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Ultraphotostable phosphorescent nanosensors have been designed for continuously sensing the lysosome pH over a long duration. The nanosensors exhibited excellent photostability, high accuracy, and capability to measure pH values during cell proliferation for up to 7 days. By arranging a metal-ligand complex of long phosphorescence lifetime and pH indicator in silica nanoparticles, we discover efficient Förster resonance energy transfer, which converts the pH-responsive UV-vis absorption signal of the pH indicator into a phosphorescent signal. Both the phosphorescent intensity and lifetime change at different pH values, and intracellular pH values can be accurately measured by our custom-built rapid phosphorescent lifetime imaging microscopy. The excellent photostability, high accuracy, and good biocompatibility prove that these nanosensors are a useful tool for tracing the fluctuation of pH values during endocytosis. The methodology can be easily adapted to design new nanosensors with different pKa or for different kinds of intracellular ions, as there are hundreds of pH and ion indicators readily available.
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Lisossomos , Nanopartículas , Concentração de Íons de Hidrogênio , Lisossomos/química , Lisossomos/metabolismo , Humanos , Nanopartículas/química , Transferência Ressonante de Energia de Fluorescência , Análise de Célula Única , Dióxido de Silício/química , Células HeLa , NanotecnologiaRESUMO
ClC is the main family of natural chloride channel proteins that transport Cl- across the cell membrane with high selectivity. The chloride transport and selectivity are determined by the hourglass-shaped pore and the filter located in the central and narrow region of the pore. Artificial unimolecular channel that mimics both the shape and function of the ClC selective pore is attractive, because it could provide simple molecular model to probe the intriguing mechanism and structure-function relevance of ClC. Here we elaborated upon the concept of molecular hourglass plus anion-π interactions for this purpose. The concept was validated by experimental results of molecular hourglasses using shape-persistent 1,3-alternate tetraoxacalix[2]arene[2]triazine as the central macrocyclic skeleton to control the conductance and selectivity, and anion-π interactions as the driving force to facilitate the chloride dehydration and movement along the channel.
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Incorporation of privileged catalytic scaffolds into a macrocyclic skeleton represents an attractive strategy to furnish supramolecular catalysis systems with enzyme-mimetic cavity and multi-site cooperation. Herein we reported the synthesis, structure, binding properties and catalytic application of a series of chiral bis-phosphate macrocycles toward the challenging asymmetric electrophilic fluorination. With a large, integrated chiral cavity and two cooperative phosphate sites, these macrocycles exhibited good inclusion toward 1,4-diazabicyclo[2.2.2]octane (DABCO) dicationic ammoniums through complementary ion-pair and C-Hâ â â O interactions, as confirmed by crystallographic and solution binding studies. In fluorocyclization of tryptamines with Selectfluor reagent which has a similar DABCO-based dicationic structure, only 2â mol% macrocycle catalyst afforded the desired pyrroloindoline products in moderate yields and up to 91 % ee. For comparison, the acyclic mono-phosphate analogue gave obviously lower reactivity and enantioselectivity (<20 % ee), suggesting a remarkable macrocyclic effect. The high catalytic efficiency and superior stereocontrol were ascribed to the tight ion-pair binding and cavity-directed noncovalent interaction cooperation.
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Silica nanoparticles (SiNPs) with a chemically modified surface typically have a complicated chemical composition, which can significantly differ from their intended design. In this study, we systematically studied the effects of two surface modification methods on active-targeting of intracellular organelles of SiNPs: (1) the widely used step-by-step approach, which involves modifying SiNPs in two steps, i.e., the outer surface of SiNPs was firstly modified with amino groups and then these amino groups were linked with targeting groups, and (2) a newly developed one-step approach in which the ligand-silane complex is initially synthesized, followed by chemically immobilizing the complex on the surface of SiNPs. In the one-step approach, the molar ratio of reactants was precisely tuned so that there are no reactive groups left on the outer surface of SiNPs. Two essential organelles, mitochondria and the nucleus, were selected to compare the targeting performances of SiNPs synthesized via these two approaches. By characterizing physicochemical properties, including structural properties, the number of amino groups, surface charge, polydispersity, and cell colocalization, we demonstrated that SiNPs synthesized via the one-step approach with no residual linkage groups on their surface showed significantly improved mitochondria- and nucleus-targeting performances. This precise control of surface properties allows for optimized biological behavior and active-targeting efficiency of SiNPs. We anticipate that such simple and efficient synthetic strategies will enable the synthesis of effective SiNPs for active-targeting organelles in various biological applications.
