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1.
PLoS Biol ; 21(12): e3002429, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38079456

RESUMO

Motile bacteria navigate toward favorable conditions and away from unfavorable environments using chemotaxis. Mechanisms of sensing attractants are well understood; however, molecular aspects of how bacteria sense repellents have not been established. Here, we identified malate as a repellent recognized by the MCP2201 chemoreceptor in a bacterium Comamonas testosteroni and showed that it binds to the same site as an attractant citrate. Binding determinants for a repellent and an attractant had only minor differences, and a single amino acid substitution in the binding site inverted the response to malate from a repellent to an attractant. We found that malate and citrate affect the oligomerization state of the ligand-binding domain in opposing way. We also observed opposing effects of repellent and attractant binding on the orientation of an alpha helix connecting the sensory domain to the transmembrane helix. We propose a model to illustrate how positive and negative signals might be generated.


Assuntos
Proteínas de Bactérias , Malatos , Proteínas Quimiotáticas Aceptoras de Metil/química , Proteínas de Bactérias/metabolismo , Ligantes , Escherichia coli/metabolismo , Quimiotaxia/fisiologia , Bactérias/metabolismo , Citratos
2.
Circ Res ; 134(7): e17-e33, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38420756

RESUMO

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.


Assuntos
Catepsina D , Diabetes Mellitus Tipo 2 , Monócitos , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Catepsina D/metabolismo , Catepsina D/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Precursores Enzimáticos , Camundongos Transgênicos , Monócitos/metabolismo , Transcitose/fisiologia
3.
J Neurosci ; 44(35)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39060175

RESUMO

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remain elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca2+-binding protein, in ribosomal RNA (rRNA) biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca2+-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DEAD (Asp-Glu-Ala-Asp) box RNA helicase (DDX21) in a Ca2+-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of ribosomal DNA. Using high-throughput screening, we identified the small molecules batefenterol and indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.


Assuntos
Calmodulina , RNA Helicases DEAD-box , Hipocampo , RNA Ribossômico , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Animais , RNA Ribossômico/metabolismo , Calmodulina/metabolismo , Hipocampo/metabolismo , Hipocampo/citologia , Humanos , Neurônios/metabolismo , Ratos , Nucléolo Celular/metabolismo , Células Cultivadas , Células HEK293 , Camundongos , Cálcio/metabolismo
4.
Nature ; 554(7691): 234-238, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29420476

RESUMO

High species diversity may result from recent rapid speciation in a 'cradle' and/or the gradual accumulation and preservation of species over time in a 'museum'. China harbours nearly 10% of angiosperm species worldwide and has long been considered as both a museum, owing to the presence of many species with hypothesized ancient origins, and a cradle, as many lineages have originated as recent topographic changes and climatic shifts-such as the formation of the Qinghai-Tibetan Plateau and the development of the monsoon-provided new habitats that promoted remarkable radiation. However, no detailed phylogenetic study has addressed when and how the major components of the Chinese angiosperm flora assembled to form the present-day vegetation. Here we investigate the spatio-temporal divergence patterns of the Chinese flora using a dated phylogeny of 92% of the angiosperm genera for the region, a nearly complete species-level tree comprising 26,978 species and detailed spatial distribution data. We found that 66% of the angiosperm genera in China did not originate until early in the Miocene epoch (23 million years ago (Mya)). The flora of eastern China bears a signature of older divergence (mean divergence times of 22.04-25.39 Mya), phylogenetic overdispersion (spatial co-occurrence of distant relatives) and higher phylogenetic diversity. In western China, the flora shows more recent divergence (mean divergence times of 15.29-18.86 Mya), pronounced phylogenetic clustering (co-occurrence of close relatives) and lower phylogenetic diversity. Analyses of species-level phylogenetic diversity using simulated branch lengths yielded results similar to genus-level patterns. Our analyses indicate that eastern China represents a floristic museum, and western China an evolutionary cradle, for herbaceous genera; eastern China has served as both a museum and a cradle for woody genera. These results identify areas of high species richness and phylogenetic diversity, and provide a foundation on which to build conservation efforts in China.


