Phase separation is required for PML nuclear body biogenesis and function.

PML nuclear body (NB) malfunction often leads to acute leukemia outbreaks and other severe diseases. PML NB rescue is the molecular basis of arsenic success in acute promyelocytic leukemia (APL) treatment. However, it is unclear how PML NBs are assembled. Here, we observed the presence of liquid-liquid phase separation (LLPS) in NB formation by fluorescence recovery after photobleaching (FRAP) experiment. Compared with the wild-type (WT) NBs, PML A216V derived from arsenic-resistant leukemia patients markedly crippled LLPS, but not altered the overall structure and PML RBCC oligomerization. In parallel, we also reported several Leu to Pro mutations that were critical to PML coiled-coil domain. FRAP characterization and comparison between L268P and A216V revealed markedly different LLPS activities in these mutant NBs. Transmission electron microscopy (TEM) inspections of LLPS-crippled and uncrippled NBs showed aggregation- and ring-like PML packing in A216V and WT/L268P NBs, respectively. More importantly, the correct LLPS-driven NB formation was the prerequisite for partner recruitment, post-translational modifications (PTMs), and PML-driven cellular regulations, such as ROS stress control, mitochondria production, and PML-p53-mediated senescence and apoptosis. Altogether, our results helped to define a critical LLPS step in PML NB biogenesis.

Cocrystal Prediction of Nifedipine Based on the Graph Neural Network and Molecular Electrostatic Potential Surface.

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.

Lauromacrogol foam injection under ultrasonic guidance for pediatric lip venous malformations.

OBJECTIVE: To evaluate the efficacy and safety of lauromacrogol foam sclerotherapy in the treatment of children with lip venous malformation. METHODS: Fifty-two children (27 males and 25 females) aged from 6 months to 17 years with lip VM who underwent lauromacrogol foam injection with ultrasonic guidance from July 2018 to December 2020 in our hospital were retrospectively recruited for this study. All the children were examined by MRI, ultrasound, blood routine and coagulation before operation. We were guided by ultrasound to locate the blood flow area (nests), injecting lauromacrogol foam to fill the venous malformation. The follow-up time was 14.31 ± 5.96 (6-24) months. Follow-up items include clinical manifestations, imaging data, efficacy and complications. RESULTS: This group of children was treated 3-5 times, an average of 4 times/case. The total effective rate was 90.38%. Pain in 4 cases, fever in 4 cases, infection in 2 cases, ulcer in 1 case. There were no serious complications such as cardiopulmonary accident. CONCLUSION: Ultrasound guiding foam sclerotherapy with lauromacrogol is effective and safe for children with lip venous malformation.

[Holocarboxylase synthetase deficiency induced by HLCS gene mutations: a rare disease study]. / ç½•è§ç— ç ”ç©¶ï¼šHLCSåŸºå› çªå˜è‡´å ¨ç¾§åŒ–é ¶åˆæˆé ¶ç¼ºä¹ç—‡.

A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.

[Recurrent vulvar rashes in a girl aged 22 months for more than half a year].

A girl, aged 22 months, attended the hospital due to recurrent vulvar rashes for more than half a year. Skin biopsy showed Langerhans cell histiocytosis, and evaluation of systemic conditions showed no systemic involvement. Therefore, the girl was diagnosed with Langerhans cell histiocytosis (skin type). In conclusion, for rashes on the vulva alone, if there are no specific clinical manifestations, the possibility of Langerhans cell histiocytosis should be considered after molluscum contagiosum, sexually transmitted diseases, and Fordyce disease are excluded.

A dual memristive Wien-bridge chaotic system with variable amplitude and frequency.

In this paper, a first-order generalized memristor and a polynomial memristor are designed to construct a dual memristive Wien-bridge chaotic system. The proposed system possesses rich dynamic characteristics, including alternating between the periodic state and the chaotic state, variable amplitude and frequency, coexisting attractors, and a locally sustained chaotic state. The dynamic behaviors are obtained and investigated by using Lyapunov exponents, bifurcation diagrams, phase portraits, time-domain waveforms, frequency spectra, and so on. The presented chaotic system is implemented by using a digital signal processing platform. Finally, the National Institute of Standards and Technology test is conducted in this paper. Since the system has rich dynamic behaviors, it has great potential value in encryption engineering fields.

