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Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.
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The study of acoustic radiation from spherical sound sources plays a crucial role in understanding the thermoviscous effects in practical acoustic problems. However, finding a general solution of acoustic radiation from spherical sound sources in thermoviscous fluids remains a formidable challenge. To advance this issue, an analytical method is developed in this paper to calculate the acoustic field radiated by spherical sound sources with the isothermal boundary condition and arbitrary velocity boundary condition. The developed method is utilized to present the solutions of the acoustic field generated by an oscillating sphere and a general spherical sound source, and the accuracy and validity of these solutions are verified through analytical and numerical methods.
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Excitation of multiple acoustic wave modes on a single chip is beneficial to implement diversified acoustofluidic functions. Conventional acoustic wave devices made of bulk LiNbO3 substrates generally generate few acoustic wave modes once the crystal-cut and electrode pattern are defined, limiting the realization of acoustofluidic diversity. In this paper, we demonstrated diversity of acoustofluidic behaviors using multiple modes of acoustic waves generated on piezoelectric-thin-film-coated aluminum sheets. Multiple acoustic wave modes were excited by varying the ratios between IDT pitch/wavelength and substrate thickness. Through systematic investigation of fluidic actuation behaviors and performances using these acoustic wave modes, we demonstrated fluidic actuation diversities using various acoustic wave modes and showed that the Rayleigh mode, pseudo-Rayleigh mode, and A0 mode of Lamb wave generally have better fluidic actuation performance than those of Sezawa mode and higher-order modes of Lamb wave, providing guidance for high-performance acoustofluidic actuation platform design. Additionally, we demonstrated diversified particle patterning functions, either on two sides of acoustic wave device or on a glass sheet by coupling acoustic waves into the glass using the gel. The pattern formation mechanisms were investigated through finite element simulations of acoustic pressure fields under different experimental configurations.
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The structures of three 1:1 cocrystal forms of etoricoxib {ETR; systematic name: 5-chloro-2-(6-methylpyridin-3-yl)-3-[4-(methylsulfonyl)phenyl]pyridine, C18H15ClN2O2S} have been synthesized and characterized by single-crystal X-ray diffraction; these are etoricoxib-benzoic acid (1/1), C18H15ClN2O2S·C7H6O2 (ETR-Bz), etoricoxib-4-fluorobenzoic acid (1/1), C18H15ClN2O2S·C7H5FO2 (ETR-PFB), and etoricoxib-4-nitrobenzoic acid (1/1), C18H15ClN2O2S·C7H5NO4 (ETR-PNB). Powder X-ray diffraction and thermal differential scanning calorimetry-thermogravimetry (DSC-TG) techniques were also used to characterize these multicomponent systems. Due to the influence of the corresponding acids, ETR shows different conformations. Furthermore, the energetic contributions of the supramolecular motifs have been established by energy framework studies of the stabilizing interaction forces and are consistent with the thermal stability of the cocrystals.
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BACKGROUND: Metabolic abnormalities and immune inflammation are deeply involved in pulmonary vascular remodelling and the development of pulmonary hypertension (PH). However, the regulatory mechanisms of glycolysis in macrophages are still elusive. Cumulative evidence indicates that ß-catenin plays a crucial role in metabolic reprogramming. This study aimed to investigate the effect of ß-catenin on macrophage glycolysis in PH. METHODS: LPS-induced BMDMs were generated via in vitro experiments. A monocrotaline (MCT)-induced PH rat model was established, and the ß-catenin inhibitor XAV939 was administered in vivo. The role of ß-catenin in glycolysis was analysed. The degree of pulmonary vascular remodelling was measured. RESULTS: ß-catenin was significantly increased in both in vitro and in vivo models. In LPS-induced BMDMs, ß-catenin increased the levels of hexokinase 2 (HK2), phosphofructokinase (PFK), M2-pyruvate kinase (PKM2), lactate dehydrogenase (LDH), and lactate (LA) and the expression of inflammatory cytokines and promoted PASMC proliferation and migration in vitro. XAV939 decreased the level of glycolysis and downregulated the expression of inflammatory cytokines in vivo. MCT promoted pulmonary arterial structural remodelling and right ventricular hypertrophy, and XAV939 alleviated these changes. CONCLUSIONS: Our findings suggest that ß-catenin is involved in the development of PH by promoting glycolysis and the inflammatory response in macrophages. Inhibition of ß-catenin could improve the progression of PH.
