Older people's experiences of hospitalization for surgical intervention for hip fracture: A systematic review.

BACKGROUND: Hip fracture always requires hospitalization with high cost, which cause the complicated experiences and feelings. OBJECTIVE: To inform pre- and in-hospital communication practices between healthcare professionals and patients through a systematic review and qualitative research that synthesizes the experiences and feelings of older patients with hip fracture during the perioperative period. METHODS: We searched the Cochrane Library, PubMed, Web of Science, CINAHL, and three Chinese databases for relevant studies. Qualitative studies were included if they were related to the experiences and needs of hospitalization of older patients with hip fracture. Study quality was evaluated using the 2016 Joanna Briggs Institute quality evaluation criteria for qualitative research, and the results were consolidated using an thematic synthesis approach. RESULTS: Sixteen studies were included in our meta-synthesis. We extracted 58 clear research topics. Eight new categories were formed after induction and integration, which were finally merged into three integrated results. Integration result 1: Patients suffered a large amount of physical and psychological trauma. Integration result 2: A balance of proper protection and independence for patients is required. Integration result 3: Adequate pre-discharge preparation is required. CONCLUSIONS: Our review suggests that healthcare professionals should reduce pain catastrophizing and the fear of falling after surgery among older people with hip fracture. Furthermore, adequate pre-discharge preparation should be made jointly with patients. Meeting patients' diverse needs by various methods will promote active and healthy aging.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3, which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

Comprehensive evaluation framework for intervention on health effects of ambient temperature.

Despite the existence of many interventions to mitigate or adapt to the health effects of climate change, their effectiveness remains unclear. Here, we introduce the Comprehensive Evaluation Framework for Intervention on Health Effects of Ambient Temperature to evaluate study designs and effects of intervention studies. The framework comprises three types of interventions: proactive, indirect, and direct, and four categories of indicators: classification, methods, scope, and effects. We trialed the framework by an evaluation of existing intervention studies. The evaluation revealed that each intervention has its own applicable characteristics in terms of effectiveness, feasibility, and generalizability scores. We expanded the framework's potential by offering a list of intervention recommendations in different scenarios. Future applications are then explored to establish models of the relationship between study designs and intervention effects, facilitating effective interventions to address the health effects of ambient temperature under climate change.

Soil Geobacteraceae are the key predictors of neurotoxic methylmercury bioaccumulation in rice.

Contamination of rice by the potent neurotoxin methylmercury (MeHg) originates from microbe-mediated Hg methylation in soils. However, the high diversity of Hg methylating microorganisms in soils hinders the prediction of MeHg formation and challenges the mitigation of MeHg bioaccumulation via regulating soil microbiomes. Here we explored the roles of various cropland microbial communities in MeHg formation in the potentials leading to MeHg accumulation in rice and reveal that Geobacteraceae are the key predictors of MeHg bioaccumulation in paddy soil systems. We characterized Hg methylating microorganisms from 67 cropland ecosystems across 3,600 latitudinal kilometres. The simulations of a rice-paddy biogeochemical model show that MeHg accumulation in rice is 1.3-1.7-fold more sensitive to changes in the relative abundance of Geobacteraceae compared to Hg input, which is recognized as the primary parameter in controlling MeHg exposure. These findings open up a window to predict MeHg formation and accumulation in human food webs, enabling more efficient mitigation of risks to human health through regulations of key soil microbiomes.

Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

A transferrin receptor targeting dual-modal MR/NIR fluorescent imaging probe for glioblastoma diagnosis.

The prognosis of glioblastoma (GBM) remains challenging, primarily due to the lack of a precise, effective imaging technique for comprehensively characterization. Addressing GBM diagnostic challenges, our study introduces an innovative dual-modal imaging that merges near-infrared (NIR) fluorescent imaging with magnetic resonance imaging (MRI). This method employs superparamagnetic iron oxide nanoparticles coated with NIR fluorescent dyes, specifically Cyanine 7, and targeted peptides. This synthetic probe facilitates MRI functionality through superparamagnetic iron oxide nanoparticles, provides NIR imaging capability via Cyanine 7 and enhances tumor targeting trough peptide interactions, offering a comprehensive diagnostic tool for GBM. Notably, the probe traverses the blood-brain barrier, targeting GBM in vivo via peptides, producing clear and discernible images in both modalities. Cytotoxicity and histopathology assessments confirm the probe's favorable safety profile. These findings suggest that the dual-modal MR\NIR fluorescent imaging probe could revolutionize GBM prognosis and survival rates, which can also be extended to other tumors type.

