"How Do I Practise Palliative Care When I Don't Know How?" Exploring the Impact of EPAN, An Online Educational Intervention on General Nurses in Singapore: An Evaluation Study.

Objective(s): The majority of deaths in Singapore (62.1%) occur in the hospital, but most nurses do not have palliative care (PC) education. An online e-learning course, "Essential Palliative Care Approach for Nurses" (EPAN), was developed to close the learning gap. The study aimed to evaluate the impact of EPAN on general nurses' knowledge, confidence, and attitude in delivering end-of-life care. Methods: Convergent parallel mixed methods design. Results: 1708 nurses (67%), mostly from inpatient and ambulatory settings, completed EPAN. Statistically significant increases in mean scores across knowledge, confidence, and attitude (p < 0.05) remained consistent immediately post-course and 3 months post-course. Respondents shared their intentions to change practice in the immediate post-course survey (n = 1155) and how they have practiced end-of-life care in the 3-month post-course survey (n = 777). Major categories from the content analysis included: (i) actualise confidence to deliver effective communication, (ii) making time and showing empathy in end-of-life care, (iii) advocating for end-of-life care, (iv) proactive collaboration with other healthcare professionals, (v) navigated and accepted end-of-life boundaries, and (vi) able to self-manage emotions. Conclusions: EPAN, developed within an Asian context, has demonstrated a significant impact on nurses' knowledge, confidence, and attitude in delivering end-of-life care. This has broader implications for general palliative care education in countries of similar cultural concerns.

Highly spontaneous spin polarization engineering of single-atom artificial antioxidases towards efficient ROS elimination and tissue regeneration.

The creation of atomic catalytic centers has emerged as a conducive path to design efficient nanobiocatalysts to serve as artificial antioxidases (AAOs) that can mimic the function of natural antioxidases to scavenge noxious reactive oxygen species (ROS) for protecting stem cells and promoting tissue regeneration. However, the fundamental mechanisms of diverse single-atom sites for ROS biocatalysis remain ambiguous. Herein, we show that highly spontaneous spin polarization mediates the hitherto unclear origin of H2O2-elimination activities in engineering ferromagnetic element (Fe, Co, Ni)-based AAOs with atomic centers. The experimental and theoretical results reveal that Fe-AAO exhibits the best catalase-like kinetics and turnover number, while Co-AAO shows the highest glutathione peroxidase-like activity and turnover number. Furthermore, our investigations prove that both Fe-AAO and Co-AAO can effectively secure the functions of stem cells in high ROS microenvironments and promote the repair of injured tendon tissue by scavenging H2O2 and other ROS. We believe that the proposed highly spontaneous spin polarization engineering of ferromagnetic element-based AAOs will provide essential guidance and practical opportunities for developing efficient AAOs for eliminating ROS, protecting stem cells, and accelerating tissue regeneration.

Fulfilling last wishes: improving the compassionate discharge process.

BACKGROUND: Compassionate discharges (ComD), commonly known as rapid discharges, are urgent one-way discharges for critically ill hospitalised patients with death expected within hours or less than 7 days, to die at their place of choice-usually in their own home. Challenges abound in this time-sensitive setting when multiple parties must work together to prepare medically unstable patients for discharge, yet healthcare staff are largely unaware of the process, resulting in delays. METHODS: Process mapping, an Ishikawa diagram and a Pareto chart were used to identify barriers, which included timely acquisition of home equipment and medication and poor communication among stakeholders. In May 2020, the Quality Improvement (QI) team embarked on a pilot project to reduce family caregiver anxiety and delays in the ComD process while maintaining a success rate above 90% over a 12-month period. INTERVENTIONS: Three Plan-Do-Study-Act (PDSA) cycles were used to refine a ComD resource package that was developed; this consisted of a checklist, a kit and caregiver resources. This was to support nurses, doctors and families during this difficult and emotional transition. Items in the ComD resource package were revised iteratively based on user feedback, with further data collected to measure its usefulness. RESULTS: The 12-month ComD success rate over 3 PDSA cycles were 88.9%, 94.2% and 96.7%, respectively, after each cycle. There was a consistent reduction in the level of family anxiety before and after caregiver training and resources. Reasons for failed ComD included acute clinical deterioration or delays in obtaining home oxygen support. CONCLUSION: The ComD resource package allowed collaborative work across different disciplines, strengthening the safety and utility of ComD and allowing patients to die in their place of choice. These are ubiquitous across settings; this QI problem is thus relevant beyond our local institution.

