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson's disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of ß2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD.
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Whether brain stimulation could modulate brain structure in autism remains unknown. This study explored the impact of continuous theta burst stimulation (cTBS) over the left dorsolateral prefrontal cortex (DLPFC) on white matter macro/microstructure in intellectually able children and emerging adults with autism. Sixty autistic participants were randomized (30 active) and received active or sham cTBS for eight weeks twice per week, 16 total sessions using a double-blind (participant-, rater-, analyst-blinded) design. All participants received high-angular resolution diffusion MR imaging at baseline and week 8. Twenty-eight participants in the active group and twenty-seven in the sham group with good imaging quality entered the final analysis. With longitudinal fixel-based analysis and network-based statistics, we found no significant difference between the active and sham groups in changes of white matter macro/microstructure and connections following cTBS. In addition, we found no association between baseline white matter macro/microstructure and autistic symptom changes from baseline to week 8 in the active group. In conclusion, we did not find a significant impact of left DLPFC cTBS on white matter macro/microstructure and connections in children and emerging adults with autism. These findings need to be interpreted in the context that the current intellectually able cohort in a single university hospital site limits the generalizability. Future studies are required to investigate if higher stimulation intensities and/or doses, other personal factors, or rTMS parameters might confer significant brain structural changes visible on MRI in ASD.
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Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a PRMT1-DDX3 axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates PINK1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer.
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Objectives This study aims to understand the statistical significance of the associations between diagnoses and symptoms based on simulations that have been used to understand the interpretability of mental illness diagnoses. Methods The symptoms for the diagnosis of major depressive episodes, dysthymic disorder, and manic episodes were extracted from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR, American Psychiatric Association, Philadelphia, Pennsylvania). Without real-world symptom data, we simulated populations using various combinations of symptom prevalence and correlations. Assuming symptoms occurred with similar prevalence and correlations, for each combination of symptom prevalence (0.05, 0.1, 0.3, 0.5, and 0.7) and correlation (0, 0.1, 0.4, 0.7, and 0.9), 100 cohorts with 10,000 individuals were randomly created. Diagnoses were made according to the DSM-IV-TR criteria. The associations between the diagnoses and their input symptoms were quantified with odds ratios and correlation coefficients. P-values from 100 cohorts for each combination of symptom prevalence and correlation were summarized. Results Three mental illness diagnoses were not significantly correlated with their own symptoms in all simulations, particularly when symptoms were not correlated, except for the symptom in the major criteria of major depressive episodes or dysthymic disorder. The symptoms for the diagnosis of major depressive episodes and dysthymic disorder were significantly correlated with these two diagnoses in some simulations, assuming 0.1, 0.4, 0.7, or 0.9 symptom correlations, except for one symptom. The overlap in the input symptoms for the diagnosis of major depressive episodes and dysthymic disorder also leads to significant correlations between these two diagnoses, assuming 0.1, 0.4, 0.7, and 0.9 correlations between input symptoms. Manic episodes are not significantly associated with the input symptoms of major depressive episodes and dysthymic disorder. Conclusion There are challenges to establish the causation between psychiatric symptoms and mental illness diagnoses. There is insufficient prevalence and incidence data to show all psychiatric symptoms exist or can be observed in patients. The diagnostic accuracy of symptoms to detect a disease cause is far from perfect. Assuming the symptoms of three mood disorders may present in patients, three diagnoses are not significantly associated with all psychiatric symptoms used to diagnose them. The diagnostic criteria of the three diagnoses have not been designed to guarantee significant associations between symptoms and diagnoses. Because statistical associations are important for making causal inferences, there may be a lack of causation between diagnoses and symptoms. Previous research has identified factors that lead to insignificant associations between diagnoses and symptoms, including biases due to data processing and a lack of epidemiological evidence to support the design of mental illness diagnostic criteria.
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BACKGROUND: Air pollution is recognized as a modifiable risk factor for dementia, and recent evidence suggests that improving air quality could attenuate cognitive decline and reduce dementia risk. However, studies have yet to explore the effects of improved air quality on brain structures. This study aims to investigate the impact of air pollution reduction on cognitive functions and structural brain differences among cognitively normal older adults. METHODS: Four hundred and thirty-one cognitively normal older adults were from the Epidemiology of Mild Cognitive Impairment study in Taiwan (EMCIT), a community-based cohort of adults aged 60 and older, between year 2017- 2021. Annual concentrations of PM2.5, NO2, O3, and PM10 at participants' residential addresses during the 10 years before enrollment were estimated using ensemble mixed spatial models. The yearly rate of change (slope) in air pollutants was estimated for each participant. Cognitive functions and structural brain images were collected during enrollment. The relationships between the rate of air pollution change and cognitive functions were examined using linear regression models. For air pollutants with significant findings in relation to cognitive function, we further explored the association with brain structure. RESULTS: Overall, all pollutant concentrations, except O3, decreased over the 10-year period. The yearly rates of change (slopes) in PM2.5 and NO2 were correlated with better attention (PM2.5: r = -0.1, p = 0.047; NO2: r = -0.1, p = 0.03) and higher white matter integrity in several brain regions. These regions included anterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, corticospinal tract, and inferior fronto-occipital fasciculus. CONCLUSIONS: Greater rate of reduction in air pollution was associated with better attention and attention-related white matter integrity. These results provide insight into the mechanism underlying the relationship between air pollution, brain health, and cognitive aging among older adults.