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Mitocôndrias , Nanopartículas , Corantes , Silanos , Dióxido de SilícioRESUMO
Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.
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Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Pancreatite/metabolismo , Pancreatite/genética , Pancreatite/patologia , Pancreatite/diagnóstico , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Prognóstico , Regulação Neoplásica da Expressão Gênica , Modelos Animais de Doenças , Linhagem Celular Tumoral , Progressão da DoençaRESUMO
It has long been an aspirational goal to create artificial channel structures that replicate the feat achieved by ion channel proteins. Biological ion channels occasionally demonstrate multiple conductance states (known as subconductance), remaining a challenging property to achieve in artificial channel molecules. We report a funnel-shaped single-molecule channel constructed by an electron-deficient macrocycle and two electron-deficient aromatic imide arms. Planar lipid bilayer measurements reveal distinct current recordings, including a closed state, two conducting states, and spontaneous transitions between the three states, resembling the events seen in biological ion channels. The transitions result from conformational changes induced by chloride transport in the channel molecule. Both opening states show a non-linear and rectifying I-V relationship, indicating voltage-dependent transport due to the asymmetrical channel structure. This work could enhance our understanding of ion permeation and channel opening mechanism.
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Photoactive black-phase formamidinium lead triiodide (α-FAPbI3) perovskite has dominated the prevailing high-performance perovskite solar cells (PSCs), normally for those spin-coated, conventional n-i-p structured devices. Unfortunately, α-FAPbI3 has not been made full use of its advantages in inverted p-i-n structured PSCs fabricated via blade-coating techniques owing to uncontrollable crystallization kinetics and complicated phase evolution of FAPbI3 perovskites during film formation. Herein, a customized crystal surface energy regulation strategy has been innovatively developed by incorporating 0.5â mol % of N-aminoethylpiperazine hydroiodide (NAPI) additive into α-FAPbI3 crystal-derived perovskite ink, which enabled the formation of highly-oriented α-FAPbI3 films. We deciphered the phase transformation mechanisms and crystallization kinetics of blade-coated α-FAPbI3 perovskite films via combining a series of in-situ characterizations and theoretical calculations. Interestingly, the strong chemical interactions between the NAPI and inorganic Pb-I framework help to reduce the surface energy of (100) crystal plane by 42 %, retard the crystallization rate and lower the formation energy of α-FAPbI3. Benefited from multifaceted advantages of promoted charge extraction and suppressed non-radiative recombination, the resultant blade-coated inverted PSCs based on (100)-oriented α-FAPbI3 perovskite films realized promising efficiencies up to 24.16 % (~26.5 % higher than that of the randomly-oriented counterparts), accompanied by improved operational stability. This result represented one of the best performances reported to date for FAPbI3-based inverted PSCs fabricated via scalable deposition methods.
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OBJECTIVE: The incidence of out-of-hospital cardiac arrest (OHCA) is high. Though extracorporeal cardiopulmonary resuscitation (ECPR) has been considered a potential treatment for refractory cardiac arrest after failure of conventional cardiopulmonary resuscitation (CCPR), the benefit of ECPR in refractory OHCA remains uncertain. METHODS: In this retrospective cohort study, we included patients with refractory OHCA who visited the Emergency Department of the Aerospace Center Hospital between January 2018 and April 2023. We divided the patients into the ECPR Group and the CCPR Group. The primary endpoint of the study was the neurological function of the patients in both groups 3 months after the cardiac arrest. We used propensity score matching to reduce selection bias and identified factors associated with good neurological function when OHCA was treated with ECPR by performing univariate and multivariate correlation analyses on surviving patients with good neurological function in the ECPR group. RESULTS: During the study period, we enrolled 133 patients, consisting of 33 in the ECPR group and 100 in the CCPR group. The survival rate of patients with good neurological function at discharge was 18.2% (6/33 cases) in the ECPR group and 9% (9/100 cases) in the CCPR group, p = .20. Three months after discharge, the survival rate of patients with good neurological function was 15.2% (5/33 cases) in the ECPR group and 8% (8/100 cases) in the CCPR group, p = .31. Using propensity score matching, we identified 22 pairs of patients for further analysis. Among these, 3 months after discharge, the survival rate of patients with good neurological function was 13.6% (3/22 cases) in the ECPR group and 4.5% (1/22 cases) in the CCPR group, p = .61, and the survival rate at discharge was 18.2% (4/22 cases) in the ECPR group and 4.5% (1/22 cases) in the CCPR group, p = .34. The univariate analysis of patients with good neurological function in the ECPR group showed that time without perfusion, hypoperfusion time, and PCI treatment were associated factors affecting the prognosis of neurological function in patients, while multivariate analysis showed that hypoperfusion time was independently associated with good neurological function, with an OR (95% CI) of 1.06 (1.00-1.14) and p = .05. CONCLUSION: Our findings suggested that ECPR failed to significantly improve neurological outcome in patients with refractory OHCA; however, the small sample size in this study may be insufficient to detect clinically relevant differences. In addition, hypoperfusion time may be a key predictive factor in identifying candidates for ECPR.