Assuntos
Biodiversidade , Magnoliopsida/classificação , Filogenia , China , Conservação dos Recursos Naturais/métodos , Evolução Molecular , Mapeamento Geográfico , Análise de Regressão , Análise Espaço-Temporal
5.
BMC Pulm Med ; 24(1): 500, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39390494

RESUMO

BACKGROUND: One-lung ventilation and intrathoracic operations during thoracoscopic surgery often result in intraoperative hypoxaemia and haemodynamic fluctuations, resulting in perioperative myocardial injury. Dexmedetomidine, an alpha-2 (α-2) agonist, has demonstrated myocardial protection. We hypothesize that the routine intravenous administration of dexmedetomidine could reduce the extent of myocardial injury during video-assisted thoracoscopic surgery (VATS). METHODS: The study included patients aged ≥ 45 years, classified as American Society of Anesthesiologists physical status I-III, who underwent general anesthesia for video-assisted thoracoscopic surgery. The patients were randomly assigned to either the intervention group, receiving general anesthesia with dexmedetomidine, or the control group, receiving general anesthesia without dexmedetomidine. Patients in the intervention group received a loading dose of dexmedetomidine (0.5 µg·kg-1) before anesthesia induction, followed by a continuous infusion (0.5 µg·kg-1·h-1) until the completion of the surgery. Placebos (saline) were administered for the control group to match the treatment. The primary outcome assessed was the high-sensitivity cardiac troponin T on postoperative day 1. Additionally, the incidence of myocardial injury after noncardiac surgery (MINS) was noted. RESULTS: A total of 110 participants completed this study. The median [interquartile range (IQR)] concentration of hs-cTnT on postoperative day 1 was lower in the intervention group compared with the control group (7 [6-9] vs. 8 [7-11] pg·ml-1; difference in medians,1 pg·ml-1; 95% confidence interval [CI], 0 to 2; P = 0.005). Similarly, on postoperative day 3, the median [IQR] concentration of hs-cTnT in the intervention group was also lower than that in the control group (6 [5-7] vs. 7 [6-9]; difference in medians,1 pg·ml-1; 95%CI, 0 to 2; P = 0.011). Although the incidence of MINS was not statistically significant (the intervention group vs. the control group, 3.8% vs. 9.1%, P = 0.465), there was a decreasing trend in the incidence of MINS in the intervention group. CONCLUSION: The administration of perioperative dexmedetomidine in patients ≥ 45 years undergoing video-assisted thoracoscopic surgery could lower the release of postoperative hs-cTnT without reducing incidence of myocardial injury. TRIAL REGISTRATION: chictr.org.cn (ChiCTR2200063193); prospectively registered 1 September 2022.


Assuntos
Dexmedetomidina , Cirurgia Torácica Vídeoassistida , Troponina T , Humanos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Masculino , Feminino , Cirurgia Torácica Vídeoassistida/efeitos adversos , Troponina T/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anestesia Geral/métodos , Método Duplo-Cego
6.
Chin J Traumatol ; 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38688817

RESUMO

PURPOSE: The retear rate of rotator cuff (RC) after surgery is high, and the rapid and functional enthesis regeneration remains a challenge. Whether acellular amniotic membrane (AAM) helps to promote the healing of tendon to bone and which treatment is better are both unclear. The study aims to investigate the effect of AAM on the healing of RC and the best treatment for RC repair. METHODS: Thirty-three Sprague Dawley rats underwent RC transection and repair using microsurgical techniques and were randomly divided into the suturing repair only (SRO) group (n = 11), the AAM overlaying (AOL) group (n = 11), and the AAM interposition (AIP) group (n = 11), respectively. Rats were sacrificed at 4 weeks, then examined by subsequent micro-CT, and evaluated by histologic and biomechanical tests. The statistical analyses of one-way ANOVA or Kruskal-Wallis test were performed using with SPSS 23.0. A p < 0.05 was considered a significant difference. RESULTS: AAM being intervened between tendon and bone (AIP group) or overlaid over tendon to bone junction (AOL group) in a rat model, promoted enthesis regeneration, increased new bone and cartilage generation, and improved collagen arrangement and biomechanical properties in comparison with suturing repair only (SRO group) (AOL vs. SRO, p < 0.001, p = 0.004, p = 0.003; AIP vs. SRO, p < 0.001, p < 0.001, p < 0.001). Compared with the AOL group, the AIP group had better results in micro-CT evaluation, histological score, and biomechanical testing (p = 0 0.039, p = 0.011, p = 0.003, respectively). CONCLUSION: In the RC repair model, AAM enhanced regeneration of the tendon to bone junction. This regeneration was more effective when the AAM was intervened at the tendon to bone interface than overlaid above the tendon to bone junction.

