A carrier-free, injectable, and self-assembling hydrogel based on carvacrol and glycyrrhizin exhibits high antibacterial activity and enhances healing of MRSA-infected wounds.

Inspired by glycyrrhizin's strong pharmacological activities and the directed self-assembly into hydrogels, we created a novel carrier-free, injectable hydrogel (CAR@glycygel) by combining glycyrrhizin with carvacrol (CAR), without any other chemical crosslinkers, to promote wound healing on bacteria-infected skin. CAR appeared to readily dissolve and load into CAR@glycygel. CAR@glycygel had a dense, porous, sponge structure and strong antioxidant characteristics. In vitro, it showed better antibacterial ability than free CAR. For methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Escherichia coli, the diameter of inhibition zone values of CAR@glycygel were 3.80 ± 0.04, 3.31 ± 0.20 and 3.12 ± 0.24 times greater, respectively, than those of free CAR. The MICs for CAR@glycygel was 156.25 µg/mL while it was 1250.00 µg/mL for free CAR to these three bacteria. Its antibacterial mechanism appeared to involve destruction of the integrity of the bacterial cell wall and biomembrane, leading to a leakage of AKP and inhibition of biofilm formation. In vivo, CAR@glycygel effectively stopped bleeding. When applied to skin wounds on rats infected with MRSA, CAR@glycygel had strong bactericidal activity and improved wound healing. The wound healing rates for CAR@glycygel were 49.59 ± 15.78 %, 93.02 ± 3.09 % and 99.02 ± 0.55 % on day 3, day 7, and day 11, respectively, which were much better than blank control and positive control groups. Mechanisms of CAR@glycygel accelerating wound healing involved facilitating epidermis remolding, promoting the growth of hair follicles, stimulating collagen deposition, mitigating inflammation, and promoting angiogenesis. Overall, CAR@glycygel showed great potential as wound dressing for infected skin wounds.

The relationships between blood lead levels and nocturia prevalence in adults: A retrospective study.

PURPOSE: The purpose of this study was to examine the association between blood lead levels and the prevalence of nocturia in American adults. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2020, focusing on individuals aged 20 years or older (n = 11,919). Blood lead levels were categorized into two groups (<2 µg/dL and ≥2 µg/dL), and the presence of nocturia was assessed based on questionnaire responses. We used multivariable logistic regression models to explore the association between blood lead levels and nocturia while adjusting for various covariates, including sex, ratio of family income to poverty (RIP), lipid profile, age, body mass index (BMI), race, citizenship, sleep trouble, diabetes, and hypertension. To verify whether certain covariates influence blood lead levels and the risk of nocturia, we conducted subgroup analyses. RESULTS: Of the study participants, 31.70% reported experiencing nocturia. Individuals with higher blood lead levels (≥2 µg/dL) exhibited a higher likelihood of experiencing nocturia compared to those with lower levels (<2 µg/dL) in all three models (Model 1: OR 1.46, 95% CI 1.29-1.66, p < 0.0001; Model 2: OR 1.25, 95% CI 1.09-1.44, p = 0.002; Model 3: OR 1.22, 95%CI 1.06-1.41, p = 0.01). Subgroup analyses revealed that factors such as age, sex, sleep trouble, diabetes, hypertension, BMI, RIP, and race did not affect the association between blood lead levels and the risk of nocturia (P for interaction >0.05). CONCLUSIONS: This study reported the correlation between blood lead levels and nocturia. We found that compared to blood lead levels below 2 µg/dL, when lead levels reached or exceeded 2 µg/dL, the risk of nocturia occurrence increased by 22%. CLINICAL TRIAL REGISTRATION: This study is based on existing data from a public database and not from a specific clinical trial; hence, clinical registration information is not provided.

Exploring the Potential of MIM-Manufactured Porous NiTi as a Vascular Drug Delivery Material.