Enhanced hippocampal TIAM2S expression alleviates cognitive deficits in Alzheimer's disease model mice.

BACKGROUND: Dendritic spine dysfunction is a key feature of Alzheimer's disease (AD) pathogenesis. Human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein, which is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth in our previous findings. However, whether enhanced hippocampal TIAM2S expression can alleviate cognitive deficits in Alzheimer's disease model mice remains unclear. METHODS: We crossbred 3xTg-AD with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). The Morris water maze and object location tests assessed hippocampus-dependent spatial memory. Lentiviral-driven shRNA or cDNA approaches were used to manipulate hippocampal TIAM2S expression. Golgi staining and Sholl analysis were utilized to measure neuronal dendrites and dendritic spines in the mouse hippocampi. RESULTS: Compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed improved cognitive functions. According to the hippocampus is one of the earliest affected brain regions by AD, we further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether manipulating hippocampal TIAM2S expression could affect AD-related cognitive functions. The results showed that the reduced hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels alleviated cognitive deficits in 3xTg-AD mice. Furthermore, we found that TIAM2S-mediated memory improvement was achieved by regulating dendritic plasticity. CONCLUSIONS: These results will provide new insights into connecting TIAM2S with AD and support the notion that TIAM2S should be investigated as potential AD therapeutic targets.

Modulating Neuromorphic Behavior of Organic Synaptic Electrolyte-Gated Transistors Through Microstructure Engineering and Potential Applications.

Organic synaptic transistors are a promising technology for advanced electronic devices with simultaneous computing and memory functions and for the application of artificial neural networks. In this study, the neuromorphic electrical characteristics of organic synaptic electrolyte-gated transistors are correlated with the microstructural and interfacial properties of the active layers. This is accomplished by utilizing a semiconducting/insulating polyblend-based pseudobilayer with embedded source and drain electrodes, referred to as PB-ESD architecture. Three variations of poly(3-hexylthiophene) (P3HT)/poly(methyl methacrylate) (PMMA) PB-ESD-based organic synaptic transistors are fabricated, each exhibiting distinct microstructures and electrical characteristics, thus serving excellent samples for exploring the critical factors influencing neuro-electrical properties. Poor microstructures of P3HT within the active layer and a flat active layer/ion-gel interface correspond to typical neuromorphic behaviors such as potentiated excitatory postsynaptic current (EPSC), paired-pulse facilitation (PPF), and short-term potentiation (STP). Conversely, superior microstructures of P3HT and a rough active layer/ion-gel interface correspond to significantly higher channel conductance and enhanced EPSC and PPF characteristics as well as long-term potentiation behavior. Such devices were further applied to the simulation of neural networks, which produced a good recognition accuracy. However, excessive PMMA penetration into the P3HT conducting channel leads to features of a depressed EPSC and paired-pulse depression, which are uncommon in organic synaptic transistors. The inclusion of a second gate electrode enables the as-prepared organic synaptic transistors to function as two-input synaptic logic gates, performing various logical operations and effectively mimicking neural modulation functions. Microstructure and interface engineering is an effective method to modulate the neuromorphic behavior of organic synaptic transistors and advance the development of bionic artificial neural networks.

Cold atmospheric plasma in combination with laser therapy provides a window for the treatment of hyperproliferative skin disease.

