Efficacy of hip abductors exercise training combined with repetitive transcranial magnetic stimulation on knee osteoarthritis: A randomized controlled trial.

BACKGROUND: Knee osteoarthritis is a common degenerative joint disease where a single treatment method often fails to fully alleviate symptoms. Hence, finding effective non-invasive combined treatment approaches is particularly crucial. OBJECTIVE: The efficacy of treating knee osteoarthritis with hip abductors exercise training combined with repetitive transcranial magnetic stimulation was assessed through functional scales and objective evaluation methods. METHODS: In this four-week randomized clinical trial, 160 patients meeting inclusion criteria were randomly assigned 1:1 to group A to receive oral celecoxib and group B to receive a combination of hip abductors exercise training and repeated transcranial magnetic stimulation. The primary outcome was the western Ontario and McMaster universities osteoarthritis index. The secondary outcomes include Visual Analogue Scale, knee outcome survey activities of daily living scale, Active Range of Motion, and the Quadriceps Angle, the tibiofemoral angle, peak adductor moment, the integrated electromyography and root mean square of the surface electromyography of the lower extremity muscles. Paired sample t test was used for Within-Group comparison of outcome indicators, and independent sample t test was used for Between-Group comparison. RESULTS: Of the 160 randomly assigned patients, 150 completed the study. After 4 weeks, the WOMAC index decreased from 61 ± 10.83 to 40.55 ± 7.58 in the combined treatment group and from 60.97 ± 10.18 to 47.7 ± 10.13 in the celecoxib group. The effect of the combined treatment group was significantly higher than that in the celecoxib group (P< 0.001). In the combined treatment group, the score of knee joint daily living scale increased (P< 0.001), the active range of motion increased (P< 0.001), the quadriceps angle decreased (P< 0.001), the tibiofemoral angle increased (P< 0.001), and the peak adduction moment decreased (P< 0.001), integrated electromyography and root mean square increased (P< 0.001), and the effect was better than that of celecoxib group (P< 0.001). The visual analog scale score in celecoxib group was lower (P< 0.001) and knee outcome survey activities of daily living scale was higher (P< 0.001). The incidence of treatment-related adverse events was 10% in the celecoxib group and 2.5% in the combined treatment group, all of which were mild. CONCLUSIONS: Hip abductors exercise training combined with repetitive transcranial magnetic stimulation can enhance abduction muscle strength, improve mobility, reduce joint pain, and enhance quality of life. This combined approach shows superior clinical effectiveness compared to oral celecoxib.

Ultrasound-Activatable In Situ Vaccine for Enhanced Antigen Self- and Cross-Presentation to Overcome Cancer Immunotherapy Resistance.

Insufficient antigen self-presentation of tumor cells and ineffective antigen cross-presentation by dendritic cells (DCs) contribute to diminished immune recognition and activation, which cause resistance to immunotherapies. Herein, we present an ultrasound-activatable in situ vaccine by utilizing a hybrid nanovesicle composed of a thylakoid (TK)/platelet (PLT) membrane and a liposome encapsulating DNA methyltransferase inhibitor zebularine (Zeb) and sonosensitizer hematoporphyrin monomethyl ether (HMME). Upon local exposure to ultrasound, reactive oxygen species (ROS) are generated and induce the sequential release of the payloads. Zeb can efficiently inhibit tumor DNA hypermethylation, promoting major histocompatibility complex class I (MHC-I) molecules-mediated antigen self-presentation to improve immune recognition. Meanwhile, the catalase on the TK membrane can decompose the tumoral overexpressed H2O2 into O2, which boosts the generation of ROS and the destruction of tumor cells, resulting in the in situ antigen release and cross-presentation of tumor antigens by DCs. This in situ vaccine simultaneously promotes antigen self-presentation and cross-presentation, resulting in heightened antitumor immunity to overcome resistance.

Water-filtered infrared A radiation hyperthermia combined with immunotherapy for advanced gastrointestinal tumours.

This study pioneered the use of WIRA whole-body infrared hyperthermia combined with ICI therapy to treat GIT and verified the feasibility and safety of HIT. The final results showed a DCR of 55.6%, with a median PFS of 53.5 days, median OS of 134 days, and an irAE incidence of 22.2%. Therefore, we believe that HIT can exert multiple synergistic sensitisation effects, thereby providing clinical benefits to patients with advanced GITs, increasing overall safety, and improving patients' QOL.