Dietary branched-chain amino acids intake and new-onset hypertension: a nationwide prospective cohort study in China.

OBJECTIVE: This study aimed to investigate the relationship between dietary branched-chain amino acids (BCAAs) and the risk of developing hypertension. METHODS: A cohort study of 14,883 Chinese adults without hypertension at baseline with were followed for an average of 8.9 years. Dietary intakes of BCAAs, including Ile, Leu, and Val, were collected using 3-day 24-h meal recall and household condiment weighing. Cox proportional hazards regression, restricted cubic splines, interaction analysis, and sensitivity analysis were used to assess the relationship between dietary BCAAs and risk of developing self-reported hypertension, adjusting for age, gender, region, body mass index (BMI), smoking and drinking status, physical activity, energy intake, salt intake. RESULTS: Among 14,883 study subjects, 6386(42.9%) subjects aged ≥ 45 years at baseline, 2692 (18.1%) had new-onset hypertension during the study period, with a median age of 56 years. High levels of dietary BCAAs were associated with an increased risk of new-onset hypertension. Compared with the 41st-60th percentile, multivariable adjusted hazard ratio (HR) for new-onset hypertension was 1.16 (95% CI 1.01-1.32) for dietary BCAAs 61st-80th percentiles, 1.30 (1.13-1.50) for 81st-95th, 1.60 (1.32-1.95) for 96th-100th. The cut-off value of new-onset hypertension risk, total BCAAs, Ile, Leu, and Val were 15.7 g/day, 4.1 g/day, 6.9 g/day, 4.6 g/day, respectively, and the proportion of the population above these intake values were 13.9%, 13.1%, 15.4%, and 14.4%, respectively. Age, BMI, and salt intake had an interactive effect on this relationship (P < 0.001). CONCLUSION: There was a significant positive association between total dietary BCAAs, Ile, Leu, Val intake and the risk of developing hypertension, after adjustment for confounders. This relationship was influenced by age, BMI, and salt intake. Further research is needed to clarify the mechanism and potential role of BCAAs in the pathogenesis of hypertension.

Direct aqueous photochemistry of methylglyoxal and its effect on sulfate formation.

In recent years, among many oxidation pathways studied for atmospheric sulfate formation, the aqueous phase oxidation pathways of H2O2 and organic hydroperoxides (ROOHs) have attracted great scientific attention. Higher concentrations of H2O2 and ubiquitous ROOHs have been observed in atmospheric aqueous phase environments (cloud water, fog droplets, etc.). However, there are still some gaps in the study of their aqueous phase generation and their influences on sulfate formation. In this study, the aqueous phase photochemical reaction of methylglyoxal, a ubiquitous organic substance in the atmospheric aqueous phase, was studied under UV irradiation, and the generation of H2O2 and ROOHs in this system was investigated. It is found for the first time that the aqueous phase photolysis of methylglyoxal not only produces H2O2 but also produces ROOHs, and UV light and O2 are necessary for the formation of H2O2 and ROOHs. Based on the experimental results, the possible mechanism of aqueous phase photochemistry of methylglyoxal and the generation of H2O2 and ROOHs were proposed. The effect of aqueous phase photolysis of methylglyoxal on sulfate formation under different conditions was also investigated. The results show that the aqueous phase photolysis of methylglyoxal significantly promoted SO2 oxidation and sulfate formation, in which SO2 oxidation was realized by the generated H2O2, ROOHs and •OH radicals, and the importance of the formed ROOHs cannot be ignored. These results fill some gaps in the field of aqueous phase H2O2 and ROOHs production, and to a certain extent confirm the important roles of the aqueous phase photolysis of methylglyoxal and the formed H2O2 and ROOHs in the production of sulfate. The study reveals the new sources of H2O2 and ROOHs, and provides a new insight into the heterogeneous aqueous phase oxidation pathways and mechanisms of SO2 in cloud and fog droplets and haze particles.