Subject(s)
Disease Models, Animal , Glycolysis , Hypertension, Pulmonary , Macrophages , Monocrotaline , Pulmonary Artery , Rats, Sprague-Dawley , Vascular Remodeling , beta Catenin , Animals , Glycolysis/drug effects , beta Catenin/metabolism , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Male , Vascular Remodeling/drug effects , Macrophages/metabolism , Macrophages/drug effects , Pulmonary Artery/metabolism , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Pulmonary Artery/pathology , Cell Proliferation/drug effects , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Signal Transduction , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/physiopathology , Hypertrophy, Right Ventricular/chemically induced , Inflammation Mediators/metabolism , Rats , Cell Movement/drug effectsABSTRACT
Background: Patients with inflammatory bowel disease (IBD) often experience worries related to travel due to frequent bowel movements. However, there is currently limited research focusing on the travel worries of patients with IBD. The aim of this study was to assess the level of worry regarding out-of-home activities in patients with IBD and identify factors associated with worry. Methods: This study included patients with IBD who visited the outpatient clinics between September 2020 and March 2022, during the COVID-19 pandemic. Participants completed a self-designed questionnaire, providing general clinical data and indicating their level of worry for out-of-home activities. Results: A total of 529 patients with IBD completed the questionnaire. Patients with Crohn's disease (CD) had a higher proportion of individuals under 40 years old and males compared to patients with ulcerative colitis (UC). Regarding out-of-home activities, patients with UC expressed greater worry about going out and taking buses than patients with CD. However, there were no significant differences observed between the two groups in terms of travel worries and worries about finding public washrooms. A significant majority (85.4%) of patients with clinically active IBD expressed worries about not finding public washrooms when going out, while 46.7% of patients in clinical remission had similar worries. Moreover, the worry about finding public washrooms was higher in patients with UC compared to those with CD, both during the clinical activity and remission. Conclusion: This survey conducted during the COVID-19 pandemic reported worries among patients with IBD about out-of-home activities. The patients with clinically active IBD, especially UC, expressed worries about not finding public washrooms when going out. We highlight the actual psychological and quality of life challenges faced by patients with IBD.
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Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by the rapid emergence of viral variants with immunoevasive properties. The development of an off-the-shelf, effective, and safe therapy against respiratory viral infections is thus desirable. Here, we develop NanoSTING, a nanoparticle formulation of the endogenous STING agonist, 2'-3' cGAMP, to function as an immune activator and demonstrate its safety in mice and rats. A single intranasal dose of NanoSTING protects against pathogenic strains of SARS-CoV-2 (alpha and delta VOC) in hamsters. In transmission experiments, NanoSTING reduces the transmission of SARS-CoV-2 Omicron VOC to naïve hamsters. NanoSTING also protects against oseltamivir-sensitive and oseltamivir-resistant strains of influenza in mice. Mechanistically, NanoSTING upregulates locoregional interferon-dependent and interferon-independent pathways in mice, hamsters, as well as non-human primates. Our results thus implicate NanoSTING as a broad-spectrum immune activator for controlling respiratory virus infection.
Subject(s)
Administration, Intranasal , Nanoparticles , SARS-CoV-2 , Animals , Nanoparticles/chemistry , Nanoparticles/administration & dosage , Mice , Cricetinae , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Disease Models, Animal , Humans , Membrane Proteins/agonists , Membrane Proteins/metabolism , Female , Nucleotides, Cyclic/pharmacology , Rats , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/virology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/drug therapy , Male , Antiviral Agents/pharmacology , Antiviral Agents/administration & dosage , Mice, Inbred C57BLABSTRACT
BACKGROUND: A promising approach to cuff-less, continuous blood pressure monitoring is to estimate blood pressure (BP) from Pulse Wave Velocity (PWV). However, most existing PWV-based methods rely on empirical BP-PWV relations and have large prediction errors, which may be caused by the implicit assumption of thin-walled, linear elastic arteries undergoing small deformations. Our objective is to understand the BP-PWV relationship in the absence of such limiting assumptions. METHOD: We performed Fluid-Structure Interaction (FSI) simulations of the radial artery and the common carotid artery under physiological flow conditions. In these dynamic simulations, we employed two constitutive models for the arterial wall: the linear elastic model, implying a thin-walled linear elastic artery undergoing small deformations, and the Holzapfel-Gasser-Ogden (HGO) model, accounting for the nonlinear effects of collagen fibers and their orientations on the large arterial deformation. RESULTS: Despite the changing BP, the linear elastic model predicts a constant PWV throughout a cardiac cycle, which is not physiological. The HGO model correctly predicts a positive BP-PWV correlation by capturing the nonlinear deformation of the artery, showing up to 50 % variations of PWV in a cardiac cycle. CONCLUSION: Dynamic FSI simulations reveal that the BP-PWV relationship strongly depends on the arterial constitutive model, especially in the radial artery. To infer BP from PWV, one must account for the varying PWV, a consequence of the nonlinear arterial response due to collagen fibers. Future efforts should be directed towards robust measurement of time-varying PWV if it is to be used to predict BP.