Porous nickel-titanium (NiTi) manufactured using metal injection molding (MIM) has emerged as an innovative generation of drug-loaded stent materials. However, an increase in NiTi porosity may compromise its mechanical properties and cytocompatibility. This study aims to explore the potential of porous NiTi as a vascular drug delivery material and evaluate the impact of porosity on its drug loading and release, mechanical properties, and cytocompatibility. MIM, combined with the powder space-holder method, was used to fabricate porous NiTi alloys with three porosity levels. The mechanical properties of porous NiTi were assessed, as well as the surface cell growth capability. Furthermore, by loading rapamycin nanoparticles onto the surface and within the pores of porous NiTi, we evaluated the in vitro drug release behavior, inhibitory effect on cell proliferation, and inhibition of neointimal hyperplasia in vivo. The results demonstrated that an increase in porosity led to a decrease in the mechanical properties of porous NiTi, including hardness, tensile strength, and elastic modulus, and a decrease in the surface cell growth capability, affecting both cell proliferation and morphology. Concurrently, the loading capacity and release duration of rapamycin were extended with increasing porosity, resulting in enhanced inhibitory effects on cell proliferation in vitro and inhibition of neointimal hyperplasia in vivo. In conclusion, porous NiTi holds promise as a desirable vascular drug delivery material, but a balanced consideration of the influence of porosity on both mechanical properties and cytocompatibility is necessary to achieve an optimal balance among drug-loading and release performance, mechanical properties, and cytocompatibility.

The complete chloroplast genome of Meconopsis torquata (Papaveraceae), a traditional Tibetan medicine.

Meconopsis torquata Prain 1906, a national second-class rare and endangered plant, is reported here for the first time for its complete chloroplast genome. The genome is 153,290 bp in length, comprising a large single-copy region (LSC, 83,918 bp), a small single-copy region (SSC, 17,740 bp), and two inverted repeat sequences (IRa and IRb, each 25,816 bp). The overall GC content is 38.7%, with the IR region having the highest content (43.1%). The genome is annotated with 112 unique genes, including 4 rRNA genes, 29 tRNA genes, and 79 protein-coding genes. Analysis of codon usage bias reveals that codons ending in A/T account for 96.7% of those with a Relative Synonymous Codon Usage (RSCU) value above 1. This predominance of A/T-ending codons might be indicative of M. torquata adaptation to high-altitude environments. Phylogenetic analysis reveals a close kinship between M. torquata and M. pinnatifolia and M. paniculata, indicating that the ancestral groups of these species might have a complex evolutionary history. This study uncovers the genetic characteristics and adaptive evolution of M. torquata, offering a new perspective in understanding the phylogenetic relationships within the genus. The findings not only provide a solid theoretical foundation for the conservation and sustainable use of this rare and endangered species but also offer significant scientific support for the conservation of biodiversity.

BR regulates wheat root salt tolerance by maintaining ROS homeostasis.

MAIN CONCLUSION: Trace amounts of epibrassinolide (EpiBL) could partially rescue wheat root length inhibition in salt-stressed situation by scavenging ROS, and ectopic expression of TaDWF4 or TaBAK1 enhances root salt tolerance in Arabidopsis by balancing ROS level. Salt stress often leads to ion toxicity and oxidative stress, causing cell structure damage and root development inhibition in plants. While prior research indicated the involvement of exogenous brassinosteroid (BR) in plant responses to salt stress, the precise cytological role and the function of BR in wheat root development under salt stress remain elusive. Our study demonstrates that 100 mM NaCl solution inhibits wheat root development, but 5 nM EpiBL partially rescues root length inhibition by decreasing H2O2 content, oxygen free radical (OFR) content, along with increasing the peroxidase (POD) and catalase (CAT) activities in salt-stressed roots. The qRT-PCR experiment also shows that expression of the ROS-scavenging genes (GPX2 and CAT2) increased in roots after applying BR, especially during salt stress situation. Transcriptional analysis reveals decreased expression of BR synthesis and root meristem development genes under salt stress in wheat roots. Differential expression gene (DEG) enrichment analysis highlights the significant impact of salt stress on various biological processes, particularly "hydrogen peroxide catabolic process" and "response to oxidative stress". Additionally, the BR biosynthesis pathway is enriched under salt stress conditions. Therefore, we investigated the involvement of wheat BR synthesis gene TaDWF4 and BR signaling gene TaBAK1 in salt stress responses in roots. Our results demonstrate that ectopic expression of TaDWF4 or TaBAK1 enhances salt tolerance in Arabidopsis by balancing ROS (Reactive oxygen species) levels in roots.