Sensitive indicators of Stipa bungeana response to precipitation under ambient and elevated CO2 concentration.

Precipitation is a primary environmental factor in the semiarid grasslands of northern China. With increased concentrations of atmospheric greenhouse gases, precipitation regimes will change, and high-impact weather events may be more common. Currently, many ecophysiological indicators are known to reflect drought conditions, but these indicators vary greatly among species, and few studies focus on the applicability of these drought indicators under high CO2 conditions. In this study, five precipitation levels (- 30%, - 15%, control, + 15%, and + 30%) were used to simulate the effects of precipitation change on 18 ecophysiological characteristics in Stipa bungeana, including leaf area, plant height, leaf nitrogen (N), and chlorophyll content, among others. Two levels of CO2 concentration (ambient, 390 ppm; 550 ppm) were used to simulate the effects of elevated CO2 on these drought indicators. Using gray relational analysis and phenotypic plasticity analysis, we found that total leaf area or leaf number (morphology), leaf water potential or leaf water content (physiology), and aboveground biomass better reflected the water status of S. bungeana under ambient and elevated CO2 than the 13 other analyzed variables. The sensitivity of drought indicators changed under the elevated CO2 condition. By quantifying the relationship between precipitation and the five most sensitive indicators, we found that the thresholds of precipitation decreased under elevated CO2 concentration. These results will be useful for objective monitoring and assessment of the occurrence and development of drought events in S. bungeana grasslands.

Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting.

Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.

miR-497 accelerates oxidized low-density lipoprotein-induced lipid accumulation in macrophages by repressing the expression of apelin.

microRNAs (miRNAs) play important roles in the pathogenesis of atherosclerosis. A previous study has reported that miR-497 is elevated in advanced atherosclerotic lesions in an apoE-deficient (apoE-/-) mouse model. The purpose of this study is to test whether miR-497 can modulate macrophage foam cell formation, an initiating event in atherosclerosis. We found that miR-497 was upregulated in THP-1 macrophages after treatment with oxidized low-density lipoprotein (oxLDL). Enforced expression of miR-497 promoted lipid accumulation and decreased cholesterol efflux in oxLDL-exposed THP-1 macrophages. In contrast, downregulation of miR-497 suppressed oxLDL-induced lipid accumulation in THP-1 macrophages. Apelin was identified to be a downstream target of miR-497. Overexpression of miR-497 significantly reduced the expression of apelin in THP-1 macrophages. Interestingly, delivery of a miR-497-resistant variant of apelin significantly inhibited lipid accumulation and enhanced cholesterol efflux in miR-497-overexpressing THP-1 macrophages in response to oxLDL. In addition, miR-497 expression was increased and negatively correlated with apelin protein expression in human atherosclerotic lesions. In conclusion, miR-497 contributes to oxLDL-induced lipid deposition in macrophages largely via targeting of apelin and thus represents a potential therapeutic target for atherosclerosis.

Elevated CO2 can modify the response to a water status gradient in a steppe grass: from cell organelles to photosynthetic capacity to plant growth.

BACKGROUND: The atmospheric CO2 concentration is rising continuously, and abnormal precipitation may occur more frequently in the future. Although the effects of elevated CO2 and drought on plants have been well reported individually, little is known about their interaction, particularly over a water status gradient. Here, we aimed to characterize the effects of elevated CO2 and a water status gradient on the growth, photosynthetic capacity, and mesophyll cell ultrastructure of a dominant grass from a degraded grassland. RESULTS: Elevated CO2 stimulated plant biomass to a greater extent under moderate changes in water status than under either extreme drought or over-watering conditions. Photosynthetic capacity and stomatal conductance were also enhanced by elevated CO2 under moderate drought, but inhibited with over-watering. Severe drought distorted mesophyll cell organelles, but CO2 enrichment partly alleviated this effect. Intrinsic water use efficiency (WUEi) and total biomass water use efficiency (WUEt) were increased by elevated CO2, regardless of water status. Plant structural traits were also found to be tightly associated with photosynthetic potentials. CONCLUSION: The results indicated that CO2 enrichment alleviated severe and moderate drought stress, and highlighted that CO2 fertilization's dependency on water status should be considered when projecting key species' responses to climate change in dry ecosystems.