7.
Biochemistry ; 62(20): 2997-3011, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37793002

RESUMO

To improve targeted cargo delivery to cancer cells, pH-Low Insertion Peptide (pHLIP) variants were developed to interact with the membrane at pH values higher than those of the WT. The Asp-to-Glu variants aim to increase side chain pKa without disturbing the sequence of protonations that underpin membrane insertion. The Thr19 variants represent efforts to perturb the critical Pro20 residue. To study the effect of cargo on pHLIP insertion, doxorubicin (Dox), a fluorescent antineoplastic drug, was conjugated to selected variants near the inserting C-terminus. Variants and conjugates were characterized on a POPC membrane using Trp and Dox fluorescence methods to define the entire pH range of insertion (pHinitial-pHfinal). Compared to WT with a pHi-pHf range of 6.7-5.6, D25E-D31E-D33E, D14E-D25E-D31E-D33E, and T19V-D25E variants demonstrated higher pHi-pHf ranges of 7.3-6.1, 7.3-6.3, and 8.2-5.4, respectively. The addition of Dox expanded the pHi-pHf range, mainly by shifting pHi to higher pH values (e.g., WT pHLIP-Dox has a pHi-pHf range of 7.7-5.2). Despite the low Hill coefficient observed for the conjugates, D14E-D25E-D31E-D33E pHLIP-Dox completed insertion by a pHf of 5.7. However, the Dox cargo remained in the hydrophobic membrane interior after pHLIP insertion, which may impede drug release. Finally, a logistic function can describe pHLIP insertion as a peripheral-to-TM (start-to-finish) two-state transition; wherever possible, we discuss data deviating from such sigmoidal fitting in support of the idea that pH-specific intermediate states distinct from the initial peripheral state and the final TM state exist at intervening pH values.


Assuntos
Antineoplásicos , Doxorrubicina , Concentração de Íons de Hidrogênio , Doxorrubicina/química , Peptídeos/química
8.
Artigo em Inglês | MEDLINE | ID: mdl-37167094

RESUMO

Two moderately halotolerant bacterium strains, designated PJ-16T and PJ-38, were isolated from a tidal flat of the red beach in Panjin City, Liaoning Province, PR China. Cells were found to be Gram-stain-negative, aerobic, motile, rod-shaped with a single polar flagellum. Optimum growth of strain PJ-16T occurred at 30 °C, pH 7.0 and 0.2-8.0  % (w/v) NaCl, and strain PJ-38 at 30 °C, pH 6.0-7.0 and 0.2-8.0  % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain PJ-16T was most closely related to Marinobacter denitrificans KCTC 62941T (99.2 % 16S rRNA gene sequence similarity), Marinobacter algicola DSM 16394T (98.6 %), Marinobacter salarius JCM 19399T (98.4 %) and Marinobacter confluentis KCTC 42705T (98.2 %), and strain PJ-38 was most closely related to M. denitrificans KCTC 62941T (99.1 %), M. algicola DSM 16394T (98.6 %), M. salarius JCM 19399T (98.4 %) and M. confluentis KCTC 42705T (98.1 %). The G+C content of the genomic DNA of strain PJ-16T based on its draft genomic sequence was 57.4 mol%. The major cellular fatty acids of strain PJ-16T were C16 : 0, C16 : 1 ω7c/C16 : 1 ω6c and C18 : 1 ω9c. The major respiratory quinone of PJ-16T was ubiquinone-9 and the major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The results of the phenotypic, phylogenetic and genomic analyses revealed that strains PJ-16T and PJ-38 represent a novel species of the genus Marinobacter, and the name Marinobacter panjinensis sp. nov. is proposed. The type strain is PJ-16T (= CGMCC 1.13694T= KCTC 72023T).