Fluorescence Lifetime Imaging of Lipid Heterogeneity in the Inner Mitochondrial Membrane with a Super-photostable Environment-Sensitive Probe.

The inner mitochondrial membrane (IMM) undergoes dynamic morphological changes, which are crucial for the maintenance of mitochondrial functions as well as cell survival. As the dynamics of the membrane are governed by its lipid components, a fluorescent probe that can sense spatiotemporal alterations in the lipid properties of the IMM over long periods of time is required to understand mitochondrial physiological functions in detail. Herein, we report a red-emissive IMM-labeling reagent with excellent photostability and sensitivity to its environment, which enables the visualization of the IMM ultrastructure using super-resolution microscopy as well as of the lipid heterogeneity based on the fluorescence lifetime at the single mitochondrion level. Combining the probe and fluorescence lifetime imaging microscopy (FLIM) showed that peroxidation of unsaturated lipids in the IMM by reactive oxygen species caused an increase in the membrane order, which took place prior to mitochondrial swelling.

A novel protein CYTB-187AA encoded by the mitochondrial gene CYTB modulates mammalian early development.

The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for oxidative phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females' fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.

Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.

Chicken gasdermins mediate pyroptosis after the cleavage by caspases.

Gasdermin (GSDM) proteins are executioners of pyroptosis in many species. Gasdermin proteins can be cleaved at their linker region between the amino domain (NT) and carboxyl domain (CT) by enzymes. The released GSDM-NTs bind cell membrane and form pores, thereby leading to the release of cellular components and lytic cell death. GSDM-mediated pyroptosis is considered to play important role in immune responses. However, little is known about the GSDM proteins and GSDM-mediated pyroptosis in birds. In the current study, genes encoding chicken gasdermin A (chGSDMA) and chGSDME were cloned. The cleavage of chGSDMA and chGSDME by chicken caspase-1 (chCASP1), chCASP3 and chCASP7 and the cleavage sites were determined. The chGSDMA-NT obtained form chCASP1-mediated cleavage and chGSDME-NT obtained from chCASP3/chCASP7-mediated cleavage could bind and damage cell membrane and lead to cell death of HEK293 cells. chGSDMA-NT also strongly localized to and formed puncta in nucleus. Besides, both chGSDMA-NT and chGSDME-NT showed growth inhibition and bactericidal activity to bacteria. In chickens challenged with Pasteurella multocida and Salmonella typhimurium, the expression of chGSDMA and chGSDME was upregulated and the activation of chCASP3 and the cleavage of chGSDME were observed. The work provides essential information for expanding our knowledge on pyroptosis in birds.

A Ni-O-Ag photothermal catalyst enables 103-m2 artificial photosynthesis with >17% solar-to-chemical energy conversion efficiency.

