Programmable DNA Scaffolds Enable Orthogonal Engineering of Cell Membrane-Based Nanovesicles for Therapeutic Development.

Cell membrane-based nanovesicles (CMNVs) play pivotal roles in biomolecular transportation in living organisms and appear as attractive bioinformed nanomaterials for theranostic applications. However, the current surface-engineering technologies are limited in flexibility and orthogonality, making it challenging to simultaneously display multiple different ligands on the CMNV surface in a precisely controlled manner. Here, we developed a DNA scaffold-programmed approach to orthogonally engineer CMNVs with versatile ligands. The designed DNA scaffolds can rapidly anchor onto the CMNV surface, and their unique sequences and hybridized properties enable independent control of the loading of multiple different types of biomolecules on the CMNVs. As a result, the orthogonal engineering of CMNVs with a renal targeted peptide and a therapeutic protein at controlled ratios demonstrated an enhanced renal targeting and repair potential in vivo. This study highlights that a DNA scaffold-programmed platform can provide a potent means for orthogonal and flexible surface engineering of CMNVs for diverse therapeutic purposes.

The transcription factor PbrbZIP52 positively affects pear pollen tube longevity by promoting callose synthesis.

In pear (Pyrus bretschneideri), pollen tube growth is critical for the double fertilization associated with seed setting, which in turn affects fruit yield. The normal deposition of callose mediates the polar growth of pollen tubes. However, the mechanism regulating callose synthesis in pollen tubes remains relatively uncharacterized. In this study, we revealed that the typical pear pollen tube lifecycle has a semi-growth duration (GD50) of 16.16 h under in vitro culture conditions. Moreover, callose plugs were deposited throughout the pollen tube lifecycle. The formation of callose plugs was inhibited by 2-deoxy-D-glucose, which also accelerated the senescence of pear pollen tubes. Additionally, PbrCalS1B.1, which encodes a plasma membrane-localized callose synthase, was expressed specifically in pollen tubes and restored the fertility of the Arabidopsis (Arabidopsis thaliana) cals5 mutant, in which callose synthesis is inhibited. However, this restoration of fertility was impaired by the transient silencing of PbrCalS1B.1, which restricts callose plug formation and shortens the pear pollen tube lifecycle. More specifically, PbrbZIP52 regulated PbrCalS1B.1 transcription by binding to promoter A-box elements to maintain the periodic formation of callose plugs and normal pollen tube growth, ultimately leading to double fertilization. This study confirmed that PbrbZIP52 positively affects pear pollen tube longevity by promoting callose synthesis. This finding may be useful for breeding high-yielding pear cultivars and stabilizing fruit setting in commercial orchards.

Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis.

Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after P. multocida infection. Given the complexity of P. multocida infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during P. multocida infection. Our findings reveal that P. multocida infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1/2, p-Lats1, and p-Yap, and downregulating the downstream effectors Birc5, Cyr61, and Slug. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that P. multocida induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during P. multocida infection. P. multocida-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that P. multocida activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in P. multocida infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis.

Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

Dissociated contributions of working memory and inhibitory control to children's and adults' analogical reasoning: Analogical strategies matter.

This study investigated whether and how each component of working memory (WM) and inhibitory control (IC) is related to analogical reasoning. Specifically, the mediating roles of analogical strategies were examined and compared across children and adults. In total, 79 children (50 girls; M ± SD = 8.43 ± 0.59 years old) and 77 adults (35 female; 19.44 ± 0.82 years old) were administered tests of WM, IC, and analogical reasoning. In addition, participants' eye movement data during the analogical reasoning task were collected to classify the analogical strategies. The results showed that the semantic-constraint strategy completely mediated the relationship between WM (rather than IC) and analogical reasoning for children. However, for adults, the project-first strategy partially mediated the association between IC (rather than WM) and analogical reasoning. These findings reveal the dissociated roles of WM and IC in analogical reasoning through analogical strategies for children and adults and highlight the importance of analogical strategies.

Training and asymmetrical transfer effects of working memory and inhibitory control in primary school children.