Assessing the impact of general practitioner team service on perceived quality of care among patients with non-communicable diseases in China: a natural experimental study.

OBJECTIVE: China issued the national primary care policy of promoting general practitioner (GP) team service in 2011. We conducted this study to assess the impact of the GP team service on quality of primary care as perceived by patients with non-communicable diseases (NCDs). DESIGN: Natural experimental study. SETTING: This study was conducted in Shanghai, where the policy was effectively implemented, and Kunming, where the policy was not implemented. PARTICIPANTS: In both cities, NCD patients were interviewed with primary care assessment tool (PCAT) after their clinical consultations in their community health centers. INTERVENTION: The implementation of GP team service policy. MAIN OUTCOME MEASURES: Multiple linear regressions were employed to compare PCAT scores between the two rounds of the surveys in each city. Difference-in-difference (DID) analysis was used to identify the changes between two cities over time. RESULTS: A total of 663 and 587 patients in Shanghai, and 400 and 441 patients in Kunming were surveyed in 2011 and 2013, respectively. The DID analysis showed that the total primary care quality scores improved in Shanghai compared with Kunming between 2011 and 2013 (ß = 1.30, 95% CI: 0.74, 1.87). In Shanghai, care quality in 2013 improved significantly for the total score and the six components when compared with those in 2011. No significant changes were observed in Kunming in the same period. CONCLUSION: Primary care policies that promote long-term provider-patient relationships, coordinated service with hospitals and capitation payment for the GP team may contribute to the improvement of care quality in Shanghai.

How does China's big data policy affect the digital economy of cities? Evidence from national big data comprehensive pilot zones.

Based on the panel data of 280 cities in China from 2011 to 2019, this paper examines the effects of big data policies on the digital economy development by using the national big data comprehensive pilot zones as a quasi-natural experiment. The findings of this paper are as follows. First, the big data policy significantly promotes China's digital economy development. Second, cities at a higher administrative level receive higher policy benefits than cities at a lower administrative level. Third, technological innovation and human capital are important ways for the big data policy to improve the development of the digital economy. The conclusions of this paper not only help to assess the effectiveness of big data policies and ensure the efficacy of policy implementation, but also provide policy support for local governments to fully explore the value of data elements and grasp the new opportunities for the digital economy development with the help of the pilot zones.

Mining the sustainability of takeaway businesses in online food delivery service supply chain.

The online food delivery service supply chain constitutes a crucial element in achieving sustainable development goals. With its prosperity, an increasing number of takeaway businesses are drawn to this sector. As their numbers rise, issues such as profitability resilience, environmental friendliness, and fulfillment of social responsibility emerge, posing potential disruptions to the service supply chain. Against this backdrop, our endeavor is to mine the sustainability of takeaway businesses using the triple bottom line. We propose a two-stage approach involving the Bayesian best-worst method and a data mining technique to derive the weights of sustainability criteria and the clusters of takeaway businesses. Subsequently, a case study is conducted focusing on takeaway businesses on the Ele.me platform in China. The results highlight economic sustainability as the most valued criterion, followed by social and environmental sustainability. Clustering outcomes reveal four distinct levels of sustainability, with a stronger performance in social sustainability compared to environmental and economic dimensions. Further discussions explore the relationship between sustainability levels, cuisine categories, and business size. Consequently, this study suggests an effective approach for advancing sustainability initiatives within the online food delivery service supply chain.

Establishment and comparison of different procedures for modeling intrauterine adhesion in rats: A preliminary study.

The establishment of a stable animal model for intrauterine adhesion (IUA) can significantly enhance research on the pathogenesis and pathological changes of this disease, as well as on the development of innovative therapeutic approaches. In this study, three different modeling methods, including phenol mucilage combined mechanical scraping, ethanol combined mechanical scraping and ethanol modeling alone were designed. The morphological characteristics of the models were evaluated. The underlying mechanisms and fertility capacity of the ethanol modeling group were analyzed and compared to those of the sham surgery group. All three methods resulted in severe intrauterine adhesions, with ethanol being identified as a reliable modeling agent and was subsequently subjected to further evaluation. Immunohistochemistry and RT-PCR results indicated that the ethanol modeling group exhibited an increase in the degree of fibrosis and inflammation, as well as a significant reduction in endometrial thickness, gland number, vascularization, and endometrial receptivity, ultimately resulting in the loss of fertility capacity. The aforementioned findings indicate that the intrauterine perfusion of 95 % ethanol is efficacious in inducing the development of intrauterine adhesions in rats. Given its cost-effectiveness, efficacy, and stability in IUA formation, the use of 95 % ethanol intrauterine perfusion may serve as a novel platform for evaluating innovative anti-adhesion materials and bioengineered therapies.

