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Palm buds are a natural green resource of the forest, which are not only rich in nutrients but contain a large number of phenolic acids and flavonoids, among other components. It has a variety of biological activities such as antioxidant and uterine smooth muscle stimulation. Aim of the study: To evaluate the safety of palm buds for use as a nutraceutical product and food by evaluating the toxicity, subacute toxicity and genotoxicity of the young palm buds. Also studied for its immune-enhancing activity. Acute toxicity tests were performed in mice using the maximum tolerance method, and the manifestations of toxicity and deaths were recorded after administration of 10,000 mg/mL for 14 consecutive d (days) of observations. To assess subacute toxicity, mice were treated with palm buds (750, 1500, or 3000 mg/mL) daily for 28 days. The teratogenicity of palm buds was assessed by the Ames test, the mouse bone marrow cell micronucleus test, and the mouse spermatozoa malformation test. In addition, we evaluated the immune-enhancing ability of palm buds by the mouse carbon profile test, delayed-type metamorphosis reaction, and serum hemolysin assay. In the acute toxicity study, the Median Lethal Dose (LD 50) was greater than 10,000 mg/kg bw in both male and female rats. There were also no deaths or serious toxicities in the subacute study. The no-observed-adverse-effect level (NOAEL) was 3000 mg/kg bw. However, the mice's food intake decreased after one week. The medium and high dose groups had a reducing effect on body weight in mice of both sexes. In addition, the changes in organ coefficients of the liver, kidney and stomach in male mice were significantly higher in the high-dose group (3.23 ± 0.35, 0.75 ± 0.05, 0.57 ± 0.05 g) than in the control group (2.94 ± 0.18, 0.58 ± 0.05, 0.50 ± 0.02 g). Hematological analyses showed that all the indices of the rats in each palm sprout dose group were within the normal range. The results of blood biochemical indicators showed that there was a significant reduction in TP in the blood of male mice in the high-dose group (44.6 ± 7.8 g/L) compared to the control group (58.3 ± 15.1 g/L). In histopathological analysis, none of the significant histopathological changes were observed. The results of the immunological experiment in mice showed that the liver coefficient and thymus coefficient of the high-dose group (8400 mg/kg) were significantly lower than the control group. There was no remarkable difference in auricle swelling between each dose palm bud group (1400, 2800, or 8400 mg/kg) and the control group. The anti-volume number of the high-dose group was significantly increased. Palm buds have non-toxic effects in vivo and have little effect on non-specific and cellular immunity in the test mice within the dose range of this experiment. The immunoenhancement in mice is mainly achieved through humoral immunity. In conclusion, our results suggest that palm buds are safe for use as healthcare products and food. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel section design for lattices structures with hollow struts is presented. • Deep learning-based approach enables tailored mechanical properties. • Significant improvement in stiffness, strength and isotropic properties is achieved. • Optimized designs prevent large drop in stress after failure. In contrast to constant-strut lattices, the introduction of innovative strut designs has the potential to enhance the mechanical properties of lattice structures. This study presents a Bézier curve-based nonuniform section design for body-centered cubic lattices with hollow struts (BCCH). Periodic boundary conditions are applied to the unit cells, and a finite element (FE) numerical homogenization method is employed to assess their elastic properties. A comprehensive dataset is generated through the FE model, which is subsequently divided into training, validation, and testing sets. The coordinates of the Bézier curve control points serve as inputs to deep learning networks, which are trained on the training dataset. Relative density and elastic properties are treated as two distinct networks, with the validation set utilized to prevent overfitting. The objective function consists of two weighted components: one aims to maximize the relative Young's modulus, while the other ensures that the relative density achieves a specified value. An evolutionary algorithm is employed to optimize the objective function, with variations in the control point coordinates constrained to specific ranges. By leveraging the fast inference ability of the deep learning model, the stiffness and orientation-dependent mechanical properties can be efficiently tailored. Our results demonstrate that the optimized structures demonstrate superior stiffness (+92.8 %) and distributed stress field compared to the benchmark lattice. The design method also enables tailoring of specific mechanical properties, including isotropic elasticity. 3D-printed lattice designs were fabricated and compression tests confirmed agreement with simulation results in terms of stiffness. Additionally, the optimized designs exhibit superior strength (+99.6 %) and toughness compared to the benchmark lattices. [Display omitted] [ABSTRACT FROM AUTHOR]