Working memory (WM) and inhibitory control (IC) are two fundamental and supportive components of executive function (EF) that are critical for school-age children. However, the direct comparison of the training and transfer effects of WM and IC training in school-age children still needs to be improved. This study adopted a "pre-, post-, and delayed posttest" design to compare the training, near-transfer, and far-transfer effects of WM and IC in school-age children. A total of 60 children aged 8 to 10 years were randomly assigned to the WM training group, IC training group, or control group. Children in the WM and IC training groups completed 12 sessions of multiple adaptive training tasks tapping different subcomponents of WM (visual-spatial and verbal WM) and IC (interference control and response inhibition) separately. In the pretraining, posttraining, and 6-month follow-up stages, we used WM and IC tasks to evaluate training and near-transfer effects and used analogical reasoning tasks to evaluate far-transfer effects. Results showed significant training effects on visual-spatial and verbal WM, near-transfer effects on response inhibition, and far-transfer effects on analogical reasoning for WM training in the posttraining stage. The improvements in verbal WM and analogical reasoning were maintained for 6 months, whereas for IC training only the training effects on response inhibition and the far-transfer effects on analogical reasoning were observed in the posttraining stage and only the training effects on response inhibition were maintained for 6 months. Results suggested positive training and asymmetrical transfer effects of WM and IC training, which provide new evidence for the effectiveness of WM and IC training in school-age children.

Plant green pigment of chlorophyllin attenuates inflammatory bowel diseases by suppressing autophagy activation in mice.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are intestinal complications characterized by chronic inflammation, autophagy abnormality, and lysosomal stress, which are derived from genetic predisposition and environmental risk factors. It is generally precepted that dietary green vegetable is beneficial for physiological homeostasis. In this study, we found that dextran sulfate sodium (DSS)-induced colitis and altered intestinal epithelia in mice were attenuated by oral administration of chlorophyllin (CHL), a water-soluble derivate of chlorophyll. In DSS-treated mice, autophagy was persistently activated in intestinal tissues and associated with bowel disorders. Conversely, supplement of CHL in diet or gavage suppressed intestinal inflammation, downregulated autophagy flux in intestinal tissue, and relieved endoplasmic reticulum stress. In vitro studies show that CHL could activate Akt and mTOR pathways, leading to downregulation of autophagic and lysosomal flux. Thus, consumption of green vegetables and chlorophyllin may be beneficial for IBD recovery in part through alleviation of inflammation and autolysosomal flux.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal disease, while the etiology remains poorly understood. Dietary composition and lifestyle are crucial for pathogenesis and progression of IBD. In this study, we observed that autophagy in the intestinal tissue was persistently activated in IBD mice. Chlorophyllin (CHL), a water-soluble derivate of chlorophyll, can attenuate colitis by regulating autophagy and inflammation. Thus, consumption of green vegetables and chlorophyllin may be beneficial for IBD recovery.

Genome-Based Analysis of Aspergillus niger Aggregate Species from China and Their Potential for Fumonisin B2 and Ochratoxin A Production.

Based on entire genome sequencing, this study focused on the classification of Aspergillus niger aggregation species and investigated their potential for fumonisin B2 (FB2) and ochratoxin A (OTA) production. In the current study, 22 strains were used, namely 17 A. niger strains, four A. welwitschiae strains, and one A. lacticoffeatus (a synonym of A. niger) strain. Traditional multigene phylogenetic analysis, average nucleotide identity analysis (ANI), and the whole-genome single-nucleotide polymorphism (SNP) analyses were used to reconfirm the taxonomic status of A. niger, A. welwitschiae, and A. lacticoffeatus. The ability of A. niger to produce FB2 and OTA on five culture substrates was determined, and the association between FB2 and OTA gene clusters and toxin-producing abilities was explored. The results revealed that the ANI method could distinguish A. niger from A. welwitschiae, with an ANI value of < 98%. The SNP-based phylogenetic analysis suggested that A. niger and A. welwitschiae were two independent phylogenetic species. The ANI, SNP, and multigene phylogenetic analysis supported previous findings that A. lacticoffeatus was a synonymous species of A. niger. Aspergillus niger strains exhibited the varied potential of producing FB2 and OTA on different culture media. The A. niger genome sequence analysis revealed no significant difference in fumonisin gene clusters between FB2-nonproducing isolates and FB2-producing isolates, and the integrity of the ochratoxin biosynthesis genes cluster was clearly associated with OTA production. In conclusion, gene sequencing can be useful in assessing A. niger's ability to produce OTA, but it cannot reliably predict its ability to produce FB2.