Subject(s)
Blood Pressure , Models, Cardiovascular , Pulse Wave Analysis , Humans , Blood Pressure/physiology , Radial Artery/physiology , Computer SimulationABSTRACT
Objective: We compared the effects of early and delayed rehabilitation on the function of patients after rotator cuff repair by meta-analysis to find effective interventions to promote the recovery of shoulder function. Methods: This meta-analysis was registered in PROSPERO (CRD42023466122). We manually searched the randomized controlled trials (RCTs) in the Cochrane Library, Pubmed, Cochrane Library, EMBASE, the China National Knowledge Infrastructure (CNKI), the China VIP Database (VIP), and the Wanfang Database to evaluate the effect of early and delayed rehabilitation after arthroscopic shoulder cuff surgery on the recovery of shoulder joint function. Review Manager 5.3 software was used to analyze the extracted data. Then, the PEDro scale was employed to appraise the methodological quality of the included research. Results: This research comprised nine RCTs and 830 patients with rotator cuff injuries. According to the findings of the meta-analysis, there was no discernible difference between the early rehabilitation group and the delayed rehabilitation group at six and twelve months after the surgery in terms of the VAS score, SST score, follow-up rotator cuff healing rate, and the rotator cuff retear rate at the final follow-up. There was no difference in the ASES score between the early and delayed rehabilitation groups six months after the operation. However, although the ASES score in the early rehabilitation group differed significantly from that in the delayed rehabilitation group twelve months after the operation, according to the analysis of the minimal clinically important difference (MCID), the results have no clinical significance. Conclusions: The improvement in shoulder function following arthroscopic rotator cuff surgery does not differ clinically between early and delayed rehabilitation. When implementing rehabilitation following rotator cuff repair, it is essential to consider the paradoxes surrounding shoulder range of motion and tendon anatomic healing. A program that allows for flexible progression based on the patient's ability to meet predetermined clinical goals or criteria may be a better option.
Subject(s)
Arthroscopy , Recovery of Function , Rotator Cuff Injuries , Humans , Arthroscopy/rehabilitation , Rotator Cuff Injuries/surgery , Rotator Cuff Injuries/rehabilitation , Rotator Cuff/surgery , Range of Motion, Articular , Time Factors , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
BACKGROUND: Cirrhosis is a common liver disease, and ascites is one of the common clinical conditions. However, the clinical manifestations of ascites combined with hyponatremia as a high-risk condition and its relationship to patient prognosis have not been fully studied. AIM: To explore the clinical manifestations, prognostic factors, and relationships of ascites with hyponatremia in patients with cirrhosis to provide better diagnostic and treatment strategies. METHODS: In this study, we retrospectively analyzed the clinical data of 150 patients diagnosed with cirrhosis and ascites between 2017 and 2022. Patients were divided into two groups: ascites combined with hyponatremia group and ascites group. We compared the general characteristics, degree of hyponatremia, complications, treatment, and prognosis between the two groups. RESULTS: In the study results, patients in the ascites combined with hyponatremia group showed an older average age (58.2 ± 8.9 years), 64.4% were male, and had a significantly longer hospitalization time (12.7 ± 5.3 d). Hyponatremia was more severe in this group, with a mean serum sodium concentration of 128.5 ± 4.3 mmol/L, which was significantly different from the ascites group of 137.6 ± 2.1 mmol/L. Patients with ascites and hyponatremia were more likely to develop hepatic encephalopathy (56.2% vs 39.0%), renal impairment (45.2% vs 28.6%) and infection (37.0% vs 23.4%). Regarding treatment, this group more frequently used diuretics (80.8% vs 62.3%) and salt supplements (60.3% vs 38.9%). Multiple logistic regression analysis identified older age [Odds ratio (OR) = 1.06, P = 0.025] and male gender (OR = 1.72, P = 0.020) as risk factors for hyponatremia combined with ascites. Overall, patients with ascites and hyponatremia present a clear high-risk status, accompanied by severe complications and poor prognosis. CONCLUSION: In patients with cirrhosis, ascites with hyponatremia is a high-risk condition that is often associated with severe complications.
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Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.