Modern medical understanding suggests that hyperproliferative skin diseases (HSDs) are complex syndromes characterized by localized hypertrophy or hyperplasia and infiltration of inflammatory cells. Various treatments, including systemic and topical pharmacotherapy, laser interventions, photodynamic therapy, and surgery, have been proposed for managing HSDs. However, challenges such as wound healing and recurrence after laser treatment have hindered the effectiveness of laser therapy. To overcome these challenges, we conducted a study combining laser therapy with cold atmospheric plasma (CAP) for the treatment of HSDs. Seven patients with different forms of HSDs, who had not responded well to conventional treatments, were enrolled in the study. These HSDs included cases of erythroplasia of Queyrat, pyoderma gangrenosum, keloids and hypertrophic scars, cellulitis, cutaneous lichen planus, and verruca vulgaris. Laser therapy was performed to remove the hyperplastic skin lesions, followed immediately by daily CAP treatment. The results were promising, with all patients successfully treated and no recurrence observed during the follow-up periods. The combined application of CAP and laser therapy proved to be an effective and complementary strategy for managing HSDs. This innovative approach provide evidence for addressing the limitation of laser therapy by utilizing CAP to promote wound healing and mitigate inflammatory responses. Chinese Clinical Trial Registry (ChiCTR2300069993).

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Can PM2.5 concentration reduced by China's environmental protection tax?

The responsibility of enhancing environmental quality is shouldered by China's Environmental Protection Tax (EPT), which constitutes a vital element of China's tax system greening initiative. Using the difference-in-differences (DID) method, the effects of the EPT on PM2.5 concentration were empirically examined in this study, through panel data of 218 cities in China from 2015 to 2021. The results indicate that the EPT can effectively reduce PM2.5 concentration by approximately 2.4 %, and this conclusion remained unchanged after a series of robustness tests. In the channel analysis, it can be found that the reduction of PM2.5 concentration by the EPT was achieved through the alleviation of financing constraints, technological advancements, and optimization of industrial structure. Heterogeneity analysis indicates that the negative impact of the EPT on PM2.5 concentration was more significant in northern cities, inland cities and non-national environmental protection model cities. Further analysis found that EPT has a stronger inhibitory effect on PM2.5 concentration within 100 % of tax increase. The conclusions remain consistent when spatial spillover effects of PM2.5 are taken into account. This paper provides important empirical evidence to support the effectiveness of emission reductions of EPT and provides valuable insights for the future improvement of EPT.

[Effects of 4-hydroxy-2(3H)-benzoxazolone on proliferation and apoptosis of pancreatic cancer L3.6 cells].

This study explored the effects of 4-hydroxy-2(3H)-benzoxazolone(HBOA) on the proliferation and apoptosis of pancreatic cancer cells and its molecular mechanism. The L3.6 cells cultured in vitro were treated with HBOA of 0-1.0 mmol·L~(-1). The cell viability was detected by the cell counting kit-8(CCK-8) method, and the half inhibitory concentration(IC_(50)) was analyzed to determine the drug concentration and time. The cell morphology was observed under an inverted microscope and by acridine orange(AO) staining. The ability of proliferation and self-renewal were evaluated through live cell counting and colony formation experiments. The cell cycle progression and cell apoptosis rate were detected by flow cytometry. The morphology of cell apoptosis was observed by scanning electron microscopy. The mRNA expression of proliferating cell nuclear antigen(PCNA), cyclinA1, cyclinA2, cyclin dependent kinase 2(CDK2), and cyclin dependent kinase inhibitor 1A(P21) were determined by qPCR. The level of reactive oxygen species(ROS), lipid peroxide, and mitochondrial membrane potential were measured by flow cytometry. The activity of protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway was detected by Western blot. Compared with the control group, the cells treated with HBOA exhibited a significant decrease in viability. Then the optimal concentration and intervention time of HBOA were determined to be 0.4 mmol·L~(-1), 0.6 mmol·L~(-1), and 48 h. Compared with the control group, groups with HBOA of 0.4 mmol·L~(-1 )and 0.6 mmol·L~(-1) showed a significant suppression in cell proliferation and colony formation ability, down-regulated mRNA of PCNA, cyclinA1, cyclinA2, and CDK2, up-regulated P21 mRNA, S-phase cell cycle arrest, and increased cell apoptosis rate. There was an appearance of apoptotic bodies, increased ROS and lipid peroxide, decreased mitochondrial membrane potential(with a significant decrease in 0.6 mmol·L~(-1) group), and down-regulated p-Akt and p-mTOR proteins. The results show that HBOA inhibits the proliferation of pancreatic cancer L3.6 cells and induces cell apoptosis, which may be related to the increase in reactive oxygen species and the inhibition of the Akt/mTOR pathway.