The scalable artificial photosynthesis composed of photovoltaic electrolysis and photothermal catalysis is limited by inefficient photothermal CO2 hydrogenation under weak sunlight irradiation. Herein, NiO nanosheets supported with Ag single atoms [two-dimensional (2D) Ni1Ag0.02O1] are synthesized for photothermal CO2 hydrogenation to achieve 1065 mmol g-1 hour-1 of CO production rate under 1-sun irradiation. This performance is attributed to the coupling effect of Ag-O-Ni sites to enhance the hydrogenation of CO2 and weaken the CO adsorption, resulting in 1434 mmol g-1 hour-1 of CO yield at 300°C. Furthermore, we integrate the 2D Ni1Ag0.02O1-supported photothermal reverse water-gas shift reaction with commercial photovoltaic electrolytic water splitting to construct a 103-m2 scale artificial photosynthesis system (CO2 + H2O → CO + H2 + O2), which achieves more than 22 m3/day of green syngas with an adjustable H2/CO ratio (0.4-3) and a photochemical energy conversion efficiency of >17%. This research charts a promising course for designing practical, natural sunlight-driven artificial photosynthesis systems.

Chromosome-scale reference genome of broccoli (Brassica oleracea var. italica Plenck) provides insights into glucosinolate biosynthesis.

Broccoli (Brassica oleracea var. italica Plenck) is an important vegetable crop, as it is rich in health-beneficial glucosinolates (GSLs). However, the genetic basis of the GSL diversity in Brassicaceae remains unclear. Here we report a chromosome-level genome assembly of broccoli generated using PacBio HiFi reads and Hi-C technology. The final genome assembly is 613.79 Mb in size, with a contig N50 of 14.70 Mb. The GSL profile and content analysis of different B. oleracea varieties, combined with a phylogenetic tree analysis, sequence alignment, and the construction of a 3D model of the methylthioalkylmalate synthase 1 (MAM1) protein, revealed that the gene copy number and amino acid sequence variation both contributed to the diversity of GSL biosynthesis in B. oleracea. The overexpression of BoMAM1 (BolI0108790) in broccoli resulted in high accumulation and a high ratio of C4-GSLs, demonstrating that BoMAM1 is the key enzyme in C4-GSL biosynthesis. These results provide valuable insights for future genetic studies and nutritive component applications of Brassica crops.

Association of diarrhea or constipation with urinary incontinence in adults: A cross-sectional analysis of the National Health and Nutrition Examination Survey.

AIMS: This study aimed to investigate the association between diarrhea or constipation and urinary incontinence (UI) in adults. METHODS: Data from the National Health and Nutrition Examination Survey for 2009-2010 was used to include 4686 adults aged 20 and over in the analysis. Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) were used as outcome variables, with diarrhea and constipation as exposure factors. We first compared the baseline characteristics of those with and without SUI, as well as those with and without UUI. The impact of diarrhea or constipation on SUI and UUI was assessed using multivariate logistic regression models. To ensure the stability of the results, subgroup and stratified analyses were conducted. RESULTS: The prevalence rates of UUI and SUI were 22.49% and 23.39%, respectively. Adjusted multivariate logistic regression analysis revealed that the risk of UUI was increased by either diarrhea (OR 1.66, 95% CI 1.36-2.04) or constipation (OR 1.42, 95% CI 1.11-1.83). The risk of SUI was also elevated by either diarrhea (OR 1.36, 95% CI 1.11-1.67) or constipation (OR 1.32, 95% CI 1.06-1.63). Subgroup analysis revealed no significant differences in the interaction tests between constipation or diarrhea and UI. CONCLUSIONS: This study found that both constipation and diarrhea increase the risk of UUI and SUI.

Malignant Melanoma of the Sphenoid Sinus: Case Report and Literature Review.

Malignant melanoma originating from the sphenoid sinus is an extremely rare but aggressive tumor of the head and neck. A 57-year-old man had a 1 month history of headache, right trigeminal paresthesias, and upper lid ptosis. Magnetic resonance imaging showed a large mass in the right sphenoid sinus and an invasion of the right cavernous sinus and clivus. The patient underwent endoscopic endonasal transsphenoidal surgery, and pathologically revealed malignant melanoma. One month after the operation, the patient was treated with radiation therapy. Unfortunately, the patient died of distant metastasis 2 years later. Due to its rarity, there is still no effective treatment strategy and no way to assess the progression of malignant melanoma.