Tannic acid-assisted fabrication of antibacterial sodium alginate-based gel beads for the multifunctional adsorption of heavy metal ions and dyes.

The existence of heavy metals and dyes seriously affects the ecological environment and human safety. Antibacterial adsorption materials with the broad-spectrum removal of multiple pollutants are urgently required for water remediation. Herein, a sustainable and antibacterial sodium alginate (SA) gel bead adsorbent with honeycomb cellular architecture is developed by the biomimetic deposition polyphenolic tannic acid (TA) induced grafting diethylenetriamine (DETA) under mild conditions for efficient removal of Cr(VI) and dyes. Taking advantage of the catechol surface chemistry, TA occurring rapid polymerization with DETA monomers not only enhances the water resistance and thermal stability of the gel bead, but also introduces abundant polyphenolic functional groups and active adsorption sites. The multifunctional gel bead showed outstanding antibacterial activity against S. aureus (sterilization rates: 83.8 %) and E. coli (sterilization rates: 99.5 %). The maximum adsorption capacity of gel bead for Cr(VI) was 163.9 mg/g. Moreover, the removal efficiency of the gel bead for dyes of Safranine T and Rhodamine B was 89.5 % (maximum adsorption capacity: 537 mg/g) and 76.7 % (maximum adsorption capacity: 460.2 mg/g), respectively, indicating its excellent broad-spectrum adsorption performance for multiple pollutants. Therefore, TA-assisted fabrication of SA-based gel bead with excellent antibacterial property is a promising multifunctional adsorption material for practical water remediation.

Noval green sodium alginate/gellan gum aerogel with 3D hierarchical porous structure for highly efficient and selective removal of Congo red from water.

Rational design of adsorbed materials with three-dimensional (3D) hierarchical porous structure, sustainable, high adsorption capacity, and excellent selective is of great significance in practical applications. Herein, a novel aerogel adsorbed material with 3D hierarchical porous architecture was fabricated by employing naturally abundant sodium alginate (SA)/gellan gum (GG) as basic construction blocks to achieve sustainability as well as applying polyethyleneimine (PEI) as functional material for highly efficient and selective capture of Congo red (CR). The aerogel sorbent exhibited strong microstructure, numerous active adsorption sites and being ultralight. The resulting aerogel adsorbent showed high adsorption capacity (3017.23 mg/g) toward CR, exceedingly most previously reported sorbents. Furthermore, the aerogel adsorbent was accompanied by outstanding selectivity for CR in four binary dye systems. Meanwhile, after 3 cycles, the adsorption capacity decreased by 14.8 %, but still maintained the adsorption capacity of 559.79 mg/g. Therefore, excellent adsorption performance, and superb selectivity prefigures its great prospects for wastewater purification.

Breast cancer cells interact with tumor-derived extracellular matrix in a molecular subtype-specific manner.

Mimicking the native microenvironment is vital for tumor engineering. Breast cancer is a highly heterogeneous disease with various molecular subtypes exhibiting distinct biological behaviors and treatment responsiveness. The heterogeneity of extracellular matrix (ECM) of breast cancer has remained largely unexplored and underestimated. The present study addressed this issue by comparing the composition, architecture, and functional roles of ECMs derived from breast cancers of two molecular subtypes, which are luminal-A breast cancer (less aggressive, ERα+)-derived ECM (LA-ECM) and triple-negative breast cancer (high aggressive, ERα-)-derived ECM (TN-ECM). Compared with normal breast tissue-derived ECMs (B-ECM), tumor-derived ECMs showed higher contents of pro-collagen I, fibronectin, and laminin, in addition with a significantly altered architecture. Transcriptome sequencing revealed that, compared with those cultured with B-ECM, MCF7 cells (an estrogen receptor (ER)α + luminal-A breast cancer cell line) cultured with LA-ECM and TN-ECM showed approximately 9.65 % and 9.04 % changes in the expression of all detected genes, respectively. The TN-ECM induced proliferation, promoted epithelial-to-mesenchymal transition, downregulated ERα expression, and reduced endocrine treatment sensitivity of MCF7. Above results have elucidated the role of phenotype-specific tumor ECM in cell phenotype maintenance, treatment sensitivity, and cancer progression, which highlighted the importance of ECM heterogeneity as well as its role in tumor microenvironment engineering and drug screening.