Heat exposure induced risks of preterm birth mediated by maternal hypertension.

Heat exposure is associated with an increased risk of preterm birth (PTB), with previous work suggesting that maternal blood pressure may play a role in these associations. Here we conducted a cohort study of 197,080 singleton live births across 8 provinces in China from 2015 to 2018. The study first estimated the associations between heat exposure, maternal hypertension and clinical subtypes of PTB, and then quantified the role of maternal hypertension in heat and PTB using mediation analyses. We show that heat exposure (>85th, 90th and 95th percentiles of local temperature distributions) spanning from conception to the 20th gestational week was associated with a 15-21% increase in PTB, and a 20-22% increase in medically indicated PTB. Heat exposure is likely to increase the risk of maternal hypertension and elevated blood pressure. Maternal hypertension mediated 15.7% and 33.9% of the effects of heat exposure (>90th percentile) on PTB and medically indicated PTB, respectively. Based on this large-population study, we found that exposure to heat in early pregnancy can increase the risk of maternal hypertension, thereby affecting the incidence of PTB.

Polymerized Network-Based Artificial Peroxisome Reprogramming Macrophages for Photoacoustic Imaging-Guided Treatment of Rheumatoid Arthritis.

Artificial peroxisomes (AP) with enzyme-mimetic catalytic activity and recruitment ability have drawn a great deal of attention in fabricating protocell systems for scavenging reactive oxygen species (ROS), modulating the inflammatory microenvironment, and reprogramming macrophages, which is of great potential in treating inflammatory diseases such as rheumatoid arthritis (RA). Herein, a macrophage membrane-cloaked Cu-coordinated polyphthalocyanine-based AP (CuAP) is prepared with a macrocyclic conjugated polymerized network and embedded Cu-single atomic active center, which mimics the catalytic activity and coordination environment of natural superoxide dismutase and catalase, possesses the inflammatory recruitment ability of macrophages, and performs photoacoustic imaging (PAI)-guided treatment. The results of both in vitro cellular and in vivo animal experiments demonstrated that the CuAP under ultrasound and microbubbles could efficiently scavenge excess ROS in cells and tissues, modulate microenvironmental inflammatory cytokines such as interleukin-1ß, tumor necrosis factor-α, and arginase-1, and reprogram macrophages by polarization of M1 (proinflammatory phenotype) to M2 (anti-inflammatory phenotype). We believe this study offers a proof of concept for engineering multifaceted AP and a promising approach for a PAI-guided treatment platform for RA.