Effectiveness of mHealth App-Based Interventions for Increasing Physical Activity and Improving Physical Fitness in Children and Adolescents: Systematic Review and Meta-Analysis.

BACKGROUND: The COVID-19 pandemic has significantly reduced physical activity (PA) levels and increased sedentary behavior (SB), which can lead to worsening physical fitness (PF). Children and adolescents may benefit from mobile health (mHealth) apps to increase PA and improve PF. However, the effectiveness of mHealth app-based interventions and potential moderators in this population are not yet fully understood. OBJECTIVE: This study aims to review and analyze the effectiveness of mHealth app-based interventions in promoting PA and improving PF and identify potential moderators of the efficacy of mHealth app-based interventions in children and adolescents. METHODS: We searched for randomized controlled trials (RCTs) published in the PubMed, Web of Science, EBSCO, and Cochrane Library databases until December 25, 2023, to conduct this meta-analysis. We included articles with intervention groups that investigated the effects of mHealth-based apps on PA and PF among children and adolescents. Due to high heterogeneity, a meta-analysis was conducted using a random effects model. The Cochrane Risk of Bias Assessment Tool was used to evaluate the risk of bias. Subgroup analysis and meta-regression analyses were performed to identify potential influences impacting effect sizes. RESULTS: We included 28 RCTs with a total of 5643 participants. In general, the risk of bias of included studies was low. Our findings showed that mHealth app-based interventions significantly increased total PA (TPA; standardized mean difference [SMD] 0.29, 95% CI 0.13-0.45; P<.001), reduced SB (SMD -0.97, 95% CI -1.67 to -0.28; P=.006) and BMI (weighted mean difference -0.31 kg/m2, 95% CI -0.60 to -0.01 kg/m2; P=.12), and improved muscle strength (SMD 1.97, 95% CI 0.09-3.86; P=.04) and agility (SMD -0.35, 95% CI -0.61 to -0.10; P=.006). However, mHealth app-based interventions insignificantly affected moderate to vigorous PA (MVPA; SMD 0.11, 95% CI -0.04 to 0.25; P<.001), waist circumference (weighted mean difference 0.38 cm, 95% CI -1.28 to 2.04 cm; P=.65), muscular power (SMD 0.01, 95% CI -0.08 to 0.10; P=.81), cardiorespiratory fitness (SMD -0.20, 95% CI -0.45 to 0.05; P=.11), muscular endurance (SMD 0.47, 95% CI -0.08 to 1.02; P=.10), and flexibility (SMD 0.09, 95% CI -0.23 to 0.41; P=.58). Subgroup analyses and meta-regression showed that intervention duration was associated with TPA and MVPA, and age and types of intervention was associated with BMI. CONCLUSIONS: Our meta-analysis suggests that mHealth app-based interventions may yield small-to-large beneficial effects on TPA, SB, BMI, agility, and muscle strength in children and adolescents. Furthermore, age and intervention duration may correlate with the higher effectiveness of mHealth app-based interventions. However, due to the limited number and quality of included studies, the aforementioned conclusions require validation through additional high-quality research. TRIAL REGISTRATION: PROSPERO CRD42023426532; https://tinyurl.com/25jm4kmf.

Facilely Modified Nickel-Based Hole Transporting Layers for Organic Solar Cells with 19.12% Efficiency and Enhanced Stability.

