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The sustainable solution to the environmental problem of polymeric materials calls for efficient and well-controlled ring-opening polymerization catalytic systems. Inspired by the highly reactive and stereospecific bimetallic catalysts, three kinds of bimetallic Salen-Mn catalysts supported by biaryl linking moieties are synthesized and applied to polymerization catalysis of lactide (LA) and ϵ-caprolactone (ϵ-CL) in this work. The polymerization is initiated inâ situ by the ring-opening of epoxide compounds, in which the ionic cocatalyst could accelerate the reaction process. The Mn-Mn coordination effect contributes to the higher activity and iso-selectivity towards LA compared to the mononuclear Salen-Mn catalyst. The reactivity and stereoselectivity are determined by the conformation of catalysts, specifically the Mn-Mn separation and dihedral angle. Finally, the CO2 -controlled switchable polymerizations are carried out with LA and ϵ-CL. The reversibility of the on-off switching operation is influenced by the combination between CO2 molecules and active species. The success in binuclear Salen-Mn catalysts not only expands the range of bimetallic catalyst analogues but also claims the promising potential of Mn-based catalysts in practical and theoretical research.
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Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an emerging malignancy due to the rising prevalence of NAFLD. However, no drug is available to target NAFLD-HCC. In this study, we aim to unravel novel therapeutic targets of NAFLD-HCC utilizing a high-throughput CRISPR/Cas9 screening strategy. We utilized the Epi-drug CRISPR/Cas9 library consisting of single-guide RNAs (sgRNAs) targeting over 1,000 genes representing the FDA-approved drug targets and epigenetic regulators to perform loss-of-function screening in two NAFLD-HCC cell lines (HKCI2 and HKCI10). CRISPR/Cas9 library screening unraveled TUBB4B as an essential gene for NAFLD-HCC cell growth. TUBB4B was overexpressed in NAFLD-HCC tumors compared with adjacent normal tissues (N = 17) and was associated with poor survival (p < 0.01). RNA-sequencing and functional assays revealed that TUBB4B knockout in NAFLD-HCC promoted cell apoptosis, cell cycle arrest, and cellular senescence, leading to suppressed NAFLD-HCC growth in vitro and in vivo. We identified that TUBB4B inhibitor mebendazole (MBZ), an FDA-approved drug, inhibited NAFLD-HCC growth by inducing apoptosis and cellular senescence. Since protein expression of pro-survival Bcl-xL was induced in TUBB4B knockout NAFLD-HCC cells, we examined combination of TUBB4B inhibition with navitoclax, a Bcl-xL inhibitor that selectively targets senescent cells. Consistent with our hypothesis, either TUBB4B knockout or MBZ synergized with navitoclax to inhibit NAFLD-HCC cell growth via the induction of intrinsic and extrinsic apoptosis pathways. In summary, TUBB4B is a novel therapeutic target in NAFLD-HCC. Inhibition of TUBB4B with MBZ in combination with navitoclax synergistically inhibited NAFLD-HCC cell growth, representing a promising strategy for the treatment of NAFLD-HCC. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: The aim of this study was to determine the serum biochemical markers that can predict the risk of haemorrhagic transformation (HT) before and after endovascular treatment (EVT). MATERIAL AND METHODS: This study included patients with anterior circulation large vessel occlusion (ACLVO) who underwent EVT within six hours of symptom onset between September 2017 and September 2022. These patients were retrospectively categorised into two groups: an HT group and a No-HT group. RESULTS: A total of 180 patients were included in the study, of whom 55 (30.6%) had HT. The monocyte count before EVT (p = = 0.005, OR = 0.694, 95% CI 0.536-0.898), the activated partial thromboplastin time before EVT (p = 0.009, OR = 0.186, 95% CI 0.699-0.952), and the eosinophil count after EVT (p = 0.038, OR = 0.001, 95% CI 0.000-0.018) were all found to be independent predictors of HT, with warning values of 6.65%, 22.95 seconds, and 0.035*10^9/L, respectively. When compared to prediction using only demographic data [AUC = 0.662,95% CI (0.545, 0.780)], adding biochemical indices before EVT [AUC = 0.719,95% CI (0.617, 0.821)], adding biochemical indices after EVT [AUC = 0.670,95% CI (0.566, 0.773)], and adding both [AUC = 0.778,95% CI (0.686, 0.870)], the prediction efficiency of HT was improved among all three combinations, with no statistical significance. CONCLUSIONS: The levels of serum biochemical markers were found to show significant changes before and after EVT in ACLVO patients. A combination of demographic data and serum biochemical markers proved to be effective in predicting the occurrence of HT in patients with ACLVO who underwent EVT.