Lipidomic analysis of serum exosomes identifies a novel diagnostic marker for type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) intricately involves disrupted lipid metabolism. Exosomes emerge as carriers of biomarkers for early diagnosis and monitoring. This study aims to identify lipid metabolites in serum exosomes for T2DM diagnosis. METHODS: Serum samples were collected from newly diagnosed T2DM patients and age and body mass index-matched healthy controls. Exosomes were isolated using exosome isolation reagent, and untargeted/targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and validate altered lipid metabolites. Receiver operating characteristic curve analysis was used to evaluate the diagnostic value of candidate lipid metabolites. RESULTS: Serum exosomes were successfully isolated from both groups, with untargeted LC-MS/MS revealing distinct lipid metabolite alterations. Notably, phosphatidylethanolamine (PE) (22:2(13Z,16Z)/14:0) showed stable elevation in T2DM-serum exosomes. Targeted LC-MS/MS confirmed significant increase of PE (22:2(13Z,16Z)/14:0) in T2DM exosomes but not in serum. PE (22:2(13Z,16Z)/14:0) levels not only positively correlated with hemoglobin A1C levels and blood glucose levels, but also effectively distinguished T2DM patients from healthy individuals (area under the curve = 0.9141). CONCLUSION: Our research sheds light on the importance of serum exosome lipid metabolites in diagnosing T2DM, providing valuable insights into the complex lipid metabolism of diabetes.

Mangrove mud clam as an effective sentinel species for monitoring changes in coastal microplastic pollution.

The worldwide mangrove shorelines are experiencing considerable contamination from microplastics (MPs). Finding an effective sentinel species in the mangrove ecosystem is crucial for early warning of ecological and human health risks posed by coastal microplastic pollution. This study collected 186 specimens of the widely distributed mangrove clam (Geloina expansa, Solander, 1786) from 18 stations along the Leizhou Peninsula, the largest mangrove coast in Southern China. This study discovered that mangrove mud clams accumulated a relatively high abundance of MPs (2.96 [1.61 - 6.03] items·g-1) in their soft tissue, wet weight, as compared to previously reported levels in bivalves. MPs abundance is significantly (p < 0.05 or 0.0001) influenced by coastal urban development, aquaculture, and shell size. Furthermore, the aggregated MPs exhibit a significantly high polymer risk index (Level III, H = 353.83). The estimated annual intake risk (EAI) from resident consumption, as calculated via a specific questionnaire survey, was at a moderate level (990 - 2475, items·g -1·Capita -1). However, the EAI based on suggested nutritional standards is very high, reaching 113,990 (79,298 - 148,681), items·g -1·Capita -1. We recommend utilizing the mangrove mud clam as sentinel species for the monitoring of MPs pollution changing across global coastlines.

[Screening for Characteristic Genes of Different Traditional Chinese Medicine Syndromes of Psoriasis Vulgaris: A Study Based on Bioinformatics and Machine Learning]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­›é€‰é“¶å±‘ç— ä¸­åŒ»è¯åž‹ç‰¹å¾åŸºå› .

Objective: To screen for the key characteristic genes of the psoriasis vulgaris (PV) patients with different Traditional Chinese Medicine (TCM) syndromes, including blood-heat syndrome (BHS), blood stasis syndrome (BSS), and blood-dryness syndrome (BDS), through bioinformatics and machine learning and to provide a scientific basis for the clinical diagnosis and treatment of PV of different TCM syndrome types. Methods: The GSE192867 dataset was downloaded from Gene Expression Omnibus (GEO). The limma package was used to screen for the differentially expressed genes (DEGs) of PV, BHS, BSS, and BDS in PV patients and healthy populations. In addition, KEGG (Kyoto Encyclopedia of Genes and Genes) pathway enrichment analysis was performed. The DEGs associated with PV, BHS, BSS, and BDS were identified in the screening and were intersected separately to obtain differentially characterized genes. Out of two algorithms, the support vector machine (SVM) and random forest (RF), the one that produced the optimal performance was used to analyze the characteristic genes and the top 5 genes were identified as the key characteristic genes. The receiver operating characteristic (ROC) curves of the key characteristic genes were plotted by using the pROC package, the area under curve (AUC) was calculated, and the diagnostic performance was evaluated, accordingly. Results: The numbers of DEGs associated with PV, BHS, BSS, and BDS were 7699, 7291, 7654, and 6578, respectively. KEGG enrichment analysis was focused on Janus kinase (JAK)/signal transducer and activator of transcription (STAT), cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), apoptosis, and other pathways. A total of 13 key characteristic genes were identified in the screening by machine learning. Among the 13 key characteristic genes, malectin (MLEC), TUB like protein 3 (TULP3), SET domain containing 9 (SETD9), nuclear envelope integral membrane protein 2 (NEMP2), and BTG anti-proliferation factor 3 (BTG3) were the key characteristic genes of BHS; phosphatase 15 (DUSP15), C1q and tumor necrosis factor related protein 7 (C1QTNF7), solute carrier family 12 member 5 (SLC12A5), tripartite motif containing 63 (TRIM63), and ubiquitin associated protein 1 like (UBAP1L) were the key characteristic genes of BSS; recombinant mouse protein (RRNAD1), GTPase-activating protein ASAP3 Protein (ASAP3), and human myomesin 2 (MYOM2) were the key characteristic genes of BDS. Moreover, all of them showed high diagnostic efficacy. Conclusion: There are significant differences in the characteristic genes of different PV syndromes and they may be potential biomarkers for diagnosing TCM syndromes of PV.