Evaluation of MTBH, a novel hesperetin derivative, on the activity of hepatic cytochrome P450 isoform in vitro and in vivo using a cocktail method by HPLC-MS/MS.

1. 8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone (MTBH), a novel hesperidin derivative, has potential in the prevention of hepatic disease, however, its effects on cytochrome P450 isoforms (CYP450s) remains unexplored. The purpose was to investigate the effects of MTBH on the mRNA, protein levels, and activities of six CYP450s (1A2, 2C11/9, 2D2/6, 3A1/4, 2C13/19, and 2E1) in vitro and in vivo.2. In vitro study, rat and human liver microsomes were adopted to elucidate the inhibitory effect of MTBH on six CYP450s using probe drugs. In vivo study, Sprague-Dawley male rats were treated with MTBH (25, 50, or 100 mg/kg for 28 consecutive days), phenobarbital (80 mg/kg for 12 consecutive days), or 0.5% CMC-Na solution (control group) by intragastric administration, then, the mRNA, protein levels and activities of liver CYP450s were analysed by real-time PCR, western blotting and probe-drug incubation systems, respectively.3. The in vitro study indicated that MTBH inhibits the activities of CYP3A1/4 and CYP2E1 in rat and human liver microsomes. In vivo data showed that MTBH inhibits mRNA, protein levels, and activities of CYP3A1 and CYP2E1 in medium- and high-dose MTBH groups.4. MTBH has the potential to cause drug-drug interactions when co-administered with drugs that are metabolised by CYP3A1/4 and CYP2E1.

Mucor rongii sp. nov., a New Cold-Tolerant Species from China.

Two strains of a new mucoralean fungus (M1 and R1) were harvested from the moist walls of Sufu workshop in Liaocheng city, Shandong province, China. Internal transcribed spacer (ITS) and the large subunit (LSU) rDNA region D1/D2 domain-based phylogenetic analysis, along with phenotypic characteristics, revealed that the strains belonged to a new genus in the Mucor category. This new category belongs to Mucor flavus complex. However, unlike M. flavus CBS 234.25 (the type species of the complex), the novel species could grow well at 25 °C and not grow at 28 °C. Moreover, the ITS rDNA sequence similarity of the two species was only 96%. Here, we present the new category Mucor rongii sp. nov. Its holotype is HMAS 248,091, the ex-type culture is M1T (= CICC 41725T), and the other culture examined was R1 (= CICC 41,726).

Internet of Things: The Optimal Generation Rates under Preemption Strategy in a Multi-Source Queuing System.

With the rapid development and wide application of the Internet of Things (IoT), how to provide timely and fresh information for strategic analysis and decision-making has become a key issue. Recent studies have shown that preemption strategies are of great importance to the improvement of information freshness. In view of this, we focus on the multi-source preemptive queuing model and investigate how to control the generation rate of each source to achieve the optimal overall information freshness. Specifically, we consider two typical preemption strategies: self-preemption strategy and global-preemption strategy. Noting that the urgency requirements of the systems on the data of each source are different, we propose the weighted average age of information (AoI) to characterize the overall information freshness of the system. For the self-preemption strategy, we prove that the optimal generation rate allocation is a convex problem and present an efficient algorithm to find the optimal solution. Additionally, we also derive a closed-form approximate optimal solution under light load cases to meet the demands for rapid deployment. For the global-preemption strategy, we directly derive the closed-form optimal solution of the corresponding problem. By comparing the optimized weighted average AoIs, the performance achieved by the global-preemption system was better than that achieved by the self-preemption system in terms of the overall timeliness. The numerical analysis verified the correctness of the theoretical analysis and that the proposed approximate solution had high accuracy not only under light load cases but also under other cases.

[Effect of active component compound of Epimedii Folium,Astragali Radix,and Puerariae Lobatae Radix on expression of ADAM17 in HT22 cells by mediating hepcidin].