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Colon cancer ranks as the third most prevalent form of cancer globally, with chemotherapy remaining the primary treatment modality. To mitigate drug resistance and minimize adverse effects associated with chemotherapy, selection of appropriate adjuvants assumes paramount importance. Caffeic acid phenethyl ester (CAPE), a naturally occurring compound derived from propolis, exhibits a diverse array of biological activities. We observed that the addition of CAPE significantly augmented the drug sensitivity of colon cancer cells to oxaliplatin. In SW480 and HCT116 cells, oxaliplatin combined with 10 µM CAPE reduced the IC50 of oxaliplatin from 14.24 ± 1.03 and 84.16 ± 3.02 µM to 2.11 ± 0.15 and 3.92 ± 0.17 µM, respectively. We then used proteomics to detect differentially expressed proteins in CAPE-treated SW480 cells and found that the main proteins showing changes in expression after CAPE treatment were p62 (SQSTM1) and LC3B (MAP1LC3B). Gene ontology analysis revealed that CAPE exerted antitumor and chemotherapy-sensitization effects through the autophagy pathway. We subsequently verified the differentially expressed proteins using immunoblotting. Simultaneously, the autophagy inhibitor bafilomycin A1 and the mCherry-EGFP-LC3 reporter gene were used as controls to detect the effect of CAPE on autophagy levels. Collectively, the results indicate that CAPE may exert antitumor and chemotherapy-sensitizing effects by inhibiting autophagy, offering novel insights for the development of potential chemosensitizing agents.
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Autofagia , Ácidos Cafeicos , Neoplasias do Colo , Oxaliplatina , Álcool Feniletílico , Humanos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Autofagia/efeitos dos fármacos , Oxaliplatina/farmacologia , Ácidos Cafeicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Células HCT116 , Sinergismo Farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacosRESUMO
BACKGROUND: Hemichorea and other hyperkinetic movement disorders are uncommon presentations of stroke and are usually secondary to deep infarctions affecting the basal ganglia and thalamus. Therefore, temporal ischemic lesions causing hemichorea are rare. We report the cases of two patients with acute ischemic temporal lobe infarct strokes that presented as hemichorea. CASE SUMMARY: Patient 1: An 82-year-old woman presented with a 1-mo history of involuntary movement of the left extremity, which was consistent with hemichorea. Her diffusion-weighted imaging (DWI) revealed an acute ischemic stroke that predominantly affected the right temporal cortex, and magnetic resonance angiography of the head showed significant stenosis of the right middle cerebral artery (MCA). Treatment with 2.5 mg of olanzapine per day was initiated. When she was discharged from the hospital, her symptoms appeared to have improved compared with those previously observed. Twenty-seven days after the first admission, she was readmitted due to acute ischemic stroke. Computed tomography perfusion showed marked hypoperfusion in the right MCA territory. An emergency transfemoral cerebral angiogram was performed and showed severe stenosis in the M1 segment of the right MCA. After percutaneous transluminal angioplasty was successfully performed, abnormal movements or other neurologic problems did not occur. Patient 2: A 76-year-old man was admitted to our hospital for a 7-d history of right-upper-sided involuntary movements. DWI showed an acute patchy ischemic stroke in the left temporal lobe without basal ganglia involvement. Subsequent diffusion tensor imaging confirmed fewer white matter fiber tracts on the left side than on the opposite side. Treatment with 2.5 mg of olanzapine per day improved his condition, and he was discharged. CONCLUSION: When acute hemichorea suddenly appears, temporal cortical ischemic stroke should be considered a possible diagnosis. In addition, hemichorea may be a sign of impending cerebral infarction with MCA stenosis.