Assuntos
Ácidos Graxos , Marinobacter , Ácidos Graxos/química , Fosfolipídeos/química , Água do Mar/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Cloreto de Sódio , DNA Bacteriano/genética , Análise de Sequência de DNA , Composição de Bases , Técnicas de Tipagem Bacteriana
9.
Stat Med ; 42(29): 5491-5512, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-37816678

RESUMO

Joint models for longitudinal and survival data (JMLSs) are widely used to investigate the relationship between longitudinal and survival data in clinical trials in recent years. But, the existing studies mainly focus on independent survival data. In many clinical trials, survival data may be bivariately correlated. To this end, this paper proposes a novel JMLS accommodating multivariate longitudinal and bivariate correlated time-to-event data. Nonparametric marginal survival hazard functions are transformed to bivariate normal random variables. Bayesian penalized splines are employed to approximate unknown baseline hazard functions. Incorporating the Metropolis-Hastings algorithm into the Gibbs sampler, we develop a Bayesian adaptive Lasso method to simultaneously estimate parameters and baseline hazard functions, and select important predictors in the considered JMLS. Simulation studies and an example taken from the International Breast Cancer Study Group are used to illustrate the proposed methodologies.


Assuntos
Algoritmos , Modelos Estatísticos , Humanos , Teorema de Bayes , Análise Multivariada , Simulação por Computador
10.
Phys Chem Chem Phys ; 26(1): 261-266, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38055329

RESUMO

With the rise of two-dimensional (2D) materials, unique properties that are completely distinct from bulk counterparts continue to emerge at low-dimensional scales, presenting numerous opportunities and challenges. It also provides a new perspective for the study of transition metal systems. Here, based on density functional theory (DFT), the physical properties of 2D monolayer LiV2S4 have been studied. Remarkable changes have been observed, i.e., vanadium dimerization, ferromagnetism, charge distribution and metal-insulator transition (MIT). It is argued that the electronic instability leads to the V dimerization, which further lifts the degeneracy of charge distribution and stabilizes the charge and spin ordering state.

11.
Environ Res ; 237(Pt 1): 116860, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37562738

RESUMO

Glyphosate, the most widely used herbicide globally, has been linked to neurological impairments in some occupational studies. However, the potential neurotoxic effects of glyphosate exposure in the general population are still not fully understood. We conducted analyses on existing data collected from 1532 adults of the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the possible relationship between glyphosate exposure and cognitive function, depressive symptoms, disability, and neurological medical conditions. Our results showed a significant negative association between urinary glyphosate levels and the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD-WLT) trial 3 recall and delayed recall scores in both models, with ß coefficients of -0.288 (S.E. = 0.111, P = 0.021) and -0.426 (S.E. = 0.148, P = 0.011), respectively. Furthermore, the odds ratio did not show a significant increase with the severity of depressive symptoms with a one-unit increase in ln-glyphosate levels. However, the odds ratio for severe depressive symptoms was significantly higher than for no symptoms (odds ratio = 4.148 (95% CI = 1.009-17.133), P = 0.049). Notably, the odds ratio showed a significant increase for individuals with serious hearing difficulty (odds ratio = 1.354 (95% CI = 1.018-1.800), P = 0.039) with a one-unit increase in ln-glyphosate levels, but not for other neurological medical conditions. In conclusion, our findings provide the first evidence that glyphosate exposure may be associated with neurological health outcomes in the US adult population. Additional investigation is necessary to understand the potential mechanisms and clinical significance of these correlations.