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Biomarcadores , Procedimentos Endovasculares , Humanos , Masculino , Feminino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso de 80 Anos ou mais , Tempo de Tromboplastina Parcial , Hemorragia Cerebral/sangue , Contagem de LeucócitosRESUMO
Designing a nanofluidic membrane with high selectivity and fast ion transport property is the key towards high-performance osmotic energy conversion. However, most of reported membranes can produce power density less than commercial benchmark (5â W/m2), due to the imbalance between ion selectivity and permeability. Here, we report a novel nanoarchitectured design of a heterogeneous membrane with an ultrathin and dense zirconium-based UiO-66-NH2 metal-organic framework (MOF) layer and a highly aligned and interconnected branched alumina nanochannel membrane. The design leads to a continuous trilayered pore structure of large geometry gradient in the sequence from angstrom-scale to nano-scale to sub-microscale, which enables the enhanced directional ion transport, and the angstrom-sized (~6.6-7â Å) UiO-66-NH2 windows render the membrane with high ion selectivity. Consequently, the novel heterogeneous membrane can achieve a high-performance power of ~8â W/m2 by mixing synthetic seawater and river water. The power density can be largely upgraded to an ultrahigh ~17.1â W/m2 along with ~48.5 % conversion efficiency at a 50-fold KCl gradient. This work not only presents a new membrane design approach but also showcases the great potential of employing the zirconium-based MOF channels as ion-channel-mimetic membranes for highly efficient blue energy harvesting.
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The switchable catalysis using a commercial salenMn catalyst was firstly developed and applied in the one-pot selective copolymerization from anhydrides, epoxides, CO2 and ϵ-caprolactone (ϵ-CL) mixtures for the precise synthesis of AB, ABA and novel ABC block copolymers. The observed unique double switch process comprising three different polymerization cycles was rationalized by theoretical calculations. Surprisingly, the first block turned out to be an efficient macromolecular initiator for the consecutive introduction of carbonate linkages into copolymers, albeit with dominant cyclization with the catalyst alone. Further, through the selective reaction on different epoxides, the switchable copolymerization of up to five monomers was achieved yielding well-defined multi-block copolymers with structural diversity and functionality.
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Reported here is a concise total synthesis of (-)-berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa-Michael cascade for the construction of the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late-stage Ni-catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.
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Homeobox B7 (HOXB7) protein is reported to be aberrantly expressed in a variety of cancers and to play an important role in multiple cellular processes. However, the specific mechanism by which HOXB7 promotes the malignant progression of intrahepatic cholangiocarcinoma (ICC) remains unclear. Therefore, we used quantitative real-time polymerase chain reaction (PCR) to detect the expression level of HOXB7 in 38 paired ICC tissue samples. Additionally, to assess correlation between HOXB7 and ICC prognosis, we performed immunohistochemistry (IHC) using 122 ICC tissues to detect HOXB7 expression. Cell Counting Kit-8 (CCK-8) and colony formation assays were employed to assess ICC cell proliferation, and Transwell assays were performed to estimate the invasion and migration abilities of ICC cells. The capillary tube formation assay was applied to explore the angiogenic effects of HOXB7. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth and lung metastasis. The results showed higher expression of HOXB7 in ICC tissues than in noncancerous tissues, and this increased expression was significantly associated with a poor prognosis. In addition, HOXB7 overexpression enhanced capillary tube formation, invasion and migration of ICC cells in vitro, whereas HOXB7 knockdown produced the opposite results in vitro. Moreover, the role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that the expression levels of MMP2, MMP9, VEGFa, and IL8 were elevated by HOXB7 and that the ERK pathway was activated. Our results demonstrate the prognostic value of HOXB7 and its role in metastasis and angiogenesis in ICC. HOXB7 upregulated MMP2, MMP9, VEGFa, and IL8 expression via the ERK pathway to accelerate the malignant progression of ICC.