The dispersed phase in liquid–liquid emulsions and air–liquid mixtures can often be fragmented into smaller sizes by the surrounding turbulent carrier phase. The critical parameter that controls this process is the breakup frequency, which is defined from the breakup kernel in the population balance equation. The breakup frequency controls how long it takes for the dispersed phase to reach the terminal size distribution for given turbulence. In this article, we try to summarize the key experimental results and compile the existing datasets under a consistent framework to find out what is the characteristic timescale of the problem and how to account for the inner density and viscosity of the dispersed phase. Furthermore, by pointing out the inconsistency of existing experimental data, the key important unsolved questions and related problems on the breakup frequency of bubbles and droplets are discussed. [Display omitted] • Compile experimental datasets on bubble and droplet breakup frequency in turbulence under a unified framework. • Discuss and compare different relevant timescales for breakup among different datasets. • Propose the mean shear time as a potential timescale for breakup in turbulent flows. [ABSTRACT FROM AUTHOR]

Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases. [Display omitted] • The expressions of vegfaa and kdrl are induced during zebrafish liver regeneration • VEGF inhibition disrupts biliary-mediated liver regeneration in zebrafish and mice • VEGF signaling governs biliary epithelial cell dedifferentiation via PI3K-mTORC1 axis Cai et al. show that VEGF signaling is triggered to initiate biliary-mediated liver regeneration upon extreme hepatocyte injury and that the PI3K-mTORC1 axis acts as the downstream effector to control biliary epithelial cell dedifferentiation and bipotential progenitor cell proliferation. [ABSTRACT FROM AUTHOR]

A major cause of intestinal failure (IF) is intestinal epithelium necrosis and massive loss of enterocytes, especially in the jejunum, the major intestinal segment in charge of nutrient absorption. However, mechanisms underlying jejunal epithelial regeneration after extensive loss of enterocytes remain elusive. Here, we apply a genetic ablation system to induce extensive damage to jejunal enterocytes in zebrafish, mimicking the jejunal epithelium necrosis that causes IF. In response to injury, proliferation and filopodia/lamellipodia drive anterior migration of the ileal enterocytes into the injured jejunum. The migrated fabp6 + ileal enterocytes transdifferentiate into fabp2 + jejunal enterocytes to fulfill the regeneration, consisting of dedifferentiation to precursor status followed by redifferentiation. The dedifferentiation is activated by the IL1β-NFκB axis, whose agonist promotes regeneration. Extensive jejunal epithelial damage is repaired by the migration and transdifferentiation of ileal enterocytes, revealing an intersegmental migration mechanism of intestinal regeneration and providing potential therapeutic targets for IF caused by jejunal epithelium necrosis. [Display omitted] • The zebrafish intestinal injury model mimics mammalian intestinal failure • Ileal enterocytes migrate and transdifferentiate to nascent jejunal enterocytes • The passive and active migration drive movements of ileal enterocytes to jejunum • The transdifferentiation of ileal enterocytes is activated by the IL1β-NFκB axis Wei et al. identify an intestinal regenerative mechanism that is fulfilled by intestinal intersegmental cell migration in combination with transdifferentiation. After extensive damage to jejunal enterocytes, ileal enterocytes migrate and transdifferentiate to nascent jejunal enterocytes, and this transdifferentiation is driven by the IL1β-NFκB axis. [ABSTRACT FROM AUTHOR]

Due to the toxicity, bioaccumulation, non-biodegradability and perseverance of heavy metals, their risk assessment is essential for soil quality management. The Hakanson potential ecological risk index (RI), which considers the effects of heavy metal concentration and toxicity, has been widely used in soil ecological risk assessment. However, RI overlooks the influence of soil properties on the mobility and availability of heavy metals in risk assessment. To fill this gap, this study sought to develop an improved ecological risk index (IRI), which incorporates soil adsorption into RI, and applied it to evaluate the ecological risk of heavy metals in the soil of the Taihu basin, China. The soil adsorption models based on the Gradient Boosting Decision Tree (GBDT) was used to predict the soil adsorption capacity of five heavy metals (i.e. cadmium, chromium, copper, lead, zinc). The soil adsorption capacity in 1446 sites in the Taihu basin was predicted by the GBDT models and was assigned as the weight of IRI. The risk assessment results of the five metals in the Taihu basin showed that 40% of the sites were at a moderate risk level and 60% of the sites were at a slight risk level based on the RI. The value of IRI in the basin ranged from 11.1 to 75.5, with a mean value of 28.1. IRI differed from RI in spatial distribution due to the influence of soil adsorption. The comparative analysis between the metal contents in sediments and surrounding soils confirmed the tremendous influence of soil adsorption on ecological risks, indicating that soil adsorption should be taken into consideration in soil risk assessment. [Display omitted] • Soil adsorption was assigned as the weight to modify the traditional risk index. • Machine learning models are effective tools to predict soil adsorption capacity. • Soil adsorption affects the mobility of heavy metals and reduces their risk. • The heterogeneity of soil properties changes the risk distribution of heavy metals. [ABSTRACT FROM AUTHOR]

