Highly Enantioselective Synthesis of Polycyclic Dihydroisoquinolinones via NHC-Catalyzed [4 + 2] Annulations.

The NHC-catalyzed enantioselective [4 + 2] annulation of 9H-fluorene-1-carbaldenydes with cyclic imines was successfully developed. A series of optically enriched polycyclic dihydroisoquinolinones were synthesized in moderate to excellent yields with good to excellent enantioselectivities. In addition, this efficient method could also be amenable to the synthesis of spirocyclic compounds by using isatin-derived ketimines as the electrophiles.

Photocatalyst Au@Ni-MOFs with Different Plasmonic Coverages for Improved Hydrogen Evolution from Water.

Plasmonic materials are fundamental photosensitizer materials for photocatalytic reactions. Various structures, including core-shell types, satellite types, and distribution types, have been designed and prepared for the optimization of photocatalytic reactions. However, understanding the profound enhancement mechanism of various structures is still challenging. Thus, the plasmonic coverage is considered to be an index for analyzing the influence mechanism. Here, Au@Ni-MOF core-shell flower sphere-like photocatalysts are prepared, and the size of the flower sphere can be precisely regulated by varying the amount of Au. Thus, different plasmonic coverages are realized through the tuning of spheres of different sizes. The high plasmonic coverage of catalysts can enhance visible light absorption, facilitate the generation of photogenerated electron-hole pairs, and shorten the photogenerated carrier transport distance. Moreover, the exponential relationship between the photocatalytic hydrogen production performance and the plasmonic coverage can also be used as a guide for material design. As a result, a photocatalytic hydrogen production rate of 3389 µmol·g-1·h-1 is achieved in the Au@Ni-MOF sample with high plasmonic coverage, which will advance the plasmonic application in photocatalytic reactions.

Fluorescent probe for imaging intercellular tension: molecular force approach.

Cellular mechanical force plays a crucial role in numerous biological processes, including wound healing, cell development, and metastasis. To enable imaging of intercellular tension, molecular tension probes were designed, which offer a simple and efficient method for preparing Au-DNA intercellular tension probes with universal applicability. The proposed approach utilizes gold nanoparticles linked to DNA hairpins, enabling sensitive visualization of cellular force in vitro. Specifically, the designed Au-DNA intercellular tension probe includes a molecular spring flanked by a fluorophore-quencher pair, which is anchored between cells. As intercellular forces open the hairpin, the fluorophore is de-quenched, allowing for visualization of cellular force. The effectiveness of this approach was demonstrated by imaging the cellular force in living cells using the designed Au-DNA intercellular tension probe.

FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

Electroacupuncture stimulation modulates functional brain connectivity in the treatment of pediatric cerebral palsy: a case report.

Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

Polyhydroxylated Spirostanol Saponins from the Rhizomes of Paris dulongensis.

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.

The effectiveness and safety of centralized early rehabilitation care for critically ill children with severe acquired brain injury: A retrospective cohort and implementation study.

BACKGROUND: Most children with neurocritical illness are at risk of physical, neurocognitive, and psychosocial sequelae and need centralized early rehabilitation care. OBJECTIVE: To identify the effectiveness and safety of centralized early rehabilitation care for children with severe acquired brain injury. METHODS: This is a mixed methods study-an implementation study and single-center retrospective cohort study with historical control. All children with severe acquired brain injury hospitalized in a specialized rehabilitation center in a comprehensive tertiary pediatric hospital between September 2016 and August 2020 were included. Patients treated in the centralized early rehabilitation unit were compared to historical controls dispersed in the normal inpatient rehabilitation ward. The effectiveness outcomes were measured by the Pediatric Cerebral Performance Category (PCPC) scale and the incidence of newly onset comorbidities. The safety outcomes were indicated by the mortality rate and the incidence of unexpected referrals. RESULTS: One hundred seventy-five patients were included. The delta PCPC scores of the first 4 weeks of inpatient rehabilitation in the intervention group were significantly lower than the control group (Z = -2.395, p = 0.017). The PCPC scores at 1 year in the intervention group were significantly reduced as compared to the control group (Z = -3.337, p = 0.001). The incidence of newly onset pneumonia/bronchitis was also decreased in the intervention group (χ2 = 4.517, p = 0.034). No death of patients was recorded, and there was no significant difference in unexpected referral rate between the two groups (χ2 = 0.374, p = 0.541). CONCLUSIONS: The centralized pediatrics early rehabilitation unit is effective and safe for children with severe acquired brain injury. Further multicenter prospective implementation studies on effectiveness, safety, and economic evaluation are needed.