Sustainable Blue Foods from Rice-Animal Coculture Systems.

Global interest grows in blue foods as part of sustainable diets, but little is known about the potential and environmental performance of blue foods from rice-animal coculture systems. Here, we compiled a large experimental database and conducted a comprehensive life cycle assessment to estimate the impacts of scaling up rice-fish and rice-crayfish systems in China. We find that a large amount of protein can be produced from the coculture systems, equivalent to ∼20% of freshwater aquaculture and ∼70% of marine wild capture projected in 2030. Because of the ecological benefits created by the symbiotic relationships, cocultured fish and crayfish are estimated to be carbon-negative (-9.8 and -4.7 kg of CO2e per 100 g of protein, respectively). When promoted at scale to displace red meat, they can save up to ∼98 million tons of greenhouse gases and up to ∼13 million hectares of farmland, equivalent to ∼44% of China's total rice acreage. These results suggest that rice-animal coculture systems can be an important source of blue foods and contribute to a sustainable dietary shift, while reducing the environmental footprints of rice production. To harvest these benefits, robust policy supports are required to guide the sustainable development of coculture systems and promote healthy and sustainable dietary change.

Probabilistic human health risk assessment of PCDD/Fs near municipal solid-waste incinerator using Monte Carlo analysis coupled with triangular fuzzy numbers.

PCDD/Fs are dioxins produced by waste incineration and pose risks to human health. We aimed to detail the health risks of airborne and soil PCDD/Fs near a municipal solid-waste incinerator (MSWI) for the surrounding population and develop a new model that improves upon existing methods. Thus, we conducted field sampling and then investigated a MSWI in the Pearl River Delta (2016-2018). Our results showed that the carcinogenic and non-carcinogenic risk values of PCDD/Fs exposed to residents in nearby areas were acceptable, with hazard index (HI) values lower than 1.0 and a total carcinogenic risk lower than 1.0E-6. Notably, the results raised concerns regarding higher non-carcinogenic risks in children than in adults. Comparative analysis of the frequency accumulation diagram, accumulated probability risk, and the absolute value of error (δ) between the 95% confidence interval (CI) and the 90% CI of the Monte Carlo stochastic simulation-triangular fuzzy number (MCSS-TFN) and the MCSS model, respectively, demonstrated that the MCSS-TFN exhibited less uncertainty than the MCSS model, regardless of the health risk value of PCDD/Fs in ambient air or in soil. This observation underscores the superiority of the MCSS-TFN model over other models in assessing the health risks associated with PCDD/Fs in situations with limited data. Our new method overcomes the limited dataset size and high uncertainty in assessing the health risks of dioxin substances, providing a more comprehensive understanding of their associated health risks than MCSS models.

Hypoxic bone marrow mesenchymal stem cell exosomes promote angiogenesis and enhance endometrial injury repair through the miR-424-5p-mediated DLL4/Notch signaling pathway.

Background: Currently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated. Objective: To investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair. Methods: The morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry. Results: Compared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage. Conclusion: The hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.