Sustainable development is characterized by the coordinated development of economic, ecological and social systems. The complex relationship among these three systems may well hinder the achievement of the Sustainable Development Goals. To guide the policies regarding regional sustainable development, this study designed a comprehensive assessment framework, which integrates the development level and the interactions among economy, society and ecology, to evaluate spatiotemporal changes in sustainable development and its driving force of the Yangtze River Delta region, China. The results showed that the sustainable development of the Yangtze River Delta region had increased continuously from the low level to the medium level since 2000. The sustainable development of cities appeared to be spatially uneven and about 24.39% of the cities reached a high sustainable development level in 2020. The spatiotemporal changes in seven factors, including the primary industry, the secondary industry, the tertiary industry, the ecosystem regulating services, the ecosystem cultural services, the population density and urbanization rate, were simulated through Geographically and Temporally Weighted Regression. The tertiary industry and the ecosystem regulating services were the main positive driving factors while population density always played a negative role in the Yangtze River Delta region. The dynamics of the driving forces help to identify key action areas for the sustainable development strategies. Moreover, eco-compensation policies help break the imbalance of urban sustainable development and achieve a win-win situation. [Display omitted] • An evaluation framework integrating system status and relationship was proposed. • The uneven regional sustainability is related to the impact of internal drivers. • The dynamic changes of drivers affect the levels of sustainable development. • Eco-compensation may be a way to break the imbalance of urban sustainability. [ABSTRACT FROM AUTHOR]

Aims The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy. Methods The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured. Results Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation. Conclusions Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications. [ABSTRACT FROM AUTHOR]

Characterized by large surface area, high vascularization and thin blood–alveolar barrier, drug delivery by the pulmonary route has benefits over other administration routes. However, to date most of the marketed inhalable products are short-acting formulations that require the patient to inhale several times every day, thus reducing patient compliance. Controlled pulmonary drug delivery is a promising system but the formidable airway clearance mechanisms need to be avoided. This review mainly introduces the barriers impeding the development of controlled pulmonary drug delivery and strategies used to overcome them. We believe that large porous particles, swellable microparticles and porous nanoparticle–aggregate-based particles are the most promising carriers to control drug release in the lung. [ABSTRACT FROM AUTHOR]

Hierarchical porous silicalite-1 with micropores and mesopores was successfully synthesized via dry gel conversion route using tetrapropylammonium hydroxide (TPAOH) and polyvinyl alcohol (PVA) as microporous and mesoporous templates, respectively. The obtained hierarchical porous silicalite-1 was characterized by X-ray diffraction (XRD), nitrogen adsorption and desorption, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The characteristics of the samples are comparable with conventional silicalite-1. The influence of the PVA on the hierarchical porous properties of the samples was investigated. The hierarchical porous silicalite-1 showed higher activity and selectivity than conventional silicalite-1 in vapor phase Beckmann rearrangement of cyclohexanone oxime to ε-caprolactam under reaction condition. [ABSTRACT FROM AUTHOR]