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Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Neovascularização Patológica/metabolismo , Animais , Neoplasias dos Ductos Biliares/mortalidade , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , China/epidemiologia , Colangiocarcinoma/mortalidade , Humanos , Interleucina-8/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Przewalskin A, a novel C23 terpenoid with anti-HIV-1 activity from Salvia przewalskii Maxim, was formed in 10 steps via isorosmanol from (+)-carnosic acid. The synthetic strategy was inspired primarily by the biogenetic hypothesis and was enabled by epoxidation, epoxide ring opening, and lactonization in one pot to prepare the 11,12-dimethoxy isorosmanol, and bismuthonium ylide-induced ring expansion of o-quinone to construct the 2-acyl-3-hydroxytropone.
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Abietanos/química , Materiais Biomiméticos/síntese química , Cicloexanonas/síntese química , Diterpenos/síntese química , Abietanos/síntese química , Materiais Biomiméticos/química , Cicloexanonas/química , Diterpenos/química , Conformação MolecularRESUMO
Purpose: This study aimed to investigate changes in metabolomic expression in the spinal dorsal horn (SDH) and thalamus during a Tuina session, aiming to elucidate the mechanism of immediate analgesia. Methods: The rats were randomly divided into three groups: the Sham group, the Model group, and the Tuina group. A minor chronic constriction injury (minor CCI) model was established in both the Model group and the Tuina group. The therapeutic effect of Tuina was determined using the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. Differential metabolites of the SDH and thalamus were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatic analysis was performed using CV, PCA, Venn, and KEGG. Results: The therapeutic effect of MWT and TWL after instant Tuina intervention was significant. The therapeutic effect of Tuina instant was significantly better compared to the Model group. In the Veen analysis, it was found that Tuina instantly regulates 10 differential metabolites in the SDH and 5 differential metabolites in the thalamus. In the KEGG enrichment analysis, we found that differential metabolites were enriched in 43 pathways in the thalamus and 70 pathways in the SDH. Conclusion: Tuina therapy may have analgesic effects by metabolizing neurotransmitters such as 2-Picolinic Acid, 5-Hydroxy-Tryptophan Glutathione Betaine-aldehyde-chloride Leucine Lysine Methionine Sarcosine Succinic Acid Histidine Acetylcholine and 5-Hydroxyindoleacetic Acid through the cAMP pathway. It also affects pathways of neurodegeneration-multiple diseases, butanoate metabolism, tyrosine metabolism.
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Tuina, as an external treatment method of traditional Chinese medicine, has been proven to have an analgesic effect on peripheral neuropathic pain (pNP) in clinical and basic research. However, the optimal time point for the analgesic effect of tuina may vary according to different injury sensations, affecting the exploration of the initiation mechanism of tuina analgesia. The research used minor chronic constriction injury (minor CCI) model rats to simulate pNP and used the intelligent tuina manipulation simulator to simulate the three methods (point-pressing, plucking, and kneading) and three acupoints (Yinmen BL37, Chengshan BL57, and Yanglingquan GB34) for performing tuina therapy. The study evaluated the changes in pain within 24 h and the optimal time point for the efficacy of tuina analgesia in rats with minor CCI models by testing cold sensitivity threshold (CST), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). Furthermore, the study evaluated IL-10 and TNF-α expression changes through Elisa detection. The results show that tuina has both immediate and sustained analgesic effects. For the three different injury sensitivity thresholds of CST, MWT, TWL, and two cytokines of IL-10 and TNF-α, the analgesic efficacy of tuina within 24 h after intervention is significantly different at different time points.