INTRODUCTION: This study aimed to validate the effectiveness, safety and feasibility of water­filtered infrared A radiation (WIRA) whole­body hyperthermia combined with immune checkpoint inhibitor (ICI) therapy (HIT) and evaluate the real­world clinical application prospects. METHODS: This open­label single­arm phase 2 clinical trial (NCT06022692) aimed to enrol advanced gastrointestinal tumour (GIT) patients with the MSS/pMMR phenotype. The patients were treated with whole­body hyperthermia on Days 1 and 8 of each HIT cycle along with administration of tislelizumab on Day 2. RESULTS: Between 1 June 2020 and 31 May 2022, 18 patients were enrolled in the study, including those with gastric cancer (n = 6), colon cancer (n = 7), rectal cancer (n = 3) and appendiceal cancer (n = 2). As of 19 May 2023, 17 of the 18 patients had died, including 14 deaths caused by tumour progression and three deaths caused by diseases other than cancer, while one patient was still undergoing follow­up. In terms of efficacy, the median DCR was 55.6%, while the median PFS and OS were 53.5 days and 134 days, respectively. Four patients (22.2%) experienced immune­related adverse events, and none of the patients reported grade 3 or higher irAEs. Hyperthermia was followed by an increase in the number of tumour immune­activated cells. CONCLUSIONS: HIT can provide survival benefits in patients with GITs by activating antitumour immune function and shows good safety and feasibility.

Factors associated with psychological insulin resistance among patients with type 2 diabetes in China.

Objective: The aim of this study was to understand the psychological insulin resistance status among Chinese patients with type 2 diabetes and investigate its associated factors in these patients. Methods: A multi-stage stratified random sampling was performed to randomly select patients with type 2 diabetes from the eastern, central, and western regions in Shandong Province, China, and 660 valid questionnaires were collected. Psychological insulin resistance was assessed by the scale of My Opinion on Insulin (MOI). Factors associated with psychological insulin resistance were examined in a binary logistic model. Results: Four-fifths of the patients with type 2 diabetes (82.1%) had psychological insulin resistance. Being female (OR = 1.770, 95% CI: 1.063-2.950, p < 0.05), having a monthly income of greater than 4,000 Renminbi (approximately $1,540) (OR = 0.444, 95% CI: 0.216-0.915, p < 0.05), living with type 2 diabetes for 11 years or more (OR = 0.387, 95% CI: 0.238-0.630, p < 0.05), self-rated poor health (OR = 1.706, 95% CI: 1.092-2.664, p < 0.05), and moderate discrimination against type 2 diabetes (OR = 1.924, 95% CI: 1.166-3.175, p < 0.05) were associated with psychological insulin resistance. Conclusions: The prevalence of psychological insulin resistance among Chinese patients with type 2 diabetes is relatively high. Approaches are needed to address the issue of psychological insulin resistance of type 2 diabetes.

Effects of combined treatment with hydrogen-rich electrolyzed water and tea polyphenols on oxidative stress, intestinal injury and intestinal flora disruption in heat-stressed mice.

Heat stress (HS) can cause damage to the organism, especially the intestinal tract. In this paper, we investigated the effects of the combined action of tea polyphenols (TP) and hydrogen-rich electrolyzed water (HRW) on HS in mice. The combination of HRW feeding and TP of intraperitoneal injection was screened by in vitro antioxidant activity assay. The results revealed that the combined treatment was more helpful in alleviating the effects of HS on the behavior, growth performance, oxidative damage, and intestinal tract of mice compared with the respective treatments of TP and HRW (P < 0.05). Additionally, the combined treatment could repair HS-induced intestinal dysbiosis in mice, augmenting the number and abundance of bacteria, increasing the number of beneficial genera (Lachnospiraceae_NK4A136_group and Lactobacillus), and decreasing the number of harmful genera (Desulfovibrio and Enterorhabdus), and the effect was significantly better than that of individual treatment (P < 0.05). In conclusion, the combined treatment of TP and HRW effectively mitigates the adverse effects of HS on mouse behavior, growth performance, oxidative damage, and intestinal dysbiosis, surpassing the efficacy of individual treatments with TP or HRW alone.

Optimizing tradeoff strategies of soil microbial community between metabolic efficiency and resource acquisition along a natural regeneration chronosequence.