Increased risk of preterm birth due to heat exposure during pregnancy: Exploring the mechanism of fetal physiology.

BACKGROUND: Heat exposure during pregnancy can increase the risk of preterm birth (PTB) through a range of potential mechanisms including pregnancy complications, hormone secretion and infections. However, current research mainly focuses on the effect of heat exposure on pathophysiological pathways of pregnant women, but ignore that maternal heat exposure can also cause physiological changes to the fetus, which will affect the risk of PTB. OBJECTIVE: In this study, we aimed to explore the mediating role of fetal heart rate (FHR) in the relationship between maternal heat exposure and PTB incidence. METHODS: We assigned heat exposure to a multi-center birth cohort in China during 2015-2018, which included all 162,407 singleton live births with several times FHR measurements during the second and third trimesters. We examined the associations between heat exposure, FHR and PTB in the entire pregnancy, each trimester and the last gestational month. The inverse odds ratio-weighted approach applied to the Cox regression was used to identify the mediation effect of heat exposure on PTB and its clinical subtypes via FHR. FINDINGS: Exposure to heat significantly increased the risk of PTB during the third trimester and the entire pregnancy, hazard ratios and 95 % CIs were 1.266 (1.161, 1.379) and 1.328 (1.218, 1.447). Heat exposure during the third trimester and entire pregnancy increased FHR in the third trimester by 0.24 bpm and 0.14 bpm. The proportion of heat exposure mediated by FHR elevation on PTB and its subtype ranged from 3.68 % to 24.06 %, with the significant mediation effect found for both medically indicated PTB and spontaneous PTB. CONCLUSIONS: This study suggests that heat exposure during pregnancy has an important impact on fetal health, and FHR, as a surrogate marker of fetal physiology, may mediate the increased risk of PTB caused by extreme heat. Monitoring and managing physiological changes in the fetus would constitute a promising avenue to reduce adverse birth outcomes associated with maternal heat exposure.

Neuron-derived neurotensin promotes pancreatic cancer invasiveness and gemcitabine resistance via the NTSR1/Akt pathway.

Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC) and link to poor outcome. However, how neural factors affect PDAC prognosis and the underlying mechanism as well as counteracting therapeutic are still unclear. In silico systematic analysis was performed with PROGgene to identify potential neural factor and its receptor in pancreatic cancer. In vitro assays including migration, invasion, 3D recruitment, and gemcitabine resistance were performed to study the effect of neuron-derived neurotensin (NTS) on pancreatic cancer behavior. Orthotopic animal study was used to validate the in vitro findings. Gene set enrichment analysis (GSEA) was performed to confirm the results from in silico to in vivo. Expression of NTS and its receptor 1 (NTSR1) predicted poor prognosis in PDAC. NTS synthetic peptide or neuron-derived condition medium promoted pancreatic cancer invasiveness and recruitment in 2D and 3D assays. NTS-induced effects depended on NTSR1 and PI3K activation. GDC-0941, a clinically approved PI3K inhibitor, counteracted NTS-induced effects in vitro. Inhibition of NTSR1 in pancreatic cancer cells resulted in decreased tumor dissemination and diminished PI3K activation in vivo. NTS boosted gemcitabine resistance via NTSR1 in pancreatic cancer. Our results suggest that neural cell-secreted NTS plays an important role in promoting PDAC.

Modeling nitrogen removal performance based on novel microbial activity indicators in WWTP by machine learning and biological interpretation.

Modeling the pollutant removal performance of wastewater treatment plants (WWTPs) plays a crucial role in regulating their operation, mitigating effluent anomalies and reducing operating costs. Pollutants removal in WWTPs is closely related to microbial activity. However, there is extremely limited knowledge on the models accurately characterizing pollutants removal performance by microbial activity indicators. This study proposed a novel specific oxygen uptake rate (SOURATP) with adenosine triphosphate (ATP) as biomass. Firstly, it was found that SOURATP and total nitrogen (TN) removal rate showed similar fluctuated trends, and their correlation was stronger than that of TN removal rate and common SOURMLSS with mixed liquor suspended solids (MLSS) as biomass. Then, support vector regressor (SVR), K-nearest neighbor regressor (KNR), linear regressor (LR), and random forest (RF) models were developed to predict TN removal rate only with microbial activity as features. Models utilizing the novel SOURATP resulted in better performance than those based on SOURMLSS. A model fusion (MF) algorithm based on the above four models was proposed to enhance the accuracy with lower root mean square error (RMSE) of 2.25 mg/L/h and explained 75% of the variation in the test data with SOURATP as features as opposed to other base learners. Furthermore, the interpretation of predictive results was explored through microbial community structure and metabolic pathway. Strong correlations were found between SOURATP and the proportion of nitrifiers in aerobic pool, as well as between heterotrophic bacteria respiratory activity (SOURATP_HB) and the proportion of denitrifies in anoxic pool. SOURATP also displayed consistent positive responses with most key enzymes in Embden-Meyerhof-Parnas pathway (EMP), tricarboxylic acid cycle (TCA) and oxidative phosphorylation cycle. In this study, SOURATP provides a reliable indication of the composition and metabolic activity of nitrogen removal bacteria, revealing the potential reasons underlying the accurate predictive result of nitrogen removal rates based on novel microbial activity indicators. This study offers new insights for the prediction and further optimization operation of WWTPs from the perspective of microbial activity regulation.

Serum interα-trypsin inhibitor heavy chain H4 may be an anti-inflammatory marker reflecting disease risk, activity and treatment outcome of ankylosing spondylitis.

Interα-trypsin inhibitor heavy chain H4 (ITIH4) modulates inflammation and immunity, which take part in the pathogenesis of ankylosing spondylitis (AS). The current research intended to discover the clinical value of serum ITIH4 quantification for AS management. Serum ITIH4 among 80 AS patients before current treatment initiation (baseline) at weeks (W) 4, 8 and 12 after treatment was detected by ELISA. Serum ITIH4 from 20 disease controls (DCs) and 20 healthy controls (HCs) was detected. ITIH4 expression was lower in AS patients than in DCs (p = 0.002) and HCs (p < 0.001). Among AS patients, ITIH4 was negatively associated with C-reactive protein (CRP) (r = -0.311, p = 0.005), bath AS disease activity index (BASDAI) (r = -0.223, p = 0.047), total pack pain (r = -0.273, p = 0.014) and AS disease activity score (ASDAS) (CRP) (r = -0.265, p = 0.018). Meanwhile, ITIH4 was negatively related to tumor necrosis factor (TNF)-α (r = -0.364, p = 0.001), interleukin (IL)-1ß (r = -0.251, p = 0.025), IL-6 (r = -0.292, p = 0.009) and IL-17A (r = -0.254, p = 0.023). After treatment, the assessment of the spondylitis arthritis international society 40 response rate was 28.7% at W4, 46.3% at W8 and 55.0% at W12; ITIH4 showed an increasing trend from baseline to W12 (p < 0.001). Furthermore, ITIH4 at W8 (p = 0.020) and W12 (p = 0.035), but not at baseline or W4 (both p > 0.05), was enhanced in response patients vs. nonresponse patients. Additionally, ITIH4 at W12 was increased in AS patients receiving TNF inhibitors vs. those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.024). Serum ITIH4 increases after treatment, and its augmentation is correlated with lower disease activity, decreased inflammation and enhanced treatment response in AS patients.