12.
BMC Pulm Med ; 23(1): 353, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37726724

RESUMO

BACKGROUND: Minimising postoperative pulmonary complications (PPCs) after thoracic surgery is of utmost importance. A major factor contributing to PPCs is the driving pressure, which is determined by the ratio of tidal volume to lung compliance. Inhalation and intravenous administration of penehyclidine can improve lung compliance during intraoperative mechanical ventilation. Therefore, our study aimed to compare the efficacy of inhaled vs. intravenous penehyclidine during one-lung ventilation (OLV) in mitigating driving pressure and mechanical power among patients undergoing thoracic surgery. METHODS: A double-blind, prospective, randomised study involving 176 patients scheduled for elective thoracic surgery was conducted. These patients were randomly divided into two groups, namely the penehyclidine inhalation group and the intravenous group before their surgery. Driving pressure was assessed at T1 (5 min after OLV), T2 (15 min after OLV), T3 (30 min after OLV), and T4 (45 min after OLV) in both groups. The primary outcome of this study was the composite measure of driving pressure during OLV. The area under the curve (AUC) of driving pressure from T1 to T4 was computed. Additionally, the secondary outcomes included mechanical power, lung compliance and the incidence of PPCs. RESULTS: All 167 participants, 83 from the intravenous group and 84 from the inhalation group, completed the trial. The AUC of driving pressure for the intravenous group was 39.50 ± 9.42, while the inhalation group showed a value of 41.50 ± 8.03 (P = 0.138). The incidence of PPCs within 7 days after surgery was 27.7% in the intravenous group and 23.8% in the inhalation group (P = 0.564). No significant differences were observed in any of the other secondary outcomes between the two groups (all P > 0.05). CONCLUSIONS: Our study found that among patients undergoing thoracoscopic surgery, no significant differences were observed in the driving pressure and mechanical power during OLV between those who received an intravenous injection of penehyclidine and those who inhaled it. Moreover, no significant difference was observed in the incidence of PPCs between the two groups.


Assuntos
Ventilação Monopulmonar , Humanos , Estudos Prospectivos , Mecânica Respiratória , Administração Intravenosa , Complicações Pós-Operatórias , Toracoscopia
13.
Chin Med Sci J ; 38(2): 147-158, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37280723

RESUMO

Objective To systematically analyze the current status of outcomes reporting in clinical trials on treating stasis acute mastitis with Traditional Chinese Medicine breast massage.Methods We searched CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, Embase, Cochrane library, JBI, CINAHL, PsycINFO, Clinical Trials Registry Platform portal, Clinical Trials Registry, Australian New Zealand Clinical Trials Registry, Center Watch Registry from inception to May 15, 2022 to find randomized controlled trials, non-randomized controlled trials, case series and cohort studies which reported the outcomes of stasis acute mastitis managed with Traditional Chinese Medicine breast massage, with search terms of mastitis, acute mastitis, lactation mastitis, puerperal mastitis, breast problem, breast engorgement, milk stasis, blocked ducked, breast pain, breast massage, and acupoint massage. Outcomes and the measurement schemes (measurement methods, timing of assessing outcome, frequency of assessing outcome, measurers) were extracted from the included studies. We used the Management of Otitis Media with Effusion in Children with Cleft Palate (MOMENT) to assess the quality of each study, then categorized outcomes derived from the included studies into different domains according to the Outcome Measures in Rheumatology Arthritis Clinic Trials (OMERACT) Filter 2.1 framework.Results We identified 85 clinical trials, in which 54 different outcomes were reported. A total of 81.2% (69/85) of studies were assessed as medium quality with a mean score of 2.6, and 18.8% (16/85) as low quality with a mean score of 0.9. These outcomes were organized in three core areas. Lump size (89.4%, 76/85) was the most frequently reported outcome, followed by breast pain (69.4%, 59/85) and milk excretion (68.2%, 58/85). Five methods were used to assess lump size and four methods to assess breast pain.Conclusions The outcomes reported in clinical trials regarding stasis acute mastitis treated by Traditional Chinese Medicine breast massage are heterogeneous. Developing a core outcome set to achieve consistent standards for reporting outcomes and modalities for validation of the outcomes is clearly warranted.


Assuntos
Mastite , Mastodinia , Criança , Feminino , Humanos , Austrália , Massagem , Mastite/terapia , Medicina Tradicional Chinesa
14.
J Am Chem Soc ; 144(30): 13839-13850, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35862295

RESUMO

Despite their multifaceted advantages, inverted perovskite solar cells (PSCs) still suffer from lower power conversion efficiencies (PCEs) than their regular counterparts, which is largely due to recombination energy losses (Eloss) that arise from the chemical, physical, and energy level mismatches, especially at the interfaces between perovskites and fullerene electron transport layers (ETLs). To address this problem, we herein introduce an aminium iodide derivative of a buckybowl (aminocorannulene) that is molecularly layered at the perovskite-ETL interface. Strikingly, besides passivating the PbI2-rich perovskite surface, the aminocorannulene enforces a vertical dipole and enhances the surface n-type character that is more compatible with the ETL, thus boosting the electron extraction and transport dynamics and suppressing interfacial Eloss. As a result, the champion PSC achieves an excellent PCE of over 22%, which is superior compared to that of the control device (∼20%). Furthermore, the device stability is significantly enhanced, owing to a lock-and-key-like grip on the mobile iodides by the buckybowls and the resultant increase of the interfacial ion-migration barrier. This work highlights the potential of buckybowls for the multifunctional surface engineering of perovskite toward high-performance and stable PSCs.