Subject(s)
Nitrates , Setaria Plant , Reactive Oxygen Species , Nitrates/pharmacology , Setaria Plant/genetics , Hydrogen Peroxide , Sodium Chloride , Oxygen , Signal Transduction , Gene Expression Profiling , NitrogenABSTRACT
Quantum chemical calculations using ab initio methods at the MRCI+Q(8,9)/def2-QZVPPD and CCSD(T)/def2-QZVPPD levels as well as using density functional theory are reported for the diatomic molecules AeN- (Ae=Ca, Sr, Ba). The anions CaN- and SrN- have electronic triplet (3Π) ground states with nearly identical bond dissociation energies De ~57â kcal/mol calculated at the MRCI+Q(8,9)/def2-QZVPPD level. In contrast, the heavier homologue BaN- has a singlet (1Σ+) ground state, which is only 1.1â kcal/mol below the triplet (3Σ-) state. The computed bond dissociation energy of (1Σ+) BaN- is 68.4â kcal/mol. The calculations at the CCSD(T)-full/def2-QZVPPD and BP86-D3(BJ)/def2-QZVPPD levels are in reasonable agreement with the MRCI+Q(8,9)/def2-QZVPPD data, except for the singlet (1Σ+) state, which has a large multireference character. The calculated atomic partial charges given by the CM5, Voronoi and Hirshfeld methods suggest small to medium-sized AeâN- charge donation for most electronic states. In contrast, the NBO method predicts for all species medium to large AeâN- electronic charge donation, which is due to the neglect of the (n)p AOs of Ae atoms as genuine valence orbitals. Neither the bond orders nor the bond lengths correlate with the bond dissociation energies. The EDA-NOCV calculations show that the heavier alkaline earth atoms Ca, Sr, Ba use their (n)s and (n-1)d orbitals for covalent bonding.
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The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.
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We identified a young female patient admitted for suspected renal malignancy. Partial nephrectomy was performed after imaging evaluation and discussion. Postoperative biopsy pathology reported multiple low-grade eosinophilic renal tumors (LOTs) with angiomyolipoma growth. After reviewing the data, we found that LOT was mostly solitary and occurred in middle-aged and elderly patients. This case is unique and we share it to improve the understanding of this disease.
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Unlike graphene derived from graphite, borophenes represent a distinct class of synthetic two-dimensional materials devoid of analogous bulk-layered allotropes, leading to covalent bonding within borophenes instead of van der Waals (vdW) stacking. Our investigation focuses on 665 vdW-stacking boron bilayers to uncover potential bulk-layered boron allotropes through vdW stacking. Systematic high-throughput screening and stability analysis reveal a prevailing inclination toward covalently bonded layers in the majority of boron bilayers. However, an intriguing outlier emerges in δ5 borophene, demonstrating potential as a vdW-stacking candidate. We delve into electronic and topological structural similarities between δ5 borophene and graphene, shedding light on the structural integrity and stability of vdW-stacked boron structures across bilayers, multilayers, and bulk-layered allotropes. The δ5 borophene analogues exhibit metallic properties and characteristics of phonon-mediated superconductors, boasting a critical temperature near 22 K. This study paves the way for the concept of "borophite", a long-awaited boron analogue of graphite.
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Spin engineering is a promising way to modulate the interaction between the metal d-orbital and the intermediates and thus enhance the catalytic kinetics. Herein, an innovative strategy is reported to modulate the spin state of Co by regulating its coordinating environment. o-c-CoSe2-Ni is prepared as pre-catalyst, then in situ electrochemical impedance spectroscopy (EIS) and in situ Raman spectroscopy are employed to prove phase transition, and CoOOH/Co3O4 is formed on the surface as active sites. In hybrid water electrolysis, the voltage has a negative shift, and in zinc-ethanol-air battery, the charging voltage is lowered and the cycling stability is greatly increased. Coordinated atom substitution and crystalline symmetry change are combined to regulate the absorption ability of reaction intermediates with balanced optimal adsorption. Coordinated atom substitution weakens the adsorption while the crystalline symmetry change strengthens the adsorption. Importantly, the tetrahedral sites are introduced by Ni doping which enables the co-existence of four-coordinated sites and six-coordination sites in o-c-CoSe2-Ni. The dz2 + dx2-y2 orbital occupancy decreases after the atomic substitution, while increases after replacing the CoSe6-Oh field with CoSe6-Oh/CoSe4-Td. This work explores a new direction for the preparation of efficient catalysts for water electrolysis and innovative zinc-ethanol-air battery.