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We report herein the synthesis of highly enantiopure inherently chiral N3,O-calix[2]arene[2]triazines from enantioselective macrocyclization enabled by chiral phosphoric acid-catalyzed intramolecular nucleophilic aromatic substitution reaction. In contrast to documented examples, the inherent chirality of the acquired compounds arises from one heteroatom difference in the linking positions of heteracalix[4](het)arenes.
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The clinical application of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) is restricted by its short serum half-life. Herein, site-selective modification of the N-terminus of rhG-CSF with PAL-PEG3-Ph-CHO was used to develop a long-acting rhG-CSF. The optimized conditions for rhG-CSF modification with PAL-PEG3-Ph-CHO were: reaction solvent system of 3% (w/v) Tween 20 and 30 mM NaCNBH3 in acetate buffer (20 mmol/L, pH 5.0), molar ratio of PAL-PEG3-Ph-CHO to rhG-CSF of 6:1, temperature of 20°C, and reaction time of 12 h, consequently, achieving a PAL-PEG3-Ph-rhG-CSF product yield of 70.8%. The reaction mixture was purified via preparative liquid chromatography, yielding the single-modified product PAL-PEG3-Ph-rhG-CSF with a HPLC purity exceeding 95%. The molecular weight of PAL-PEG3-Ph-rhG-CSF was 19297 Da by MALDI-TOF-MS, which was consistent with the theoretical value. The circular dichroism analysis revealed no significant change in its secondary structure compared to unmodified rhG-CSF. The PAL-PEG3-Ph-rhG-CSF retained 82.0% of the in vitro biological activity of unmodified rhG-CSF. The pharmacokinetic analyses showed that the serum half-life of PAL-PEG3-Ph-rhG-CSF was 7.404 ± 0.777 h in mice, 4.08 times longer than unmodified rhG-CSF. Additionally, a single subcutaneous dose of PAL-PEG3-Ph-rhG-CSF presented comparable in vivo efficacy to multiple doses of rhG-CSF. This study demonstrated an efficacious strategy for developing long-acting rhG-CSF drug candidates.
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OBJECTIVE: To construct percutaneous vertebroplasty for predicting osteoporotic vertebral compression fractures (OVCFs) nomogram of residual back pain (RBP) after percutaneous vertebroplasty(PVP). METHODS: Clinical data of 245 OVCFs patients who were performed PVP from January 2020 to December 2022 were retrospectively analyzed, including 47 males and 198 females, aged from 65 to 77 years old with an average of (71.47±9.03) years old, and were divided into RBP group and non-RBP group according to whether RBP occurred. Gender, age, comorbidities, fracture stage, body mass index (BMI), bone mineral density (BMD), visual analogue scale (VAS), Oswestry disability index (ODI) and other general information were collected; anterior vertebral height (AVH), anterior vertebral height ratio (AVH), anterior vertebral height ratio(AVHR), Cobb angle, intravertebral vacuum cleft (IVC), thoracolumbar fascia (TLF) injury, paravertebral muscle steatosis, injection volume and leakage of bone cement, bone cement dispersion pattern, anterior vertebral height recovery ratio (AVHRR), Cobb angle changes, etc. imaging parameters before operation and 24 h after operation were collected. Univariate analysis was performed to analysis above factors, and multivariate Logistic regression model was used to investigate independent risk factors for postoperative RBP, and Nomogram model was constructed and verified;receiver operating characteristic(ROC) curve and calibration curve were used to determine predictive performance and accuracy of the model, and Hosmer-Lemeshow (H-L) test was used for evaluation. The area under curve (AUC) of ROC was calculated, and Harrell consistency index (C index) was used to evaluate the predictive efficiency of model;decision curve analysis (DCA) was used to evaluate clinical practicability of model. RESULTS: There were 34 patients in RBP group and 211 patients in non-RBP group. There were no significant differences in gender, age, comorbidities, fracture stage, BMI, BMD, VAS, ODI, AVH, AVHR and Cobb angle between two groups (P>0.05). Univariate analysis showed 6 patients occurred IVC in RBP group and 13 patients in non-RBP, the number of IVC in RBP group was higher than that in non-RBP group (χ2=5.400, P=0.020);6 patients occuured TLF injury in RBP group and 11 patients in non-RBP group, the number of TLF injury in RBP group was higher than that in non-RBP group (χ2=7.011, P=0.008);In RBP group, 18 patients with grade 3 to 4 paraptebral steatosis and 41 patients in non-RBP group, RBP group was higher than non-RBP group (χ2=21.618, P<0.001), and the proportion of bone