Hole transporting layers (HTLs), strategically positioned between electrode and light absorber, play a pivotal role in shaping charge extraction and transport in organic solar cells (OSCs). However, the commonly used poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) HTL, with its hygroscopic and acidic nature, undermines the operational durability of OSC devices. Herein, an environmentally friendly approach is developed utilizing nickel acetate tetrahydrate (NiAc·4H2O) and [2-(9H-carbazol-9-yl)ethyl] phosphonic acid (2PACz) as the NiAc·4H2O/2PACz HTL, aiming at overcoming the limitations posed by the conventional PEDOT:PSS one. Encouragingly, a remarkable power conversion efficiency (PCE) of 19.12% is obtained for the OSCs employing NiAc·4H2O/2PACz as the HTL, surpassing that of devices with the PEDOT:PSS HTL (17.59%), which is ranked among the highest ones of OSCs. This improvement is attributed to the appropriate work function, enhanced hole mobility, facilitated exciton dissociation efficiency, and lower recombination loss of NiAc·4H2O/2PACz-based devices. Furthermore, the NiAc·4H2O/2PACz-based OSCs exhibit superior operational stability compared to their PEDOT:PSS-based counterparts. Of significant note, the NiAc·4H2O/2PACz HTL demonstrates a broad generality, boosting the PCE of the PM6:PY-IT and PM6:Y6-based OSCs from 16.47% and 16.79% (with PEDOT:PSS-based analogs as HTLs) to 17.36% and 17.57%, respectively. These findings underscore the substantial potential of the NiAc·4H2O/2PACz HTL in advancing OSCs, offering improved performance and stability, thereby opening avenue for highly efficient and reliable solar energy harvesting technologies.

Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.

The Heptazine-Based Materials through Intrinsically Modification for the Cycloaddition of CO2 and Bisepoxides.

For the efficient utilization of CO2 into valuable product, the attractive carbon nitride catalysts have been widely studied. In this work, heptazine-related materials with varying degree of polymerization were designed by an intrinsically modification strategy and employed in the cycloaddition of CO2 with the bisepoxide 1, 4-butanediol diglycidyl ether (BDODGE). We initially figured out that the sample prepared at 450 °C contained more melem hydrate, exhibiting the best performance. The epoxides conversion and corresponding cyclic carbonates selectivity could achieve 93.1 % and 99.3 % at 140 °C for 20 h without any cocatalyst and solvent, respectively. Results of the catalytic tests suggested that the high catalytic activity was dependent on big size porous structure and the synergetic effect of active amino groups and -OH groups. The role of water in maintaining the specific structure and providing active site has been proved. Moreover, the CN-450-W catalyst exhibited outstanding recycling stability. And finally, a plausible reaction mechanism was proposed.

Enhancing prime editor flexibility with coiled-coil heterodimers.

BACKGROUND: Prime editing enables precise base substitutions, insertions, and deletions at targeted sites without the involvement of double-strand DNA breaks or exogenous donor DNA templates. However, the large size of prime editors (PEs) hampers their delivery in vivo via adeno-associated virus (AAV) due to the viral packaging limit. Previously reported split PE versions provide a size reduction, but they require intricate engineering and potentially compromise editing efficiency. RESULTS: Herein, we present a simplified split PE named as CC-PE, created through non-covalent recruitment of reverse transcriptase to the Cas9 nickase via coiled-coil heterodimers, which are widely used in protein design due to their modularity and well-understood sequence-structure relationship. We demonstrate that the CC-PE maintains or even surpasses the efficiency of unsplit PE in installing intended edits, with no increase in the levels of undesired byproducts within tested loci amongst a variety of cell types (HEK293T, A549, HCT116, and U2OS). Furthermore, coiled-coil heterodimers are used to engineer SpCas9-NG-PE and SpRY-PE, two Cas9 variants with more flexible editing scope. Similarly, the resulting NG-CC-PE and SpRY-CC-PE also achieve equivalent or enhanced efficiency of precise editing compared to the intact PE. When the dual AAV vectors carrying CC-PE are delivered into mice to target the Pcsk9 gene in the liver, CC-PE enables highly efficient precise editing, resulting in a significant reduction of plasma low-density lipoprotein cholesterol and total cholesterol. CONCLUSIONS: Our innovative, modular system enhances flexibility, thus potentially facilitating the in vivo applicability of prime editing.