Toxicity study of rats treated by plasma-activated solution.

Background: Cold atmospheric plasma (CAP) is an effective treatment for various skin diseases. Plasma-activated solution (PAS) is an indirect method of CAP treatment that produces biological effects similar to those of direct treatment with plasma devices. The anticancer and bacteriostatic effects of PAS have been demonstrated in vitro experiments; however, on the basis of the lack of toxicological studies on PAS, its effects on living mammals when administered by subcutaneous injection is poorly known. Purpose: The purpose of this study was to evaluate the effects of PAS on local skin tissue cells, blood system, heart, liver, lungs, kidneys and other vital organs of the rat when injected subcutaneously. Methods: PAS was prepared by CAP irradiation of phosphate-buffered saline (PBS). PBS and different PBS groups (CAP irradiation for 1, 3, or 5 min) were injected subcutaneously once every 48 h. The rats were euthanized immediately after 10 cycles of therapy. Results: No adverse effects were observed during the entire period of the experiment. Histopathological examination of organs and tissues revealed no structural changes. Moreover, no obvious structural changes were observed in skin tissue. DNA damage and cancerous proliferative changes were not detected in skin tissue treated with PAS. Subsequently, RNA sequencing and western blotting were performed. The results showed that PAS increased the expression of growth factors like transforming growth factor beta (TGF-ß) and vascular endothelial growth factor A (VEGFA). These results might be directly linked to the role of PAS in stimulating TGF-ß receptor signaling pathway and angiogenesis. Conclusion: The results showed that multiple subcutaneous injections of PAS did not show significant toxic side effects on local skin tissues and some vital organs in rats, providing a scientific basis to support the future treatment of skin diseases with PAS.

Current status of GABA receptor subtypes in analgesia.

Gamma-aminobutyric acid (GABA), a non-protein-producing amino acid synthesized from the excitatory amino acid glutamate via the enzyme glutamic acid decarboxylase, is extensively found in microorganisms, plants and vertebrates, and is abundantly expressed in the spinal cord and brain. It is the major inhibitory neurotransmitter in the mammalian nervous system. GABA plays crucial roles in the regulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of insomnia and depression. As the major inhibitory neurotransmitter, GABA plays pivotal roles in the regulation of pain sensation, which is initiated by the activation of peripheral nociceptors and transmitted to the spinal cord and brain along nerves. GABA exerts these roles by directly acting on three types of receptors: ionotropic GABAA and GABAC receptors and G protein-coupled GABAB receptor. The chloride-permeable ion channel receptors GABAA and GABAC mediate fast neurotransmission, while the metabotropic GABAB receptor mediates slow effect. Different GABA receptors regulate pain sensation via different signaling pathways. Here we highlight recent updates on the involvement of specific GABA receptors and their subtypes in the process of pain sensation. Further understanding of different GABA receptors and signaling pathways in pain sensation will benefit the development of novel analgesics for pain management by targeting specific GABA receptor subtypes and signaling pathways.