Highlights: [•] The review describes general properties of carrageenan. [•] The review presents a comprehensive overview of carrageenan's applications in various drug delivery systems. [•] The review provides suggestions for future development of carrageenan in drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: The present study examined age-related differences in collision detection performance when contrast of the driving scene was reduced by simulated fog. Older and younger drivers were presented with a collision detection scenario in a simulator in which an object moved at a constant speed on a linear trajectory towards the driver. Drivers were shown part of the motion path of an approaching object that would eventually either collide with or pass by the driver and were required to determine whether or not the object would collide with the driver. Driver motion was either stationary or moving along a linear path down the roadway. A no fog condition and three different levels of fog were examined. Detection performance decreased when dense fog was simulated for older but not for younger observers. An age-related decrement was also found with shorter display durations (longer time to contact). When the vehicle was moving decrements in performance were observed for both younger and older drivers. These results suggest that under inclement weather conditions with reduced visibility, such as fog, older drivers may have an increased crash risk due to a decreased ability to detect impending collision events. [Copyright &y& Elsevier]

Abstract: Percutaneous vertebroplasty (PVP) has been used widely to treat pain caused by osteolytic spinal lesions, whereas vertebroplasty for osteoblastic spinal lesions is less known. The purpose of this study is to describe PVP as a highly effective miniinvasive procedure to treat painful osteoblastic metastatic spinal lesions. Four patients with painful osteoblastic metastatic spinal lesions were treated by PVP in the authors'' department, and immediately relief of pain was achieved in all of them. The findings from this study may encourage more studies of PVP in palliative treatment of patients with osteoblastic lesions. [Copyright &y& Elsevier]

Abstract: The present study examined the limits of spatial attention while performing two driving relevant tasks that varied in depth. The first task was to maintain a fixed headway distance behind a lead vehicle that varied speed. The second task was to detect a light-change target in an array of lights located above the roadway. In Experiment 1 the light detection task required drivers to encode color and location. The results indicated that reaction time to detect a light-change target increased and accuracy decreased as a function of the horizontal location of the light-change target and as a function of the distance from the driver. In a second experiment the light change task was changed to a singleton search (detect the onset of a yellow light) and the workload of the car following task was systematically varied. The results of Experiment 2 indicated that RT increased as a function of task workload, the 2D position of the light-change target and the distance of the light-change target. A multiple regression analysis indicated that the effect of distance on light detection performance was not due to changes in the projected size of the light target. In Experiment 3 we found that the distance effect in detecting a light change could not be explained by the location of eye fixations. The results demonstrate that when drivers attend to a roadway scene attention is limited in three-dimensional space. These results have important implications for developing tests for assessing crash risk among drivers as well as the design of in vehicle technologies such as head-up displays. [ABSTRACT FROM AUTHOR]

Abstract: Previous research () has found that temporal interocular unmatched (IOUM) features generate a perception of subjective contours and can result in a perception of quantitative depth. In the present study we examine in detail the factors important for quantitative depth perception from IOUM features. In Experiments 1 and 2 observers were shown temporal IOUM features based on three dots that disappeared behind an implicit surface. Subjects reported a perception of a subjective surface and were able to perceive qualitative depth. In Experiments 3 and 4 metrical depth was perceived when binocular disparity features were added to the display. These results suggest that quantitative depth from IOUM information is perceived when binocular matched information is present in regions adjacent to the surface. In addition, the perceived depth of the subjective surface decreased with an increase in the width of the subjective surface suggesting a limitation in the propagation of quantitative depth to surface regions where qualitative depth information is available. [Copyright &y& Elsevier]

Abstract: The present study examined age-related differences in car following performance when contrast of the driving scene was reduced by simulated fog. Older (mean age of 72.6) and younger (mean age of 21.1) drivers were presented with a car following scenario in a simulator in which a lead vehicle (LV) varied speed according to a sum of three sine wave functions. Drivers were shown an initial following distance of 18m and were asked to maintain headway distance by controlling speed to match changes in LV speed. Five simulated fog conditions were examined ranging from a no fog condition (contrast of 0.55) to a high fog condition (contrast of 0.03). Average LV speed varied across trials (40, 60, or 80km/h). The results indicated age-related declines in car following performance for both headway distance and RMS (root mean square) error in matching speed. The greatest decline occurred at moderate speeds under the highest fog density condition, with older drivers maintaining a headway distance that was 21% closer than younger drivers. At higher speeds older drivers maintained a greater headway distance than younger drivers. These results suggest that older drivers may be at greater risk for a collision under high fog density and moderate speeds. [Copyright &y& Elsevier]