Alzheimer's disease(AD) patients in China have been surging, and the resultant medical burden and care demand have a huge impact on the development of individuals, families, and the society. The active component compound of Epimedii Folium, Astragali Radix, and Puerariae Lobatae Radix(YHG) can regulate the expression of iron metabolism-related proteins to inhibit brain iron overload and relieve hypofunction of central nervous system in AD patients. Hepcidin is an important target regulating iron metabolism. This study investigated the effect of YHG on the expression of a disintegrin and metalloprotease-17(ADAM17), a key enzyme in the hydrolysis of ß amyloid precursor protein(APP) in HT22 cells, by mediating hepcidin. To be specific, HT22 cells were cultured in vitro, followed by liposome-mediated siRNA transfection to silence the expression of hepcidin. Real-time PCR and Western blot were performed to examine the silencing result and the effect of YHG on hepcidin in AD cell model. HT22 cells were randomized into 7 groups: control group, Aß25-35 induction(Aß) group, hepcidin-siRNA(siRNA) group, Aß25-35 + hepcidin-siRNA(Aß + siRNA) group, Aß25-35+YHG(Aß+YHG) group, hepcidin-siRNA+YHG(siRNA+YHG) group, Aß25-35+hepcidin-siRNA+YHG(Aß+siRNA+YHG) group. The expression of ADAM17 mRNA in cells was detected by real-time PCR, and the expression of ADAM17 protein by immunofluorescence and Western blot. Immunofluorescence showed that the ADAM17 protein expression was lower in the Aß group, siRNA group, and Aß+siRNA group than in the control group(P<0.05) and the expression was lower in the Aß+siRNA group(P<0.05) and higher in the Aß+YHG group(P<0.05) than in the Aß group. Moreover, the ADAM17 protein expression was lower in the Aß+siRNA group(P<0.05) and higher in the siRNA+YHG group(P< 0.05) than in the siRNA group. The expression was higher in the Aß+siRNA+YHG group than in the Aß+siRNA group(P<0.05). The results of Western blot and real-time PCR were consistent with those of immunofluorescence. The experiment showed that YHG induced hepcidin to up-regulate the expression of ADAM17 in AD cell model and promote the activation of non-starch metabolic pathways, which might be the internal mechanism of YHG in preventing and treating AD.

Liver Injury Impaired 25-Hydroxylation of Vitamin D Suppresses Intestinal Paneth Cell defensins, leading to Gut Dysbiosis and Liver Fibrogenesis.

Vitamin D deficiency is co-prevalent with various liver diseases including cirrhosis, while the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulates the intestinal Paneth cells and their production of defensins to restrain microbiome growth in the small intestine. In this study we found that in carbon tetrachloride-induced liver injury, hepatic 25-hydroxylation of vitamin D was impaired, leading to down regulated expression of Paneth cell fensins in the small intestine, gut dysbiosis, and endotoxinemia. While intraperitoneal injection of endotoxin (lipopolysaccharides) alone did not elicit liver fibrosis, it exacerbated the carbon tetrachloride initiated liver fibrogenesis. Oral gavage of synthetic Paneth cell alpha-defensin 5 (DEFA5) restored the homeostasis of gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, Cholestyramine, cationic resin that can sequestrate endotoxin in the intestine, attenuated the liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdrconditional knockout mice exhibited reduction of Paneth cell defensins and lysozyme production, and worsened liver injury and fibrogenesis. Thus, liver injury impairs synthesis of 25(OH)VD3, which consequently impedes the Paneth cells functions in the small intestine, leading to gut dysbiosis for liver fibrogenesis.

Novosphingobium clariflavum sp. nov., isolated from a household product plant.