15.
Anal Chem ; 94(17): 6529-6539, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35442638

RESUMO

The disease progression of COVID-19 varies from mild to severe, even death. However, the link between COVID-19 severities and humoral immune specificities is not clear. Here, we developed a multiplexed spike variant protein microarray (SVPM) and utilized it for quantifying neutralizing activity, drug screening, and profiling humoral immunity. First, we demonstrated the competition between antispike antibody and ACE2 on SVPM for measuring the neutralizing activity against multiple spike variants. Next, we collected the serums from healthy subjects and COVID-19 patients with different severities and profile the neutralizing activity as well as antibody isotypes. We identified the inhibition of ACE2 binding was stronger against multiple variants in severe compared to mild/moderate or critical patients. Moreover, the serum IgG against nonstructural protein 3 was elevated in severe but not in mild/moderate and critical cases. Finally, we evaluated two ACE2 inhibitors, Ramipril and Perindopril, and found the dose-dependent inhibition of ACE2 binding to all the spike variants except for B.1.617.3. Together, the SVPM and the assay procedures provide a tool for profiling neutralizing antibodies, antibody isotypes, and reagent specificities.


Assuntos
COVID-19 , Análise Serial de Proteínas , Enzima de Conversão de Angiotensina 2 , Anticorpos Neutralizantes , Humanos , Isotipos de Imunoglobulinas
16.
Nephrology (Carlton) ; 27(11): 897-900, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35951741

RESUMO

Bardet-Biedl syndrome type 5 (BBS5) has never been reported in Chinese populations. The aim of this study is to report the first BBS5 case in China, explore the phenotype and genotype correlation. The case was male, Han nationality, born with polydactyly and gained weight after birth, accompanied by polydipsia, polyuria and nocturia. He was found to have low vision at the age of 7 years, and having insufficient renal function at the age of 20 years. After hospitalization, he was found to have suffered from atrophy of the whole layer of macular retina, and end stage of kidney disease, presenting with shrinking and cyst-like changes of bilateral kidneys. Whole-exome sequencing was performed among the proband and his parents (Trios), further validated using Sanger sequencing and quantitative polymerase chain reaction. Two novel compound heterozygous variants of BBS5 gene [a missense variant NC_000002.12, NM_152384.3:c.1A>G(p.Met1?) & a large deletion c.(?_-60)_(386 + 1_387-1)del] were detected. BBS is rare, whereas BBS5 is rarer. Herein, we reported a Chinese BBS5 patient with severe renal phenotype and identified two novel BBS5 variants.


Assuntos
Síndrome de Bardet-Biedl , Nefropatias , Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/genética , Criança , Proteínas do Citoesqueleto/genética , Genótipo , Humanos , Rim/fisiologia , Masculino , Mutação , Fenótipo , Proteínas de Ligação a Fosfato/genética , Adulto Jovem
17.
Biomed Chromatogr ; 36(10): e5441, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35789496

RESUMO

Terrestrosin D (TED) is the active ingredient of Tribulus terrestris L., which is used in traditional Chinese medicine (TCM) formulations and has a wide range of pharmacological activities. A previous study showed that TED alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice. However, the mechanisms underlying the therapeutic effect of TED are still unclear and need further investigation. In this study, we evaluated the effect of TED in a mice of BLM-induced PF in terms of histopathological and biochemical indices. UHPLC-MS-based plasma metabolomics combined with network pharmacology was used to explore the pathological basis of PF and the mechanism of action of TED. Histological and biochemical analyses showed that TED mitigated inflammatory injury in the lungs, especially at the dosage of 20 mg/kg. Furthermore, BLM changed the plasma metabolite profile in the mice, which was reversed by TED via regulation of amino acid and lipid metabolism. Subsequently, a biomarkers-targets-disease network was constructed, and tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß1 were identified as the putative therapeutic targets of TED. Both factors were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA). Taken together, the combination of UHPLC-MS-based metabolomics and network pharmacology can unveil the mechanisms of diseases and drug action.