Triptolide attenuates CCL4-induced liver fibrosis by regulating the differentiation of CD4+ T cells in mice.

Liver fibrosis is a major global health issue, and immune dysregulation is a main contributor. Triptolide is a natural immunosuppressive agent with demonstrated effectiveness in ameliorating liver fibrosis, but whether it exerts anti-liver fibrotic effects via immunoregulation remains obscure. In this study, first, by employing a CCL4-induced liver fibrosis mouse model, we demonstrated that triptolide could alleviate pathological damage to liver tissue and attenuate liver function damaged by CCL4. In addition, triptolide inhibited the expression of liver fibrotic markers such as hydroxyproline, collagen type IV, hyaluronidase, laminin, and procollagen type III, and the protein expression of α-SMA in CCL4-induced liver fibrosis. Second, with the help of network pharmacology, we predicted that triptolide's anti-liver fibrotic effects might occur through the regulation of Th17, Th1, and Th2 cell differentiation, which indicated that triptolide might mitigate liver fibrosis via immunoregulation. Finally, multiplex immunoassays and flow cytometry were adopted to verify this prediction. The results suggested that triptolide could reverse the aberrant expression of inflammatory cytokines caused by CCL4 and regulate the differentiation of Th1, Th2, Th17, and Treg cells. In conclusion, triptolide could attenuate CCL4-induced liver fibrosis by regulating the differentiation of CD4+ T cells. The results obtained in this study extended the application of triptolide and introduced a new mechanism of triptolide's anti-liver fibrotic effects.

A new methodology of understanding the mechanism of high shear wet granulation based on experiment and molecular dynamics simulation.

In high shear wet granulation (HSWG), the interaction mechanism between binder and powder with different sugar content is still unclear. Herein, the law and mechanism of the interaction between binder and powder were studied on the molecular level by combining experiment analysis through the Kriging model and molecular dynamics (MD) simulation. For the sticky powder with high sugar content, the ethanol in the binder played a pivotal role in dispersing water into powders, and the amount of water determined the growth of granules. In the saturating stage, the reduction of sugar content facilitates the penetration of ethanol molecules. The concentration of ethanol determines whether the mixture is blended uniformly in the merging stage. The simulation results are consistent with the actual situation and explain the competition mechanism of interaction with binder and powder. Therefore, this research offers an efficient strategy for the in-depth understanding of the HSWG process where the powder is sticky, as well as providing guidelines for the practical application of preparation for Traditional Chinese Medicine (TCM) granules.

Evolution characteristics of micromechanics provides insights into the microstructure of pharmaceutical tablets fabricated by bimodal mixtures.

This research focuses on the evolution of mechanical behavior of bimodal mixtures undergoing compaction and diametrical compression. The clusters were built and discrete element method (DEM) was used to investigate the densification process and micromechanics of bimodal mixtures. Additionally, a more comprehensive investigate of the respective breakage of the bimodal mixtures has been carried out. On this basis, qualitative and quantitative analysis of the compressive force, force chain, contact bonds and density field evolution characteristics of the clusters are investigated during the compression process. The entire loading process of the clusters is divided into three stages: rearrangement, breakage and elastic-plastic deformation. Additionally, there are differences in the evolution of micromechanics behavior of different particles in the bimodal mixture, with pregelatinized starch breakage and deformation occurring before microcrystalline cellulose. With the tablet deformation, the fragmentation process of the tablet started at the point of contact and extended toward the center, and the curvature of the force chain increased. This approach may potentially hold a valuable new information relevant to important transformation forms batch manufacturing to advanced manufacturing for the oral solid dosage form.