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Interleucina-10 , Neuralgia , Ratos , Animais , Ratos Sprague-Dawley , Interleucina-10/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Neuralgia/terapia , Analgésicos/farmacologia , Analgésicos/uso terapêuticoRESUMO
Tuina is a treatment method in traditional Chinese medicine which has analgesic effects and effectively alleviates the symptoms of neuropathic pain (NP). Transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) play major roles in transmitting nociceptive sensory signals in the nociceptive primary sensory dorsal root ganglion (DRG) nerve. The nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate(cGMP) pathway exerts both nociceptive and antinociceptive effects in various chronic pain models. TRPV1 and TRPA1 mediate the influx of calcium, which stimulates the generation of NO. Subsequently, NO activates the NO/cGMP/protein kinase G (PKG) signaling pathway, thereby improving hyperalgesia. In the present study, oa rat model of NP with minor chronic constriction injury (CCI) of the right sciatic nerve of NP was established. The results of behavioral testing showed that, after a one-time tuina intervention, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were prolonged to varying degrees in the tuina group compared with the model group. Similarly, the expression of TRPV1, TRPA1, NO, soluble guanylate cyclase ß (sGCß), cGMP, and PKG1 was significantly decreased in the DRG of the tuina and tuina + TRPV1/TRPA1 antagonist group was significantly decreased. These findings suggest that the tuina intervention can effectively improve the symptoms of thermal and mechanical allodynia caused by peripheral nerve injuries. Tuina exerts immediate analgesic effects through the TRPV1/TRPA1-NO-cGMP-PKG signaling pathway.
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GMP Cíclico , Modelos Animais de Doenças , Gânglios Espinais , Ratos Sprague-Dawley , Transdução de Sinais , Canal de Cátion TRPA1 , Canais de Cátion TRPV , Animais , Gânglios Espinais/metabolismo , Canais de Cátion TRPV/metabolismo , Masculino , GMP Cíclico/metabolismo , Canal de Cátion TRPA1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ratos , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Hiperalgesia/metabolismo , Hiperalgesia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional ChinesaRESUMO
The N6-methyladenosine (m6A) RNA binding protein YTHDF1 is frequently overexpressed in colorectal cancer (CRC) and drives chemotherapeutic resistance. To systematically identify druggable targets in CRC with high expression of YTHDF1, we employed a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets.RUVBL1/2 were overexpressed in primary CRC samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth ofYTHDF1-high CRC cells, patient-derived primary CRC organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feed-forward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Co-IP and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribo-seq revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS and PI3K-AKT signaling induced by YTHDF1. Finally, blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing CRC in vitro and in vivo. Together, this study uncovered that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high CRC.
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Acute basilar artery occlusion (ABAO) after endovascular treatment (EVT) is often associated with a poor prognosis, particularly in patients with cerebellar infarction who may develop malignant cerebellar edema. The present study aimed to investigate how massive cerebellar infarction (MCI) affects hospitalization outcomes in ABVO patients who undergo EVT. We conducted a retrospective study of ABVO patients who underwent EVT at our hospital between September 2017 and September 2022. MCI was diagnosed using imaging techniques, and various prognostic scores were assessed during hospitalization to examine the relationship between MCI and these outcomes. We identified 42 ABAO patients, of whom 22 (52.4%) had MCI. Patients with MCI had a higher modified Rankin Scale (mRS) score at discharge compared to those without MCI (4.36 ± 1.14 vs 3.05 ± 1.85, P = .042, odds ratio [OR] (95% confidence interval [CI]) = 1.093 (0.083, 2.103)), and a lower Glasgow Coma Scale score (6.59 ± 4.0 vs 10.10 ± 5.07, P = .036, OR (95% CI) = -3.444 (-6.518, -0.369)). MCI was identified as an independent risk factor for an extremely poor prognosis (mRS ≥ 5) at discharge (P = .036, OR (95% CI) = 15.531 (1.603, 313.026)) and for no improvement in mRS score compared to onset (P = .013, OR (95% CI) = 0.025 (0.001, 0.274)). Additionally, an extremely poor prognosis was independently associated with stent implantation, EVT duration, and body mass index, while mRS score improvement was correlated with EVT duration and pulmonary infection. MCI in ABAO patients is a significant independent risk factor for a poor prognosis at discharge and no improvement in function score compared to onset. Early diagnosis and intervention are necessary to improve outcomes, particularly in high-risk populations.