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INTRODUCTION: While Alzheimer's disease (AD) is defined by amyloid-ß plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other. METHODS: Twenty-five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU-N, n = 26) using commercial single- and multi-plex immunoassays. RESULTS: We noted that while AD was associated with increased levels of only three biomarkers (MMP-10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP-10, MMP-2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU-N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP-10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress. DISCUSSION: Better understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid-ß and tau will be crucial for optimizing personalized treatment strategies. Highlights: A panel of 25 highly validated biomarker assays were measured in CSF.MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis.Many individuals with AD had increased levels of more than one biomarker.Markers of metabolism and oxidative stress contributed to an AD multianalyte profile.Assessing multiple biomarker domains is important to understand disease heterogeneity.
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Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.
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Electroporation, or the use of electric pulses to facilitate the intracellular delivery of DNA, RNA, and other molecules, is a well-established technique, that has been demonstrated to significantly augment the immunogenicity of DNA/mRNA vaccines and therapeutics. However, the clinical translation of traditional electroporators has been limited due to high costs, large size, complex user operation, and poor tolerability in humans due to nerve stimulation. In prior work, we introduced ePatch: an ultra-low-cost, handheld, battery-free electroporator employing a piezoelectric pulser coupled with a microneedle electrode array that showed enhanced immunogenic responses to an intradermal SARS-CoV-2 DNA vaccine in mice. The current study shifts focus from efficacy to tolerability, hypothesizing that ePatch's microneedle array, which localizes the electric field to the superficial skin strata, will minimize nerve stimulation and improve patient comfort. We tested this hypothesis in 14 healthy adults, monitoring pain and other potential adverse effects associated with electroporation. Compared to the insertion of a traditional hypodermic needle, the ePatch was less painful. Adverse effects such as pain, tenderness, erythema and swelling at the application sites were minimal, transient, and statistically indistinguishable between the experimental and placebo ePatch application, suggesting excellent tolerability towards electroporation. In summary, ePatch has a favorable tolerability profile in humans and offers the potential for the safe use of electroporation in a variety of clinical settings, including DNA and mRNA vaccination.
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BACKGROUND: Type 2 diabetes is often linked with osteoporosis (T2DOP), a condition that accelerates bone degeneration and increases the risk of fractures. Unlike conventional menopausal osteoporosis, the diabetic milieu exacerbates the likelihood of fractures and osteonecrosis. In particular poliumoside (Pol), derived from Callicarpa kwangtungensis Chun, has shown promising anti-oxidant and anti-inflammatory effects. Yet, its influence on T2DOP remains to be elucidated. PURPOSE: The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP. STUDY DESIGN: A murine model of T2DOP was established using a minimal dosage of streptozotocin (STZ) through intraperitoneal infusion combined with a diet high in fat and sugar. Concurrently, to mimic the diabetic condition in a lab environment, bone mesenchymal stem cells (BMSCs) were maintained in a high-glucose and high-fat (HGHF) setting. METHODS: The impact of Pol on BMSCs in an HGHF setting was determined using methods, such as BODIPY-C11, FerroOrange staining, mitochondrial functionality evaluations, and Western blot methodologies, coupled with immunoblotting and immunofluorescence techniques. To understand the role of Pol in a murine T2DOP model, techniques including micro-CT, hematoxylin and eosin (H&E) staining, dual-labeling with calcein-alizarin red, and immunohistochemistry were employed for detailed imaging and histological insights. RESULTS: Our findings suggest that Pol acts against HGHF-induced bone degradation and ferroptosis, as evidenced by an elevation in glutathione (GSH) and a decline in malondialdehyde (MDA) levels, lipid peroxidation, and mitochondrial reactive oxygen species (ROS). Furthermore, Pol treatment led to increased bone density, enhanced GPX4 markers, and reduced ROS in the distal femur region. On investigating the underlying mechanism of action, it was observed that Pol triggers the Nrf2/GPX4 pathway, and the introduction of lentivirus-Nrf2 negates the beneficial effects of Pol in HGHF-treated BMSCs. CONCLUSION: Pol is effective in treating T2DOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.