The tradeoff between community-level soil microbial metabolic efficiency and resource acquisition strategies during natural regeneration remains unclear. Herein, we examined variations in soil extracellular enzyme activity, microbial metabolic quotient (qCO2), and microbial carbon use efficiency (CUE) along a chronosequence of natural regeneration by sampling secondary forests at 1, 10, 20, 30, 40, and 100 years after rubber plantation (RP) clearance. The results showed that the natural logarithms of carbon (C)-, nitrogen (N)-, and phosphorus (P)-acquiring enzyme activities were 1:1.68:1.37 and 1:1.54:1.38 in the RP and secondary forests, respectively, thus demonstrating that microbial metabolism was co-limited by N and P. Moreover, the soil microbial C limitation initially increased (1-40 years) and later decreased (100 years). Overall, the qCO2 increased, decreased, and then increased again in the initial (< 10 years), middle (10-40 years), and late (100 years) successional stages, respectively. Except for specific P-acquiring enzyme activities, the changes in other indicators with natural regeneration were consistent in the dry and wet seasons. Both qCO2 and CUE were mainly predicted by microbial community composition and physiological traits. These results indicate that soil microbial communities could employ tradeoff strategies between metabolic efficiency and resource acquisition to cope with variations in resources. Our findings provide new information on tradeoff strategies between metabolic efficiency and resource acquisition during natural regeneration.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Understanding the in-situ transformation of CuxO interlayers to increase the water splitting efficiency in NiO/n-Si photoanodes.

The buried interface tens of nanometers beneath the solid-liquid junction is crucial for photocarrier extraction, influencing the overall efficiency of photoelectrochemical devices. Precise characterization of the interfacial properties is essential for device optimization but remains challenging. Here, we directly probe the in situ transformation of a CuxO interlayer at the NiO/n-Si interface by hard X-ray photoelectron spectroscopy. It is found that Cu(I) in the CuxO interlayer gradually transforms to Cu(II) with air exposure, forming an energetically more favorable interface and improving photoanode's efficiency. Based on this finding, a reactive e-beam evaporation process is developed for the direct deposition of a CuO interlayer, achieving a half-cell solar-to-hydrogen efficiency of 4.56% for the optimized NiO/CuO/n-Si heterojunction photoanode. Our results highlight the importance of precision characterization of interfacial properties with advanced hard X-ray photoelectron spectroscopy in guiding the design of efficient solar water-splitting devices.

HPS6 Deficiency Leads to Reduced V-ATPase and Impaired Biogenesis of Lamellar Bodies in Alveolar Type II Cells.

Lamellar body (LB) is a tissue-specific lysosome-related organelle in type II alveolar cells, which is the main site for the synthesis, storage and secretion of pulmonary surfactants. Defects in pulmonary surfactants lead to a variety of respiratory and immune-related disorders. LB biogenesis is closely related to its function, but the underlying regulatory mechanism is largely unclear. Here, we found that deficiency of HPS6, a subunit of BLOC-2 (biogenesis of lysosome-related organelles complex-2), led to the reduction of the steady-state level of V-ATPase and the increase of luminal pH of LB. Furthermore, we observed increased LB size, accumulated surfactant proteins, and altered lipid profiling of lung tissue and bronchoalveolar lavage fluid due to HPS6 deficiency. These findings suggest that HPS6 regulates the distribution of V-ATPase on LBs to maintain its luminal acidity and LB homeostasis. This may provide new insights into the LB pathology.

Identification of O-Methyltransferases Potentially Contributing to the Structural Diversity of 2-(2-Phenylethyl)chromones in Agarwood.

2-(2-Phenylethyl)chromones (PECs) are the primary constituents responsible for the promising pharmacological activities and unique fragrance of agarwood. However, the O-methyltransferases (OMTs) involved in the formation of diverse methylated PECs have not been reported. In this study, we identified one Mg2+-dependent caffeoyl-CoA-OMT subfamily enzyme (AsOMT1) and three caffeic acid-OMT subfamily enzymes (AsOMT2-4) from NaCl-treated Aquilaria sinensis calli. AsOMT1 not only converts caffeoyl-CoA to feruloyl-CoA but also performs nonregioselective methylation at either the 6-OH or 7-OH position of 6,7-dihydroxy-PEC. On the other hand, AsOMT2-4 preferentially utilizes PECs as substrates to produce structurally diverse methylated PECs. Additionally, AsOMT2-4 also accepts nonPEC-type substrates such as caffeic acid and apigenin to generate methylated products. Protein structure prediction and site-directed mutagenesis revealed that residues of L313 and I318 in AsOMT3, as well as S292 and F313 in AsOMT4 determine the distinct regioselectivity of these two OMTs toward apigenin. These findings provide important biochemical evidence of the remarkable structural diversity of PECs in agarwood.