A Gram-stain-negative, rod-shaped, bright-yellow-pigmented bacterium, designated 164T, was isolated from a used sponge for equipment cleaning at a household product plant in China. The 16S rRNA gene sequence comparisons indicated that strain 164T was most closely related to Novosphingobium panipatense DSM 22890T (98.28 % similarity) and shared sequence similarities of 97.73-98.27 % with other members of the genus Novosphingobium. In DNA-DNA hybridization studies the relatedness between strain 164T and its closest phylogenetic neighbours was <70 %, which indicated that strain 164T represented a novel species of the genus Novosphingobium. The DNA G+C content of strain 164T was 65.9 mol%. The major respiratory quinone was ubiquinone Q-10 (83.5 %) with minor amounts of Q-9 (16.5 %). The polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, sphingoglycolipid, phosphatidylcholine, unidentified aminolipids and unidentified aminophospholipids. Spermidine was the major polyamine. The major fatty acids were summed feature 8 (consisting of C18 : 1ω7c and/or C18 : 1ω6c) and C14 : 0 2-OH. The results obtained from phylogenetic analysis, DNA-DNA hybridization, and chemotaxonomic and phenotypic analysis support the conclusion that strain 164T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium clariflavum sp. nov. is proposed. The type strain is 164T (=CICC 11035sT=DSM 103351T).

Halomonas alkalicola sp. nov., isolated from a household product plant.

A Gram-stain-negative, alkaliphilic and moderately halophilic bacterium, designated 56-L4-10aEnT, was isolated from a household product plant in China. Cells of the novel isolate were rod-shaped, non-spore-forming and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 56-L4-10aEnT belongs to the genus Halomonas, with the six closest neighbours being Halomonas mongoliensis Z-7009T (97.59 % 16S rRNA gene sequence similarity), Halomonas ventosae Al12T (97.35 %), Halomonas campaniensis 5AGT (97.22 %), Halomonas alimentaria YKJ-16T (97.22 %), Halomonas shengliensis SL014B-85T (97.12 %) and Halomonas fontilapidosi 5CRT (97.09 %). The main polar lipids of strain 56-L4-10aEnT contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The predominant respiratory quinone was Q-9, with Q-8 as a minor component. The major fatty acids were C18 : 1ω7c/C18 : 1ω6c and C16 : 0. Strain 56-L4-10aEnT was clearly distinguished from the type strains mentioned above through phylogenetic analysis, DNA-DNA hybridization, fatty acid composition data and a range of physiological and biochemical characteristics comparisons. It is evident from the genotypic and phenotypic data that strain 56-L4-10aEnTcould be classified as a representative of a novel species of the genus Halomonas, for which the name Halomonas alkalicola sp. nov. is proposed. The type strain is 56-L4-10aEnT (=CICC 11012sT=DSM 103354T).

Enhancing milk quality and modulating rectal microbiota of dairy goats in starch-rich diet: the role of bile acid supplementation.

BACKGROUND: Diets rich in starch have been shown to increase a risk of reducing milk fat content in dairy goats. While bile acids (BAs) have been used as a lipid emulsifier in monogastric and aquatic animals, their effect on ruminants is not well understood. This study aimed to investigate the impact of BAs supplementation on various aspects of dairy goat physiology, including milk composition, rumen fermentation, gut microbiota, and BA metabolism. RESULTS: We randomly divided eighteen healthy primiparity lactating dairy goats (days in milk = 100 ± 6 d) into two groups and supplemented them with 0 or 4 g/d of BAs undergoing 5 weeks of feeding on a starch-rich diet. The results showed that BAs supplementation positively influenced milk yield and improved the quality of fatty acids in goat milk. BAs supplementation led to a reduction in saturated fatty acids (C16:0) and an increase in monounsaturated fatty acids (cis-9 C18:1), resulting in a healthier milk fatty acid profile. We observed a significant increase in plasma total bile acid concentration while the proportion of rumen short-chain fatty acids was not affected. Furthermore, BAs supplementation induced significant changes in the composition of the gut microbiota, favoring the enrichment of specific bacterial groups and altering the balance of microbial populations. Correlation analysis revealed associations between specific bacterial groups (Bacillus and Christensenellaceae R-7 group) and BA types, suggesting a role for the gut microbiota in BA metabolism. Functional prediction analysis revealed notable changes in pathways associated with lipid metabolism, suggesting that BAs supplementation has the potential to modulate lipid-related processes. CONCLUSION: These findings highlight the potential benefits of BAs supplementation in enhancing milk production, improving milk quality, and influencing metabolic pathways in dairy goats. Further research is warranted to elucidate the underlying mechanisms and explore the broader implications of these findings.

The CDK9 inhibitor enitociclib overcomes resistance to BTK inhibition and CAR-T therapy in mantle cell lymphoma.