cement mass in RBP group was higher than non-RBP group (χ2=6.836, P=0.009). Multivariate Logistic regression analysis showed IVC (χ2=4.974, P=0.025), TLF injury (χ2=5.231, P=0.023), Goutallier grade of paravertebral steatosis >2 (χ2=15.124, P<0.001) and proportion of bone cement (χ2=4.168, P=0.038) were independent risk factors for RBP after PVP. ROC curve of model showed AUC of original model was 0.816[OR=2.862, 95%CI (0.776, 0.894), P<0.001]. The internal verification of model through 200 bootstrap samples showed the value of C index was 0.936, and calibration curve showed predicted probability curve was close to actual probability curve. H-L goodness of fit test results were χ2=5.796, P=0.670. DCA analysis results showed the decision curve was above None line and All line when the threshold value ranged from 6% to 71%. CONCLUSION: IVC, TLF combined injury, paravertebral muscle steatosis with Goutallier grade> 2, and bone cement diffusion with mass type are independent risk factors for RBP after PVP. The risk prediction model for RBP after PVP established has good predictive performance and good clinical practicability.
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Dor nas Costas , Fraturas por Compressão , Nomogramas , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Masculino , Feminino , Idoso , Fraturas por Compressão/cirurgia , Vertebroplastia/métodos , Fraturas da Coluna Vertebral/cirurgia , Fraturas por Osteoporose/cirurgia , Estudos Retrospectivos , Dor nas Costas/etiologiaRESUMO
Presented herein is the exploration of a novel non-covalent anion-carbonyl (X-···CâO) interaction using aromatic imides as receptors and halides as lone pair donors. Combined theoretical calculations and experimental methods including 13C NMR, IR, and crystallographic analyses were performed to provide the physical origin and experimental evidence of anion-carbonyl interactions. The EDA analysis (energy decomposition analysis) based on DFT calculation indicates that electrostatic terms are the dominant contributions for the binding energy while electron delocalization also significantly contributes alongside the electrostatic attraction. Orbital interaction (n â π*) involving the delocalization of halide lone pairs on the carbonyl antibonding orbitals was visualized with NBO (Natural Bond Orbital) analysis. 13C NMR and IR spectra demonstrated upfield chemical shifts and red-shift frequency of hosts upon the addition of halides, reflecting the effect of orbital overlap between the halide lone pairs and π* of carbonyl (n â π* contribution). The anion-carbonyl interactions were directly revealed by X-ray structural analysis of anion and benzene triimide complexes.
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Shallow groundwater is the main source of water for living and industrial and agricultural production in Anqing City, which is an important basic guarantee to maintain the sustainable development of the social economy and regional ecological environment. In order to further study the water chemical characteristics and controlling factors of shallow groundwater in Anqing City, 196 groups of shallow groundwater samples were collected. A Piper diagram graph, Gibbs chart, ion ratio, and mathematical statistics were comprehensively used to study the water chemical characteristics and controlling factors of groundwater in Anqing City, and the contribution of different sources to the water chemical components of groundwater was quantitatively evaluated. The results showed that the shallow groundwater in Anqing City was weakly alkaline, with pH values ranging from 5.84 to 8.38, with an average value of 7.21. The TDS ranged from 47 to 1 620 mg·L-1, with an average of 324.21 mg·L-1. HCO3- and Ca2+ were the main anions, and the water chemical type was HCO3-Ca type. The chemical components of groundwater were affected by rock weathering leaching, cation alternating adsorption, mineral dissolution and precipitation, and human activities. Ca2+, Mg2+, and HCO3- were mainly derived from the weathering dissolution of carbonate and silicate; Na+, Cl-, and SO42- were affected by industrial activities and domestic sewage discharge; and K+ and NO3- were affected by agricultural activities. The APCS-MLR receptor model analysis further revealed that the chemical components of groundwater were mainly geological factors, industrial factors, agricultural factors, and unknown sources, and their contribution rates were 45.35%, 14.19%, 25.38%, and 15.08%, respectively. Geological factors were important sources of hydrochemical components of shallow groundwater, and human activities aggravated the evolution of groundwater hydrochemistry.