Strategies for Achieving Ultra-Long ORR Durability-Rh Activates Interatomic Interactions in Alloys.

The stability of platinum-based alloy catalysts is crucial for the future development of proton exchange membrane fuel cells, considering the potential dissolution of transition metals under complex operating conditions. Here, we report on a Rh-doped Pt3Co alloy that exhibits strong interatomic interactions, thereby enhancing the durability of fuel cells. The Rh-Pt3Co/C catalyst demonstrates exceptional catalytic activity for oxygen reduction reactions (ORR) (1.31 A mgPt -1 at 0.9 V vs. the reversible hydrogen electrode (RHE) and maintaining 92 % of its mass activity after 170,000 potential cycles). Long-term testing has shown direct inhibition of Co dissolution in Rh-Pt3Co/C. Furthermore, tests on proton exchange membrane fuel cells (PEMFC) have shown excellent performance and long-term durability with low Pt loading. After 50,000 cycles, there was no voltage loss at 0.8 A cm-2 for Rh-Pt3Co/C, while Pt3Co/C experienced a loss of 200 mV. Theoretical calculations suggest that introducing transition metal atoms through doping creates a stronger compressive strain, which in turn leads to increased catalytic activity. Additionally, Rh doping increases the energy barrier for Co diffusion in the bulk phase, while also raising the vacancy formation energy of the surface Pt. This ensures the long-term stability of the alloy over the course of the cycle.

Biocontrol potential of Cladosporium sphaerospermum against the wheat powdery mildew fungus Blumeria graminis f. sp. tritici.

Cladosporium spp. are known to be mycoparasites and inhibit phytopathogenic fungi. However, so far, little information is available on the impacts of Cladosporium spp. on powdery mildews. Based on the morphological characteristics and molecular analysis, C. sphaerospermum was identified as a mycoparasite on the wheat powdery mildew fungus (Blumeria graminis f. sp. tritici, Bgt, recently named as B. graminis s. str.). C. sphaerospermum was capable of preventing colony formation and conidial distribution of Bgt. The biomasses of Bgt notably decreased by 1.3, 2.2, 3.6 and 3.8 times at 2 dpi, 4 dpi, 6 dpi and 8 dpi, respectively. In addition, biomasses of C. sphaerospermum at 2 dpi, 4 dpi, 6 dpi and 8 dpi significantly increased to 5.6, 13.9, 18.2 and 67.3 times, respectively. In vitro, C. sphaerospermum exudates significantly impaired appressorial formation of Bgt. Thus, C. sphaerospermum acts as a potential biological control agent by suppressing the formation, distribution and development of Bgt conidia and is a viable alternative for managing the wheat powdery mildew. These results suggest that C. sphaerospermum is an antagonistic parasite of the wheat powdery mildew fungus, and hence, provide new knowledge about the biological control of phytopathogenic fungi.

The Effectiveness of Exercise-Based Rehabilitation in People With Hand Osteoarthritis: A Systematic Review With Meta-analysis.

OBJECTIVE: To investigate the effectiveness of exercise-based rehabilitation programs compared with nonexercise intervention or no intervention for people with hand osteoarthritis (OA). DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: We searched 5 databases on July 23, 2023. STUDY SELECTION CRITERIA: We included randomized controlled trials that compared the effectiveness of rehabilitation programs that included an exercise component, with nonexercise intervention or no intervention for people with hand OA. DATA SYNTHESIS: Standardized mean differences (SMDs) were pooled using a random-effects model. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. The certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: Fourteen trials were included in the meta-analysis (n = 1341 participants). In the immediate term (<24 weeks), there was low-certainty evidence of an effect of exercise-based rehabilitation on improving pain (13 trials; SMD = -0.65; 95% CI: -1.06, -0.25), function (11 trials; SMD = -0.35; 95% CI: -0.54, -0.15), and grip strength (14 trials; SMD = 0.21; 95% CI: 0.03, 0.38). There was moderate-certainty evidence of an effect on reducing stiffness (7 trials; SMD = -0.33; 95% CI: -0.51, -0.16). There was low-certainty evidence of no effect on improving pinch strength and quality of life. For the long term (≥24 weeks), there was low-certainty evidence that exercise-based rehabilitation had no additional effect on improving pain, function, and stiffness. CONCLUSION: Exercise-based rehabilitation improved pain, function, stiffness, and grip strength in people with hand OA in the immediate term; the benefits were not maintained in the long term. J Orthop Sports Phys Ther 2024;54(7):1-11. Epub 20 March 2024. doi:10.2519/jospt.2024.12241.

New clinical trial design in precision medicine: discovery, development and direction.