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Lysine acetylation of non-histone proteins plays crucial roles in many cellular processes. In this study, we examine the role of lysine acetylation during sister chromatid separation in mitosis. We investigate the acetylation of securin at K21 by cell-cycle-dependent acetylome analysis and uncover its role in separase-triggered chromosome segregation during mitosis. Prior to the onset of anaphase, the acetylated securin via TIP60 prevents its degradation by the APC/CCDC20-mediated ubiquitin-proteasome system. This, in turn, restrains precocious activation of separase and premature separation of sister chromatids. Additionally, the acetylation-dependent stability of securin is also enhanced by its dephosphorylation. As anaphase approaches, HDAC1-mediated deacetylation of securin promotes its degradation, allowing released separase to cleave centromeric cohesin. Blocking securin deacetylation leads to longer anaphase duration and errors in chromosome segregation. Thus, this study illustrates the emerging role of securin acetylation dynamics in mitotic progression and genetic stability.
Subject(s)
Chromatids , Lysine , Separase/metabolism , Securin/genetics , Securin/metabolism , Chromatids/metabolism , Acetylation , Lysine/genetics , Lysine/metabolism , Cell Cycle Proteins/metabolism , Anaphase , Endopeptidases , Chromosome SegregationABSTRACT
BACKGROUND: This study aimed to determine the incidence and influencing factors of venous thromboembolism (VTE) in patients with traumatic rib fractures. METHODS: The retrospective study analyzed medical records of patients with traumatic rib fractures from 33 hospitals. RESULTS: The overall incidence of VTE in hospitalized patients with traumatic rib fractures was 8.1%. Patients with isolated traumatic rib fractures had a significantly lower incidence of VTE (4.4%) compared to patients with rib fractures combined with other injuries (12.0%). Multivariate analysis identified the number of rib fractures as an independent risk factor for thrombosis. Surgical stabilization of isolated rib fractures involving three or more ribs was associated with a lower VTE incidence compared to conservative treatment. CONCLUSIONS: Patients with rib fractures have a higher incidence of VTE, positively correlated with the number of rib fractures. However, the occurrence of thrombosis is relatively low in isolated rib fractures. Targeted thromboprophylaxis strategies should be implemented for these patients, and surgical stabilization of rib fractures may be beneficial in reducing the risk of VTE.
Subject(s)
Rib Fractures , Thrombosis , Venous Thromboembolism , Humans , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Rib Fractures/complications , Rib Fractures/epidemiology , Anticoagulants/therapeutic use , Incidence , Retrospective Studies , Risk Factors , RibsABSTRACT
Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.
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Introduction: Dental erosion and abrasion pose significant clinical challenges, often leading to exposed dentinal tubules and dentine demineralization. The aim of this study was to analyse the efficacy of quercetin-encapsulated hollow mesoporous silica nanocomposites (Q@HMSNs) on the prevention of dentine erosion and abrasion. Method: Q@HMSNs were synthesized, characterized, and evaluated for their biocompatibility. A total of 130 dentine specimens (2 mm × 2 mm × 2 mm) were prepared and randomly distributed into 5 treatment groups (n = 26): DW (deionized water, negative control), NaF (12.3 mg/mL sodium fluoride, positive control), Q (300 µg/mL quercetin), HMSN (5.0 mg/mL HMSNs), and Q@HMSN (5.0 mg/mL Q@HMSNs). All groups were submitted to in vitro erosive (4 cycles/d) and abrasive (2 cycles/d) challenges for 7 days. The specimens in the DW, NaF, and Q groups were immersed in the respective solutions for 2 min, while treatment was performed for 30 s in the HMSN and Q@HMSN groups. Subsequently, the specimens were subjected to additional daily erosion/abrasion cycles for another 7 days. The effects of the materials on dentinal tubule occlusion and demineralized organic matrix (DOM) preservation were examined by scanning electron microscopy (SEM). The penetration depth of rhodamine B fluorescein into the etched dentine was assessed using confocal laser scanning microscopy (CLSM). The erosive dentine loss (EDL) and release of type I collagen telopeptide (ICTP) were measured. The data were analysed by one-way analysis of variance (ANOVA) with post hoc Tukey's test (α = 0.05). Results: Q@HMSNs were successfully synthesized and showed minimal toxicity to human dental pulp stem cells (HDPSCs) and gingival fibroblasts (HGFs). Q@HMSNs effectively occluded the dentinal tubules, resulting in a thicker DOM in the Q@HMSN group. The CLSM images showed more superficial penetration in the HMSN and Q@HMSN groups than in the quercetin, NaF, and DW groups. The Q@HMSN group exhibited a significantly lower EDL and reduced ICTP levels compared to the other groups (p < 0.05). Conclusion: Q@HMSNs hold promise for inhibiting dentine erosion and abrasion by promoting tubule occlusion and DOM preservation.