Trends in maternal and child health in China and its urban and rural areas from 1991 to 2020: a joinpoint regression model.

The long-term trends in maternal and child health (MCH) in China and the national-level factors that may be associated with these changes have been poorly explored. This study aimed to assess trends in MCH indicators nationally and separately in urban and rural areas and the impact of public policies over a 30‒year period. An ecological study was conducted using data on neonatal mortality rate (NMR), infant mortality rate (IMR), under-five mortality rate (U5MR), and maternal mortality ratio (MMR) nationally and separately in urban and rural areas in China from 1991 to 2020. Joinpoint regression models were used to estimate the annual percentage changes (APC), average annual percentage changes (AAPC) with 95% confidence intervals (CIs), and mortality differences between urban and rural areas. From 1991 to 2020, maternal and child mortalities in China gradually declined (national AAPC [95% CI]: NMRs - 7.7% [- 8.6%, - 6.8%], IMRs - 7.5% [- 8.4%, - 6.6%], U5MRs - 7.5% [- 8.5%, - 6.5%], MMRs - 5.0% [- 5.7%, - 4.4%]). However, the rate of decline nationally in child mortality slowed after 2005, and in maternal mortality after 2013. For all indicators, the decline in mortality was greater in rural areas than in urban areas. The AAPCs in rate differences between rural and urban areas were - 8.5% for NMRs, - 8.6% for IMRs, - 7.7% for U5MRs, and - 9.6% for MMRs. The AAPCs in rate ratios (rural vs. urban) were - 1.2 for NMRs, - 2.1 for IMRs, - 1.7 for U5MRs, and - 1.9 for MMRs. After 2010, urban‒rural disparity in MMR did not diminish and in NMR, IMR, and U5MR, it gradually narrowed but persisted. MCH indicators have declined at the national level as well as separately in urban and rural areas but may have reached a plateau. Urban‒rural disparities in MCH indicators have narrowed but still exist. Regular analyses of temporal trends in MCH are necessary to assess the effectiveness of measures for timely adjustments.

Effect of Wearing Noise-Canceling Headphones on Delivery Process in Natural Childbirth Puerperae: A Single-Center Study.

OBJECTIVE: To investigate the effect of incorporating noise-canceling headphones into the delivery process for natural childbirth puerperae. METHODS: We conducted a retrospective analysis of clinical data encompassing natural childbirth puerperae in the People's Hospital of Suzhou New District from January 2021 to February 2023. The implementation of routine noise reduction management was done from January 2021 to January 2022. During this interval, 69 natural childbirth puerperae were selected as subjects, with 7 excluded, resulting in 62 participants constituting the reference group. Subsequently, noise-canceling headphones were distributed to natural childbirth puerperae from February 2022 to February 2023. In this phase, 66 subjects were selected, and 6 were excluded, resulting in 60 participants forming the observation group. Following admission, both groups underwent corresponding nursing management. Emotional states, pain levels, and various indicators were systematically collected and meticulously compared. RESULTS: The observation group exhibited significantly lower Hamilton Anxiety Rating Scale scores than the reference group before delivery and during the first stage of labor (P < 0.05). The observation group demonstrated significantly lower visual analog scale scores and substance P, nitric oxide, and prostaglandin E2 levels than the reference group during the first stage of labor (P < 0.001). During the second stage of labor, the visual analog) scale scores were significantly lower in the observation group than in the reference group (P < 0.05). The durations of first and second labor stages were significantly shorter in the observation group than in the reference group (P < 0.05). No significant difference existed in Apgar scores between the two groups (P > 0.05). CONCLUSION: The utilization of noise-canceling headphones emerges as an effective intervention, alleviating anxiety, reducing pain during T1, and abbreviating total labor time in natural childbirth puerperae, suggesting its substantial clinical application value and potential as a beneficial addition to maternity care practices.

Interprovincial spatial distribution patterns and socioeconomic factors on traditional Chinese medicine (TCM) service utilization in China.