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Clinical and Genetic Analysis of Multiple Idiopathic Cervical Root Resorption.

OBJECTIVE: To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family. METHODS: The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function. RESULTS: The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity. CONCLUSION: A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.

Activation of the p62-Keap1-Nrf2 pathway improves pulmonary arterial hypertension in MCT-induced rats by inhibiting autophagy.

Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62-Keap1-Nrf2 pathway affects the development of PAH by mediating autophagy. A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co-IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62-Keap1-Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.

A Novel Multi-compartment Rotating Bioreactor for Improving ADSC--Spheroid Formation and its Application in Neurogenic Erectile Dysfunction.

OBJECTIVE: The aim of this study was to construct a multicompartment synchronous rotating bioreactor (MCSRB) for batch-production of homogenized adipose-derived stem cell (ADSC) microspheres and treat neurogenic erectile dysfunction (ED). METHODS: Firstly, an MCSRB was constructed using a centrifugal device and hinged trays. Secondly, influence factors (density, rotational speed) on the formation of ADSC-spheroids were explored. Finally, a neurogenic ED model was established to verify the effectiveness and safety of ADSC-spheroids for ED treatment. RESULTS: An MCSRB promoted ADSCs to gather microspheres, most of which were 90-130 µm in diameter. Supernatant from three-dimensional culture led to a significant increase in cytokine expression in ADSCs and migration rate in human umbilical vein endothelial cells (HUVECs) compared to control groups. The erectile function and pathological changes of the penis were improved in the ADSC-spheroids treatment group compared to the traditional ADSCs treatment group (p < 0.01). CONCLUSION: Efficient, batch, controlled and homogenized production of ADSC stem cell microspheres, and effective improvement of erectile dysfunction in neurogenic rats can be achieved using the MCSRB device.

Drug-repurposing by virtual and experimental screening of PFKFB3 inhibitors for pancreatic cancer therapy.

Pancreatic cancer (PC) is the most frequently occurring cancer, with few effective treatments and a 5-year survival rate of only about 11%. It is characterized by stiff interstitium and pressure on blood vessels, leading to an increased glycolytic metabolism. PFKFB3 plays an important role in glycolysis, and its products (fructose-2,6-bisphosphate), which are allosteric PFK1 activators, limit the glycolytic rate. In this study, 14 PFKFB3 inhibitors were obtained by virtually screening the FDA-approved compound library. Subsequently, the in-vitro investigations confirmed that Lomitapide and Cabozantinib S-malate exhibit the excellent potential to inhibit PFKFB3. The combined administration of Lomitapide and Gemcitabine at a certain molar ratio indicated an enhanced anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This investigation provides a new treatment strategy for PC therapy.

Astragaloside IV targeting autophagy of T cells improves inflammation of asthma.

Astragaloside IV (AST) has been confirmed to have antiasthmatic effects. However, the underline mechanism is unclear. The study aimed to explore the treatment mechanism of AST based on autophagy of memory T cells. AST treatment significantly decreased the number of T effector cells in asthma mice blood and the nude mice that received AST-treated TCMs had relieved inflammation compared with the untreated group; meanwhile, we found that AST significantly decreased the autophagy level and inhibited OX40/OX40L signal pathway of lymphocytes. The results highlighted that AST regulated autophagy to inhibit differentiation of effector T-cell phenotype.

Multicomponent chitosan complex/polyvinyl alcohol blended film with full-band UV-shielding performance and excellent antioxidant property for active food packaging.

Utilizing renewable natural resources to construct multifunctional packaging materials is critical to achieving sustainable development in the food packaging industry. In this study, we crafted transparent films with comprehensive UV-shielding and antioxidant properties by blending a multicomponent chitosan complex with polyvinyl alcohol (PVA), subsequently applied to preserve peanut butter. The multicomponent chitosan complex, synthesized from chitosan, ferulic acid (FA), and 5-oxo-3,5-dihydro-2H-thiazolo [3,2-a] pyridine-7-carboxylic acid (TPCA) through direct heating in water, served as the foundation. This chitosan complex was seamlessly blended with PVA, resulting in the creation of a transparent film through the solvent casting method. A meticulous investigation into the chemical structure and physicochemical properties of the blended films was conducted. The FA and TPCA components exhibited robust ultraviolet absorption properties, conferring virtually complete full-band ultraviolet shielding ability to the blend film. Additionally, FA endowed the blended film with significant antioxidant activity. The effectiveness of the chitosan complex/PVA blended film in preserving peanut butter from oxidative spoilage was demonstrated, showcasing its robustness in food preservation. Our research underscores the significance of creating advanced packaging materials from sustainable sources.

Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.