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An intriguing phenomenon in molecular collisions is the occurrence of scattering resonances, which originate from bound and quasi-bound states supported by the interaction potential at low collision energies. The resonance effects in the scattering behavior are extraordinarily sensitive to the interaction potential, and their observation provides one of the most stringent tests for theoretical models. We present high-resolution measurements of state-resolved angular scattering distributions for inelastic collisions between Zeeman-decelerated C(3P1) atoms and para-H2 molecules at collision energies ranging from 77 cm-1 down to 0.5 cm-1. Rapid variations in the angular distributions were observed, which can be attributed to the consecutive reduction of contributing partial waves and effects of scattering resonances. The measurements showed excellent agreement with distributions predicted by ab initio quantum scattering calculations. However, discrepancies were found at specific collision energies, which most likely originate from an incorrectly predicted quasi-bound state. These observations provide exciting prospects for further high-precision and low-energy investigations of scattering processes that involve paramagnetic species.
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Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteína BRCA1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteômica , Proteína BRCA2/genética , Proteínas Oncogênicas , Linhagem Celular Tumoral , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases/genéticaRESUMO
Abstract Serrapeptase, a proteolytic enzyme, has been used for the adjuvant treatment of many diseases. However, its fibrinolytic activity is still uncertain. Herein, the fibrinolytic activity of serrapeptase and its in vitro thrombolytic effects were investigated. The results showed that the fibrinolytic activity of serrapeptase was 1295 U/mg, and the specific activity was 3867 U/mg of protein when its proteolytic activity toward casein was 2800 U/mg. The optimum temperature and pH for serrapeptase activity were 37-40°C and 9.0, respectively. At 1 mmol/L, Zn2+, Mn2+ and Fe2+ could activate the fibrinolytic activity of serrapeptase, while K+, Cu2+, sodium dodecyl sulfate (SDS) and ethylene diamine tetraacetic acid (EDTA) inhibited it. In vitro tests showed that serrapeptase could completely prevent blood coagulation at 150 U/mL, and the percentage of blood clot lysis reached 96.6% at 37°C after 4 h at 300 U/mL. These results indicate that serrapeptase has excellent fibrinolytic activity, and can be used as a health food or candidate drug for the prevention or treatment of thrombotic diseases.
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Trombose/patologia , Técnicas In Vitro/métodos , Peptídeo Hidrolases/efeitos adversos , Preparações Farmacêuticas/administração & dosagemRESUMO
We investigated inheritance and carried out gene fine mapping of aroma in crosses between the aromatic elite hybrid rice Oryza sativa indica variety Chuanxiang-29B (Ch-29B) and the non-aromatic rice O. sativa indica variety R2 and O. sativa japonica Lemont (Le). The F1 grains and leaves were non-aromatic while the F2 non-aroma to aroma segregation pattern was 3:1. The F3 segregation ratio was consistent with the expected 1:2:1 for a single recessive aroma gene in Ch-29B. Linkage analysis between simple sequence repeat (SSR) markers and the aroma locus for the aromatic F2 plants mapped the Ch-29B aroma gene to a chromosome 8 region flanked by SSR markers RM23120 at 0.52 cM and RM3459 at 1.23 cM, a replicate F2 population confirming these results. Three bacterial artificial chromosome (BAC) clones cover chromosome 8 markers RM23120 and RM3459. Our molecular mapping data from the two populations indicated that the aroma locus occurs in a 142.85 kb interval on BAC clones AP005301 or AP005537, implying that it might be the same gene reported by Bradbury et al (2005a; Plant Biotec J. 3:363-370). The flanking markers Aro7, RM23120 and RM3459 identified by us could greatly accelerate the efficiency and precision of aromatic rice breeding programs.