Inhibitors of Bruton's tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.

The Impact of Air Pollution Controls on Health and Health Inequity Among Middle-Aged and Older Chinese: Evidence From Panel Data.

Objectives: We evaluated the long-term effects of air pollution controls on health and health inequity among Chinese >45 years of age. Methods: Data were derived from the China Health Aging and Retirement Longitudinal Survey and the China National Environmental Monitoring Centre. Decreases in PM2.5 and PM10 were scaled to measure air quality controls. We used a quasi-experimental design to estimate the impact of air quality controls on self-reported health and health inequity. Health disparities were estimated using the concentration index and the horizontal index. Results: Air pollution controls significantly improved self-reported health by 20% (OR 1.20, 95% CI, 1.02-1.42). The poorest group had a 40% (OR 1.41, 95% CI, 0.96-2.08) higher probability of having excellent self-reported health after air pollution controls. A pro-rich health inequity was observed, and the horizontal index decreased after air pollution controls. Conclusion: Air pollution controls have a long-term positive effect on health and health equity. The poorest population are the main beneficiaries of air pollution controls, which suggests policymakers should make efforts to reduce health inequity in air pollution controls.

Gelatin/heparin coated bio-inspired polyurethane composite fibers to construct small-caliber artificial blood vessel grafts.

Long-term patency and ability for revascularization remain challenges for small-caliber blood vessel grafts to treat cardiovascular diseases clinically. Here, a gelatin/heparin coated bio-inspired polyurethane composite fibers-based artificial blood vessel with continuous release of NO and biopeptides to regulate vascular tissue repair and maintain long-term patency is fabricated. A biodegradable polyurethane elastomer that can catalyze S-nitrosothiols in the blood to release NO is synthesized (NPU). Then, the NPU core-shell structured nanofiber grafts with requisite mechanical properties and biopeptide release for inflammation manipulation are fabricated by electrospinning and lyophilization. Finally, the surface of tubular NPU nanofiber grafts is coated with heparin/gelatin and crosslinked with glutaraldehyde to obtain small-caliber artificial blood vessels (ABVs) with the ability of vascular revascularization. We demonstrate that artificial blood vessel grafts promote the growth of endothelial cells but inhibit the growth of smooth muscle cells by the continuous release of NO; vascular grafts can regulate inflammatory balance for vascular tissue remodel without excessive collagen deposition through the release of biological peptides. Vascular grafts prevent thrombus and vascular stenosis to obtain long-term patency. Hence, our work paves a new way to develop small-caliber artificial blood vessel grafts that can maintain long-term patency in vivo and remodel vascular tissue successfully.

The effect of music on pain management in preterm infants during daily painful procedures: a systematic review and meta-analysis.

Background: The present systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to investigate the effects of music on pain management in preterm neonates during painful procedures. Methods: The PubMed, Embase, Web of Science, EBSCO and Cochrane Library databases were searched to identify relevant articles published from their inception to September 2023. The study search strategy and all other processes were implemented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Four RCTs that satisfied the inclusion criteria were included in this meta-analysis. The music group had significantly lower Premature Infant Pain Profile (PIPP) scores during (RR = -1.21; 95% CI = -2.02--0.40, p = 0.0032) and after painful procedures (RR = -0.65; 95% CI = -1.06--0.23, p = 0.002). The music group showed fewer changes in PIPP scores after invasive operations than did the control group (RR = -2.06; 95% CI -3.16--0.96; p = 0.0002). Moreover, our results showed that music improved oxygen saturation during (RR = 3.04, 95% CI = 1.64-4.44, p < 0.0001) and after painful procedures (RR = 3.50, 95% CI = 2.11-4.90, p < 0.00001). However, the change in peak heart rate during and after painful procedures was not statistically significant (RR = -12.14; 95% CI = -29.70-5.41 p = 0.18; RR = -10.41; 95% CI = -22.72-1.90 p = 0.10). Conclusion: In conclusion, this systematic review demonstrated that music interventions are effective for relieving procedural pain in preterm infants. Our results indicate that music can reduce stress levels and improve blood oxygen saturation. Due to the current limitations, large-scale, prospective RCTs should be performed to validate the present results.