Associations between waist circumference and nocturia in adults: National health and nutrition examination survey 2005-2020.

BACKGROUND: The relationship between waist circumference and nocturia has not been previously studied. This study investigated the association between waist circumference and the occurrence of nocturia in adults. METHODS: We analyzed data from the National Health and Nutrition Examination Survey covering 2005-2020, encompassing 6287 adults aged ≥20. Nocturia was defined as the need to urinate two or more times during the night. First, we compared baseline characteristics between the nocturia and non-nocturia groups. Subsequently, we used multivariate logistic regression analysis to investigate the relationship between waist circumference and nocturia prevalence. We also employed restricted cubic spline analysis to study the potential nonlinear correlation between waist circumference and the prevalence of nocturia. Recognizing the baseline data's heterogeneity based on nocturia prevalence, we conducted subgroup analyses according to age, sex, body mass index (BMI), and ethnicity. RESULTS: Our findings indicated that females, individuals aged ≥50, citizens, Non-Hispanic Black, those with lower education levels (high school or less), higher BMIs, lower family income-to-poverty ratios, higher waist circumference, hypertension, and diabetes were more likely to experience nocturia. Compared with individuals in the lowest waist circumference quartile (Q1), those in the higher quartiles (Q4) exhibited an increased risk of nocturia in Model 1 (Q4, OR:2.00, 95% CI:1.64, 2.45, p < 0.0001). These results remained consistent after adjusting for covariates in models 2 and 3. A restricted cubic spline analysis suggested a linear association between waist circumference and nocturia (P for nonlinearity = 0.066). Subgroup analyses based on age, sex, BMI, and ethnicity revealed no significant differences in the interaction tests between waist circumference and nocturia (P for interaction = 0.437, 0.331, 0.121, and 0.889, respectively), indicating that these baseline characteristics did not influence the association. CONCLUSIONS: Our findings indicated an association between increased waist circumference and a higher prevalence of nocturia. Knowledge of this association reinforces the importance of lifestyle modifications in maintaining a healthy waist circumference and informs public health strategies to address other potential risk factors for nocturia.

Examining the safety of mirabegron: an analysis of real-world pharmacovigilance data from the US FDA adverse event reporting system (FAERS) database.

Background: Mirabegron, the first ß-3 adrenergic receptor agonist, received approval from the Food and Drug Administration (FDA) in 2012 for the treatment of overactive bladder (OAB). This pharmacovigilance study investigated the safety profile of mirabegron treatment using the US FDA Adverse Event Reporting System (FAERS) database. Methods: This study employed disproportionality analyses, including the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) algorithm, to quantify signals of adverse events associated with mirabegron. Results: From the first quarter of 2012 to the third quarter of 2023, a comprehensive total of 14,356,234 adverse event (AE) reports were submitted to the FDA Adverse Event Reporting System database. Within this dataset, encompassing 18,763 reports specifically associated with mirabegron, healthcare professionals notably contributed 2,902 of these reports. A total of 80 preferred terms (PTs) of interest were identified using both the ROR and information component algorithms. The most common AEs included blood pressure increased, urinary retention, atrial fibrillation, dry mouth, and tachycardia, which were consistent with the product instructions. Unexpected significant AEs, such as arrhythmia, palpitations, dementia, transient ischemic attack, Parkinson's disease, anti-neutrophil cytoplasmic antibody positive vasculitis, lip swelling, and swollen tongue, were also identified. The study findings indicated that the majority of onset time occurred within 30 days (n = 358, 55.68%). However, AEs were still possible after 1 year of mirabegron treatment. Conclusion: This study provided valuable evidence for the real-world safety of mirabegron, helping clinical professionals enhance their understanding of mirabegron's safety in clinical practice. It also contributed valuable evidence for further safety studies on mirabegron.