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Arteriopatias Oclusivas , Isquemia Encefálica , Doenças Cerebelares , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Artéria Basilar , Estudos Retrospectivos , Resultado do Tratamento , Arteriopatias Oclusivas/etiologia , Isquemia Encefálica/etiologia , Trombectomia/métodos , Hospitalização , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Doenças Cerebelares/etiologia , Infarto/etiologia , Acidente Vascular Cerebral/etiologiaRESUMO
Cancer has become a leading cause of death and aroused the cancer scare. Breast and cervical cancer are two main health threats for women. In order to reduce mortality through early detection and early treatment, cancer screening has been widely recommended and applied for breast and cervical cancer detection and prevention. However, the benefit of cancer screening has been a controversial issue for the recent decades. The Chinese government has launched a free screening program on breast and cervical cancer for women since 2009. There is lack of strong data and sufficient information, however, to examine the effect of breast and cervical cancer screening. A Difference-in-Difference model estimated by Cox proportional hazard estimation was applied to evaluate the effects of breast and cervical cancer screening using data from Nown County Cancer Registry between the year 2009 and 2013. Based on the case study in a county of central China, this study found that the screening program reduced the risk of death, but found the lion's share for the benefit has been mainly due to the cervical cancer screening rather breast cancer screening, which may be related to the difference between early detection screening and preventive screening. Our results suggest sufficient funding and better education of related cancer knowledge will be meaningful measures for the prevention and treatment of breast and cervical cancer.
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Neoplasias da Mama , Neoplasias do Colo do Útero , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Longevidade , Programas de Rastreamento/métodos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controleRESUMO
We present a semi-automatic method for producing human bas-relief from a single photograph. Given an input photo of one or multiple persons, our method first estimates a 3D skeleton for each person in the image. SMPL models are then fitted to the 3D skeletons to generate a 3D guide model. To align the 3D guide model with the image, we compute a 2D warping field to non-rigidly register the projected contours of the guide model with the body contours in the image. Then the normal map of the 3D guide model is warped by the 2D deformation field to reconstruct an overall base shape. Finally, the base shape is integrated with a fine-scale normal map to produce the final bas-relief. To tackle the complex intra- and inter-body interactions, we design an occlusion relationship resolution method that operates at the level of 3D skeletons with minimal user inputs. To tightly register the model contours to the image contours, we propose a non-rigid point matching algorithm harnessing user-specified sparse correspondences. Experiments demonstrate that our human bas-relief generation method is capable of producing perceptually realistic results on various single-person and multi-person images, on which the state-of-the-art depth and pose estimation methods often fail.
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Gráficos por Computador , Imageamento Tridimensional , Humanos , Imageamento Tridimensional/métodos , AlgoritmosRESUMO
The purpose of this study is to explore hotspots or clusters of gastrointestinal tumors (GI) and their spatiotemporal distribution characteristics and the changes over time in 293 villages and communities in Jianze County, central China, through the kernel density estimation (KDE) method based on the rarely considered heterogeneous background. The main findings were: (1) Heterogeneous background impact: there were substantial differences in the GI case rate among people of different ages and genders in Jianze County. Specifically, the GI case rate was significantly higher in the elderly population over 65 than in the population under 65, and higher in men than in women. (2) GI in Jianze County exhibited spatial specific and aggregated hotspots. The high-value spatial clusters were mainly located in Hujindian Town in the northern county, Wupu Town and Geputan Town in the middle, and Xiaxindian Town in the south. Some villages had persistent hot spots for multiple years. (3) Most GI hotspots in Jianze County were concentrated in areas with both high density of local chemical plants and with water systems in the neighbourhood. We expect that this study provides a scientific basis for exploring unknown risk factors of tumor occurrence from a spatial perspective in the future.