Assessing the effects of tempol on renal fibrosis, inflammation, and oxidative stress in a high-salt diet combined with 5/6 nephrectomy rat model: utilizing oxidized albumin as a biomarker.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD), prompting the exploration of antioxidants as a potential therapeutic avenue for mitigating disease progression. This study aims to investigate the beneficial impact of Tempol on the progression of CKD in a rat model utilizing oxidized albumin as a biomarker. METHODS: After four weeks of treatment, metabolic parameters, including body weight, left ventricle residual weight, kidney weight, urine volume, and water and food intake, were measured. Systolic blood pressure, urinary protein, oxidized albumin level, serum creatinine (Scr), blood urea nitrogen (BUN), 8-OHdG, TGF-ß1, and micro-albumin were also assessed. Renal fibrosis was evaluated through histological and biochemical assays. P65-NF-κB was quantified using an immunofluorescence test, while Smad3, P65-NF-κB, and Collagen I were measured using western blot. TNF-α, IL-6, MCP-1, TGF-ß1, Smad3, and P65-NF-κB were analyzed by RT-qPCR. RESULTS: Rats in the high-salt diet group exhibited impaired renal function, characterized by elevated levels of blood urea nitrogen, serum creatinine, 8-OHdG, urine albumin, and tubulointerstitial damage, along with reduced body weight. However, these effects were significantly ameliorated by Tempol administration. In the high-salt diet group, blood pressure, urinary protein, and oxidized albumin levels were notably higher compared to the normal diet group, but Tempol administration in the treatment group reversed these effects. Rats in the high-salt diet group also displayed increased levels of proinflammatory factors (TNF-α, IL-6, MCP1) and profibrotic factors (NF-κB activation, Collagen I), elevated expression of NADPH oxidation-related subunits (P65), and activation of the TGF-ß1/Smad3 signaling pathway. Tempol treatment inhibited NF-κB-mediated inflammation and TGF-ß1/Smad3-induced renal fibrosis signaling pathway activation. CONCLUSION: These findings suggest that Tempol may hold therapeutic potential for preventing and treating rats undergoing 5/6 nephrectomy. Further research is warranted to elucidate the mechanisms underlying Tempol's protective effects and its potential clinical applications. Besides, there is a discernible positive relationship between oxidized albumin and other biomarkers, such as 8-OHG, urinary protein levels, mALB, Scr, BUN, and TGF-ß1 in a High-salt diet combined with 5/6 nephrectomy rat model. These findings suggest the potential utility of oxidized albumin as a sensitive indicator for oxidative stress assessment.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α.

AIM/HYPOTHESIS: The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes. METHODS: TET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays. RESULTS: TET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation. CONCLUSIONS/INTERPRETATION: Our results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome. DATA AVAILABILITY: Sequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.

Nitrogen fertilizer affects the cooking quality and starch properties of proso millet (Panicum miliaceum L.).

Nitrogen has a critical influence on the yield and quality of proso millet. However, the exact impact of nitrogen on the cooking quality of proso millet is not clear. In this study, the cooking quality and starch properties of two proso millet varieties (waxy-Shaanxi millet [wSM] variety and non-waxy-Shaanxi millet [nSM] variety) were compared and analyzed under nitrogen fertilizer treatment (N150, 150 kg/hm2) and a control group without nitrogen application (N0, 0 kg/hm2). Compared with the N0 group, the N150 treatment significantly increased protein content, amylose levels, and total yield. Employing rapid visco analyser and differential scanning calorimetry analyses, we observed that under the N150 treatment, the peak viscosity and breakdown viscosity of proso millet powder were diminished, while the setback viscosity and enthalpy values (ΔH) increased. In addition, nitrogen treatment increased the solids content in the obtained rice soup and significantly hardened the texture of the rice. At the same time, we noticed that the absorption capacity of starch in water and oil was enhanced. These results showed that nitrogen fertilizer had significant effects on the cooking quality and starch properties of proso millet.

Efficacy of Paravertebral Injection of Interferon-α2b Combined with High-Voltage, Long-Term Pulsed Radiofrequency in DRG in Mitigation of Postherpetic Neuralgia: A Retrospective Study.