The traditional Chinese medicine (TCM) industry in China exhibits significant regional disparities in health service utilization, the underlying reasons for which are yet to be fully explored. This study employs Geodetector models to analyze the factors affecting TCM service utilization, providing the first examination of spatial distribution patterns and influencing factors for both TCM outpatient (TCMOSU) and inpatient services (TCMISU). The findings of this study reveal spatial disparities across China's provinces, showing a prevalence of TCMOSU in the east and TCMISU decreasing from southwest to northeast. Global Moran's I autocorrelation analysis revealed a positive spatial correlation between TCMOSU and TCMISU across Chinese provinces, suggesting spatial clustering and the potential for interregional collaboration in the development of TCM services. Local Moran's I autocorrelation analysis revealed clusters of TCMOSU in wealthier eastern provinces, such as Jiangsu and Tianjin, and clusters of TCMISU in the southwest. Factor detector analysis revealed that disposable income per capita was the most significant factor linking higher incomes with increased TCMOSU. In contrast, TCMISU was primarily influenced by demographic factors, such as the illiteracy rate and population urbanization rate, emphasizing traditional practices in lower education regions. Interaction detector analysis revealed the joint effects of these factors, demonstrating how regional economic status, health status, and healthcare resource indicators interact with other factors for TCMOSU and how demographic factors significantly influence the prevalence of TCMISU. This study highlights the importance of considering health status together with regional economic, demographic, and healthcare resources when formulating TCM healthcare policies and allocating such resources in China. Promoting the balanced and coordinated regional development of TCM services across the country requires the development of strategies that account for these varied regional characteristics.

Forsythoside A regulates pulmonary fibrosis by inhibiting endothelial-to-mesenchymal transition and lung fibroblast proliferation via the PTPRB signaling.

BACKGROUND: Pulmonary fibrosis (PF) is an end-stage change in many interstitial lung diseases, whereas no proven effective anti-pulmonary fibrotic treatments. Forsythoside A (FA) derived from Forsythia suspensa (Thunb.) Vahl, has been found to possess lung-protective effect. However, studies on its anti-pulmonary fibrosis effect are limited and its mechanism of action remains unknown. PURPOSE: This study aimed to explore the underlying mechanism of FA on PF. METHODS: Male C57BL/6 mice were randomized into normal (CON), model (BLM), pirfenidone (PFD), low- and high-dose FA (FA-L, FA-H, respectively). Except for the CON group, which was injected with the same dose of saline, the model of PF was established by intratracheal instillation of BLM, during which the survival rate and body weight changes of the mice were measured. The lung histopathology was evaluated by Hematoxylin-eosin, Sirius red, and Masson staining. Transcriptome analysis was performed to screen for the differential genes associated with the role of FA in PF. Differential genes in normal and pulmonary fibrosis patients with the GSE2052 dataset were analyzed in the GEO database. The levels of CTGF, α-SMA, MMP-8 in lung and TNF-α in bronchoalveolar lavage fluid (BALF) were detected by ELISA. The levels of HYP in lungs were detected by digestion. The mRNA and protein levels of MMP-7, E-cadherin, CD31, α-SMA, TGF-ß1, IL-6, ß-catenin, ZO-1, PTPRB, E-cadherin, and vimentin in lungs were detected by RT-qPCR and Western blot. The expression of CD31, α-SMA, TGF-ß1 and ZO-1 were detected by immunofluorescence. TGF-ß1-stimulated HFL1 cells and human umbilical vein endothelial cells (HUVECs) were used in an attempt to explore the possible role of protein tyrosine phosphatase receptor type B (PTPRB) involved in FA-induced improvement of PF. RESULTS: The results showed that FA could improve the survival rate and body weight of PF mice. FA could alleviate the symptoms of alveolar wall thickening, inflammatory cell infiltration, blue collagen fiber deposition, collagen fiber type Ⅰ and type Ⅲ in mice with PF. In addition, FA could reduce the levels of HYP, CTGF, α-SMA, TGF-ß1, TNF-α, ß-catenin and MMP8, and regulate the expression levels of CD31, ZO-1, PTPRB and E-cadherin in lung of mice with PF, inhibiting endothelial-to-mesenchymal transition (EndMT) and fibroblasts proliferation. In the GSE2052 dataset, the expression level of PTPRB is reduced in lung tissue from PF patients, and results from transcriptome sequencing indicate that PTPRB expression is also reduced in PF mice. In addition, the effect of FA on TGF-ß1-induced HFL1 or HUVECs cells could be attenuated by the inhibitor of PTPRB, suggesting that the effect of FA on PF is related to PTPRB. CONCLUSION: This study demonstrated that FA could ameliorate PF by inhibiting lung fibroblast proliferation and EndMT, and that PTPRB might be a target of FA to ameliorate PF, which provided evidence to support FA as a candidate phytochemical for PF.

Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Impact of Preseason Climate Factors on Vegetation Photosynthetic Phenology in Mid-High Latitudes of the Northern Hemisphere.

During the period preceding the vegetation growing season (GS), temperature emerges as the pivotal factor determining phenology in northern terrestrial ecosystems. Despite extensive research on the impact of daily mean temperature (Tmean) during the preseason period, the influence of diurnal temperature range (DTR) on vegetation photosynthetic phenology (i.e., the impact of the plant photosynthetic cycle on seasonal time scale) has largely been neglected. Using a long-term vegetation photosynthetic phenology dataset and historical climate data, we examine vegetation photosynthetic phenology dynamics and responses to climate change across the mid-high latitudes of the Northern Hemisphere from 2001 to 2020. Our data reveal an advancing trend in the start of the GS (SOS) by -0.15 days per year (days yr-1), affecting 72.1% of the studied area. This is particularly pronounced in western Canada, Alaska, eastern Asia, and latitudes north of 60°N. Conversely, the end of the GS (EOS) displays a delaying trend of 0.17 days yr-1, impacting 62.4% of the studied area, especially northern North America and northern Eurasia. The collective influence of an earlier SOS and a delayed EOS has resulted in the notably prolonged length of the GS (LOS) by 0.32 days yr-1 in the last two decades, affecting 70.9% of the studied area, with Eurasia and western North America being particularly noteworthy. Partial correlation coefficients of the SOS with preseason Tmean, DTR, and accumulated precipitation exhibited negative values in 98.4%, 93.0%, and 39.2% of the study area, respectively. However, there were distinct regional variations in the influence of climate factors on the EOS. The partial correlation coefficients of the EOS with preseason Tmean, DTR, and precipitation were positive in 58.6%, 50.1%, and 36.3% of the region, respectively. Our findings unveil the intricate mechanisms influencing vegetation photosynthetic phenology, holding crucial significance in understanding the dynamics of carbon sequestration within terrestrial ecosystems amidst climate change.

Research on the connectivity of urban river network-wetland and water quality simulation.

The connectivity of urban river networks plays an important role in cities in many aspects, such as urban water safety, water quality (WQ), and aquatic ecological balance. This study focuses on the river network and the Majiawan Wetland in the Chaoyang District of Beijing by establishing a two-dimensional hydrological WQ model employing various water allocation schemes between the river network and the wetland. Water circulation and WQ are the main indexes, and the effects of different scenarios on improving water circulation and WQ are simulated and compared. This study demonstrates that the addition of water replenishment at the intersection of river network and internal slow-water zones of the wetland (Scheme 2) has greater effectiveness in improving both hydrology and WQ compared to two other schemes. The water area of the Majiawan Wetland has expanded, and water velocity has increased. Using chemical oxygen demand, total nitrogen, and total phosphorus as the index values for determining the water class, the WQ of about 20% of the wetland area was reached Water Class II (domestic drinking water), with Water Class III (general industrial water) accounting for the other 80%. This study provides valuable evaluation and reference for similar areas of urban river network connectivity.

Letter to the Editor Regarding "Effect of Ropivacaine Intercostal Nerve Block Combined with Patient Controlled Intravenous Analgesia on Postoperative Analgesia After Breast Augmentation".

We read the recently published article "Effect of Ropivacaine Intercostal Nerve Block Combined with Patient Controlled Intravenous Analgesia on Postoperative Analgesia after Breast Augmentation" by You et al. We have noticed several issues in the methods and results of this study and would appreciate the responses from the authors. We question several aspects, opioid-sparing effect, sufentanil consumption, sample size evaluation, exclusion reasons, and side effects.

Integrating single-cell and spatial analysis reveals MUC1-mediated cellular crosstalk in mucinous colorectal adenocarcinoma.

BACKGROUND: Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. METHODS: We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. RESULTS: This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. CONCLUSIONS: Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. KEY POINTS: Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.