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Neoplasias Gastrointestinais , Características de Residência , Idoso , China/epidemiologia , Feminino , Neoplasias Gastrointestinais/epidemiologia , Humanos , Masculino , Análise Espacial , Análise Espaço-TemporalRESUMO
Understanding the water content variations in Yunnan laterite (red loam soil, SR) in small-scale environments and exploring the potential for crop water-use efficiency (WUE) improvement are crucial for improving water-saving irrigation technologies used in greenhouse agriculture in Yunnan, China. In this study, a closed-loop model for calculating soil water in greenhouse potted cultivation was established based on water conservation. A Yunnan SR, yellow sand soil (SY), and a 1:1 SR-SY mixture (SM) subjected to root-zone micro-irrigation or surface-drip irrigation were experimentally examined to compare their water content variations and pepper WUEs. The results showed that the soil type and soil type-irrigation mode interaction had significant effects on both soil evaporation and pepper WUE, and that the variations in soil evaporation with respect to time can be expressed using a cubic polynomial function. In small-scale greenhouse cultivation, IG has good water-saving potential and is suitable for the SR (which has a better water-retention capacity), whereas IM is more suitable for the SY (which has a better water-penetration capacity). Mixing certain proportions of the SY into the SR will effectively impact the water content variations and crop WUE and provide opportunities for further improving the water-saving efficiency.
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Metal-organic framework (MOF) membranes are potentially useful in gas separation applications. Conventional methods of MOF membrane preparation require multiple steps and high-pressure conditions. In this study, a reliable one-step interfacial synthesis method under atmospheric pressure has been developed to prepare zeolitic imidazolate framework-8 (ZIF-8) membranes supported on porous α-Al2O3 disks. To obtain optimal ZIF-8 membranes, three reaction parameters were investigated, namely, reaction temperature, reaction time, and concentration of the organic linker (i.e., 2-methylimidazole). The growth of ZIF-8 membranes under various parameters was evaluated by field-emission scanning electron microscopy, and the optimal synthesis conditions were determined (i.e., 80 °C for 12 h in 50 mM of 2-methylimidazole). The as-synthesized ZIF-8 membranes were then applied to CO2/N2 gas separation, which exhibited a maximum separation factor of 5.49 and CO2 gas permeance of 0.47 × 10-7 mol·m-2·s-1·Pa-1.
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Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-ß signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas CRISPR-Cas , Colesterol/biossíntese , Neoplasias do Colo/tratamento farmacológico , Dimetilaliltranstransferase/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Farnesiltranstransferase/antagonistas & inibidores , Geraniltranstransferase/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Apoptose , Proliferação de Células , Colesterol/química , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Humanos , Lovastatina/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Ácido Zoledrônico/administração & dosagemRESUMO
OBJECTIVE: To explore the efficacy difference of electroacupuncture at lower he-sea point and he-sea matching front-mu points for the treatment of gastroparesis. METHODS: A total of 63 patients with gastroparesis were randomly divided into a lower he point group (group A, 32 cases, 2 cases dropped off) and a he matching mu points group (group B, 31 cases, 1 case dropped off). The group A was treated with electroacupuncture at Zusanli (ST 36), and the group B was treated with electroacupuncture at Zusanli (ST 36) and Zhongwan (CV 12). Both groups were treated with continuous wave (2 Hz in frequency) for 30 min, once a day, 5 times a week for 3 weeks. The gastroparesis cardinal symptom index (GCSI) score, gastric half-emptying time (T1/2) and the 180 min gastric residual rate of the two groups before and after treatment were observed, and the clinical effective rate was compared. RESULTS: After treatment, the total GCSI scores, T1/2 and the 180 min gastric residual rates in both groups were lower than those before treatment (P<0.01), and the 180 min gastric residual rate and T1/2 in the group A were lower than those in the group B (P<0.05). The total effective rate was 93.3% (28/30) in the group A, which was superior to 70.0% (21/30) in the group B (P<0.05). CONCLUSION: Electroacupuncture at lower he-sea point and he-sea matching front-mu points can both be used to treat gastroparesis, but electroacupuncture at Zusanli (ST 36) has a better effect. The acupoints of Zusanli (ST 36) and Zhongwan (CV 12) may have antagonistic effects.