Abstract: The aim of this study was to assess whether patients with neurodegenerative disease, namely Alzheimer''s disease (AD) and Parkinson''s disease (PD), differed from age-matched, neurologically normal comparison participants in their ability to detect impending collisions. Six AD patients and 8 PD patients, together comprising the neurodegenerative disease group, and 18 comparison participants completed a collision detection simulation task where they must judge whether approaching objects would collide with them or pass by them. The neurodegenerative disease group was less sensitive in detecting collisions than the comparison group, and sensitivity worsened with increasing number of objects in the display and increasing time to contact of those objects. Poor performance on tests of cognition and visual attention were associated with poor collision detection sensitivity. The results of this study indicate that neurodegenerative disease impairs the ability to accurately detect impending collisions and that these decrements are likely the combined result of visual and cognitive disturbances related to disease status. [Copyright &y& Elsevier]

Upon extensive hepatocyte loss or impaired hepatocyte proliferation, liver regeneration occurs via biliary epithelial cell (BEC) transdifferentiation, which includes dedifferentiation of BECs into bipotential progenitor cells (BP-PCs) and then redifferentiation of BP-PCs to nascent hepatocytes and BECs. This BEC-driven liver regeneration involves reactivation of hepatoblast markers, but the underpinning mechanisms and their effects on liver regeneration remain largely unknown. Using a zebrafish extensive hepatocyte ablation model, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a liver regeneration mutant, liver logan (lvl), in which the telomere maintenance 2 (tel2) gene is mutated. During liver regeneration, the tel2 mutation specifically inhibits transcriptional activation of a hepatoblast marker, hematopoietically expressed homeobox (hhex), in BEC-derived cells, which blocks BP-PC redifferentiation. Mechanistic studies show that Tel2 associates with the hhex promoter region and promotes hhex transcription. Our results reveal roles of Tel2 in the BP-PC redifferentiation process of liver regeneration by activating hhex. [Display omitted] • Tel2 governs biliary-driven liver regeneration in zebrafish larvae • Mutation of tel2 blocks redifferentiation of bipotential progenitor cells • Tel2 regulates reactivation of hhex during liver regeneration • Overexpression of hhex rescues liver regeneration defects in tel2 mutant Zhang et al. reveal a critical role of Tel2 in regulating redifferentiation and proliferation of bipotential progenitor cells during the biliary-driven liver regeneration in zebrafish, in which Tel2 modulates transcriptional reactivation of the hepatoblast marker hhex in biliary epithelial cell (BEC)-derived cells. [ABSTRACT FROM AUTHOR]

Abstract: Age-related declines in vision are well documented in the literature. In the present study we examined whether changes in spatial or temporal integration contribute to this decline. Younger (mean age of 21) and older (mean age of 745) subjects were asked to identify 2D shapes based on kinetic occlusion information---the accretion and deletion of texture during motion. The results of the first experiment indicated age-related decrements in spatial but not temporal integration. In the second experiment we manipulated the lifetime of motion stimuli to more directly examine temporal integration. The results indicated no differential effect of age on temporal integration. The results considered together suggest age related changes in recovering 2D shape from occlusion are the result of spatial but not temporal integration. Age-related changes in neural inhibition and ACh for regulating spatial integration are proposed as possible mechanisms for this decline. [Copyright &y& Elsevier]

Shock wave propagation and their damage to solid structures, which involve complex multiphase and multiphysics phenomena, are difficult problems to address. In this paper, a three-dimensional graphics processing unit (GPU)-accelerated finite difference-smoothed particle hydrodynamics (FD-SPH) method was developed for the prediction of strongly compressible fluid flow and strong fluid-structure interactions. The conventional mesh-based finite difference method was used to simulate shock wave propagation, while the smoothed particle hydrodynamics method was employed to predict the dynamic behavior of solid materials. In addition, the immersed boundary method (IBM) was implemented in the GPU-accelerated FD-SPH solver for the boundary treatment of the interface between solid and fluid materials. Four numerical cases, namely shock-cylinder obstacle interaction, elastic panel deformation induced by shock wave propagation, the response of stainless steel tubes under internal blast loading, and the damage of blast loading on reinforced concrete slab, were conducted for verification of the GPU-accelerated FD-SPH solver. The numerical results were compared against the available experimental data, which shows that the GPU-accelerated FD-SPH solver is capable of capturing the shock wave propagation and its damage to structures very well. • A GPU accelerated coupled FD-SPH method is developed to solve strong fluid-structure interaction problems. • The immersed boundary method is used in the solver to impose boundary conditions on the fluid-structure interface. • The propagation of shock waves and its damage to the structure is well captured. [ABSTRACT FROM AUTHOR]

Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection. We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post–lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest. Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety. [ABSTRACT FROM AUTHOR]

• A point mutation in a two-component regulatory system gene, crrB , was identified in mutants overexpressing KexD, an RND-type multidrug efflux pump, in Klebsiella pneumoniae. • Overexpression of CrrA changed the expression of kexD via crrB mutation. • Colistin resistance was not increased in our KexD-overexpressing mutants. RND-type multidrug efflux systems in Gram-negative bacteria protect them against antimicrobial agents. Gram-negative bacteria generally possess several genes which encode such efflux pumps, but these pumps sometimes fail to show expression. Generally, some multidrug efflux pumps are silent or expressed only at low levels. However, genome mutations often increase the expression of such genes, conferring the bacteria with multidrug-resistant phenotypes. We previously reported mutants with increased expression of the multidrug efflux pump KexD. We aimed to identify the cause of KexD overexpression in our isolates. Furthermore, we also examined the colistin resistant levels in our mutants. A transposon (Tn) was inserted into the genome of Klebsiella pneumoniae Em16-1, a KexD-overexpressing mutant, to identify the gene(s) responsible for KexD overexpression. Thirty-two strains with decreased kexD expression after Tn insertion were isolated. In 12 of these 32 strains, Tn was identified in crrB , which encodes a sensor kinase of a two-component regulatory system. DNA sequencing of crrB in Em16-1 showed that the 452nd cytosine on crrB was replaced by thymine, and this mutation changed the 151st proline into leucine. The same mutation was found in all other KexD-overexpressing mutants. The expression of crrA increased in the mutant overexpressing kexD , and the strains in which crrA was complemented by a plasmid showed elevated expression of kexD and crrB from the genome. The complementation of the mutant-type crrB also increased the expression of kexD and crrA from the genome, but the complementation of the wild-type crrB did not. Deletion of crrB decreased antibiotic resistance levels and KexD expression. CrrB was reported as a factor of colistin resistance, and the colistin resistance of our strains was tested. However, our mutants and strains carrying kexD on a plasmid did not show increased colistin resistance. Mutation in crrB is important for KexD overexpression. Increased CrrA may also be associated with KexD overexpression. [ABSTRACT FROM AUTHOR]

Terminalia bellirica (Gaertn.) Roxb. (TBR) , a popular herbal remedy in India and Southeast Asia, has been demonstrated to possess multiple pharmacological activities. However, systematic studies on the medicinal effects and mechanism of TBR for the androgenetic alopecia (AGA) treatment are deficient. Human Umbilical Vein Endothelial Cells (HUVECs) and testosterone-induced AGA mice were used to evaluate the hair regrowth activity of TBR extracts. Chemical constituents and potential active components of TBR extracts were analyed by UPLC-Q-TOF-MS in vitro / vivo. The hair regrowth mechanisms of TBR were elucidated through network pharmacology and experimental validation. Totally 28 chemical constituents in TBR were identified, of which 15 were predicted as potential active components for AGA therapy. TBR could significantly scavenge ROS, promote VEGF level/cell migration of HUVECs, and inhibiting type II 5α-reductase activity (the inhibit rate: 82.35 ± 1.02 %). Pharmacodynamic evaluation suggested that TBR effectively led to hair regrowth in C57BL6 mice compared to minoxidil. TBR promoted the hair follicle (HF) transition from the telogen phase to anagen phase by decreasing MDA levels, increasing VEFG expression and up-regulating phosphorylated P38/ERK protein levels in the MAPK signalling pathway. TBR reversed AGA via inhibiting SRD5A2 activity and stimulating the MAPK pathway. Meantime, TBR could remodel the follicle microenvironment by reducing oxidative stress and increasing angiogenesis. [Display omitted] • TBR, a traditional Tibetan medicine, could reverses AGA by multiple pathways. • UPLC-TOP-MS integrated network pharmacological to investigate the mechanism of TBR in AGA therapy. • TBR reverses AGA by regulating MAPK-related pathways. [ABSTRACT FROM AUTHOR]

To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2166-2176, 2014 [ABSTRACT FROM AUTHOR]