Assuntos
Fibrose Pulmonar , Saponinas , Animais , Bleomicina , Metabolômica , Camundongos , Farmacologia em Rede , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Saponinas/farmacologia , Fator de Necrose Tumoral alfa
18.
Proc Jpn Acad Ser B Phys Biol Sci ; 98(7): 361-377, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35908957

RESUMO

Previous studies showed that lanthanum hydroxide (LH) has a therapeutic effect on chronic kidney disease (CKD) and vascular calcification, which suggests that it might have clinical value. However, the target and mechanism of action of LH are unclear. Metabolomics of clinical samples can be used to predict the mechanism of drug action. In this study, metabolomic profiles in patients with end-stage renal disease (ESRD) were used to screen related signaling pathways, and we verified the influence of LH on the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway by western blotting and quantitative real-time RT-qPCR in vivo and in vitro. We found that ROS and SLC16A10 genes were activated in patients with ESRD. The SLC16A10 gene is associated with six significant metabolites (L-cysteine, L-cystine, L-isoleucine, L-arginine, L-aspartic acid, and L-phenylalanine) and the PI3K-AKT signaling pathway. The results showed that LH inhibits the ESRD process and its cardiovascular complications by inhibiting the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway. Collectively, LH may be a candidate phosphorus binder for the treatment of vascular calcification in ESRD.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Falência Renal Crônica , Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/tratamento farmacológico , Lantânio , Metabolômica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética
19.
Int J Mol Sci ; 23(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36555582

RESUMO

The loss of seed shattering is an important event in crop domestication, and elucidating the genetic mechanisms underlying seed shattering can help reduce yield loss during crop production. This study is the first to systematically identify and analyse the BELL family of transcription factor-encoding genes in Chinese wild rice (Zizania latifolia). ZlqSH1a (Zla04G033720) and ZlqSH1b (Zla02G027130) were identified as key candidate genes involved in seed shattering in Z. latifolia. These genes were involved in regulating the development of the abscission layer (AL) and were located in the nucleus of the cell. Over-expression of ZlqSH1a and ZlqSH1b resulted in a complete AL between the grain and pedicel and significantly enhanced seed shattering after grain maturation in rice. Transcriptome sequencing revealed that 172 genes were differentially expressed between the wild type (WT) and the two transgenic (ZlqSH1a and ZlqSH1b over-expressing) plants. Three of the differentially expressed genes related to seed shattering were validated using qRT-PCR analysis. These results indicate that ZlqSH1a and ZlqSH1b are involved in AL development in rice grains, thereby regulating seed shattering. Our results could facilitate the genetic improvement of seed-shattering behaviour in Z. latifolia and other cereal crops.


Assuntos
Oryza , Domesticação , Genes de Plantas , Sementes , Grão Comestível/genética
20.
Molecules ; 27(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35807373

RESUMO

A novel method of ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed for the identification and quantification of four potential genotoxic impurities (PGIs) in the active pharmaceutical ingredients of TSD-1, a novel P2Y12 receptor antagonist. Four PGIs were named, 4-nitrobenzenesulfonic acid, methyl 4-nitrobenzenesulfonate, ethyl 4-nitrobenzenesulfonate, and isopropyl 4-nitrobenzenesulfonate. Following the International Conference of Harmonization (ICH) guidelines, this methodology is capable of quantifying four PGIs at 15.0 ppm in samples of 0.5 mg/mL concentration. This validated approach presented very low limits (0.1512−0.3897 ng/mL), excellent linearity (coefficients > 0.9900), and a satisfactory recovery range (94.9−115.5%). The method was sufficient in terms of sensitivity, linearity, precision, accuracy, selectivity, and robustness and, thus, has high practicality in the pharmaceutical quality control of TSD-1.


Assuntos
Contaminação de Medicamentos , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Dano ao DNA , Preparações Farmacêuticas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
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