OBJECTIVE: This investigation aims to evaluate the effectiveness of the paravertebral injection of recombinant human interferon-α2b in conjunction with high-voltage, long-term, pulsed radiofrequency (PRF) in the dorsal root ganglion for the mitigation of postherpetic neuralgia (PHN). METHODS: This retrospective study included 84 individuals with acute PHN. The participants were divided into 3 groups. Group H was treated with interferon-α2b combined with high-voltage long-term PRF. Group C was treated with a combination of high-voltage, long-term PRF and a paravertebral injection (without recombinant human interferon-α2b), and group I was treated with interferon-α2b only. All the patients in the 3 groups were orally administered a 5-mg morphine hydrochloride quick-release tablet when a burst of pain occurred during treatment. The numerical rating scale for pain score, the interleukin-6 and galectin-3 levels, and the incidence of PHN were documented before and after therapy. RESULTS: The pain intensity of all individuals decreased after therapy. Compared with group C, the numerical rating scale scores for group H were significantly reduced at 4, 8, and 12 weeks following therapy, and the PHN incidence was significantly lower. Compared with prior treatment, the recommended dosage of gabapentin capsules and immediate-release morphine hydrochloride tablets was reduced for group H. Compared with group C, the requirement for orally administrated gabapentin capsules and morphine hydrochloride tablets in group H was reduced significantly after treatment. No serious adverse reactions occurred in any of the 3 groups. CONCLUSIONS: Within the context of treatment of acute PHN, the injection of interferon-α2b in conjunction with high-voltage, long-term application of PRF is more effective than PRF or the injection of interferon-α2b alone.

Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

PARP7 plays a crucial role in cancer immunity. The inhibition of PARP7 has shown potential in boosting the immune response against cancer, making it an attractive target for cancer immunotherapy. Herein, we employed a rigid constraint strategy (reduction in molecular flexibility) to design and synthesize a series of novel indazole-7-carboxamide derivatives based on the structure of RBN-2397. Among these derivatives, (S)-XY-05 was identified as the most promising PARP7 inhibitor (IC50: 4.5 nM). Additionally, (S)-XY-05 showed enhanced selectivity toward PARP7 and improved pharmacokinetic properties (oral bioavailability: 94.60%) compared with RBN-2397 (oral bioavailability: 25.67%). In the CT26 syngeneic mouse model, monotherapy with (S)-XY-05 displayed a strong antitumor effect (TGI: 83%) by activating T-cell-mediated immunity within the tumor microenvironment. Collectively, we confirmed that (S)-XY-05 has profound effects on tumor immunity, which paves the way for future studies of PARP7 inhibitors that could be utilized in cancer immunotherapy.

Coagulation performance and mechanism of different hydrolyzed aluminum species for the removal of composite pollutants of polyethylene and humic acid.

Microplastics (MPs) and natural organic matter (NOM) composite pollutants have become emerging contaminants with potential threats. Coagulation has been widely used to remove MPs and NOM, but the underlying mechanisms for the removal of MPs-NOM composite pollutants by hydrolyzed Al species remain unclear. Therefore, the coagulation performance and mechanism of AlCl3, polyaluminum chloride with basicity of 2.2 (PAC22), and PAC25 in treating polyethylene (PE), humic acid (HA), and PE-HA composite systems were systematically investigated. The results showed that in the single PE system, PAC25 with hexagonal clusters achieved the maximum removal (68.09 %) (pH: 5, dosage: 0.5 mM) since adsorption bridging and sweeping effect were the main mechanisms for PE removal. The adsorption of HA on the PE surface enhanced its hydrophilicity and electrostatic repulsion, resulting in decreased PE removal. In the AlCl3-PE-HA system, the oligomeric Al first interacted with the -COOH and C-OH of HA through complexation, followed by the meso- and polymers of Al interacted with PE by electrostatic adsorption. The pre-formed medium polymeric Al species (Alb) and colloidal or solid Al species (Alc) in PAC22 and PAC25 formed complexes with the -OH and -COOH groups of HA, respectively, and then removed PE by adsorption bridging and sweeping effect.

DCLK1 and its oncogenic functions: A promising therapeutic target for cancers.

Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and ß-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.

Heritable changes of epialleles near genes in maize can be triggered in the absence of CHH methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (Mediator of paramutation1), with that of their parents, wild-type siblings, and backcrossed progeny in maize (Zea mays). Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of these DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that both TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in most TCM DMRs in F1 plants required Mop1, initiation of a new epigenetic state of these DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is independent of RNA-directed DNA methylation.