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1.
Ultrason Sonochem ; 105: 106859, 2024 May.
Article in English | MEDLINE | ID: mdl-38552298

ABSTRACT

With the tertiary oil recovery in the oilfield, the content of aging oil emulsion with high water content and complex components has become more prevalent, so it is crucial for aging oil to break the emulsification. In this paper, the experimental laws of water content are explored under the conditions of different transducer input powers through the ultrasonic reforming of aging oil, and the microscopic topography, particle size, components, etc. of oil samples before and after the irradiation of ultrasound are characterized through the microscopic analysis, particle size analysis and component analysis and other ways. The results show that the oil samples achieve the effect of demulsification and dehydration in the presence of ultrasonic cavitation effect, with a maximum dehydration rate of 98.24 %, and that the dehydration rate follows an "M-type" trend with the increase of power. The results of microscopic and particle size analyses demonstrate that ultrasonic irradiation destabilizes the oil-water interfacial membrane, and causes droplets of different sizes to collide, agglomerate, and settle. It was also observed that the droplets of the emulsion system are more evenly distributed and the intervals are increased. Furthermore, we hypothesize that ultrasound may be less irreversible in demulsification and dehydration of aging oil.

2.
J Med Chem ; 67(5): 3287-3306, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38431835

ABSTRACT

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.


Subject(s)
Respiratory Tract Diseases , Transient Receptor Potential Channels , Humans , Transient Receptor Potential Channels/metabolism , TRPA1 Cation Channel , Aldehyde Oxidase/metabolism , Oxidoreductases/metabolism , Cytoskeletal Proteins/metabolism
3.
Rev Med Virol ; 34(1): e2503, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38282397

ABSTRACT

The diverse and severe nature of neurological manifestations associated with coronavirus disease 2019 (Covid-19) has garnered increasing attention. Exploring the potential to decrease neurological complications in Covid-19 patients involves targeting the mammalian target of rapamycin (mTOR) pathway as a therapeutic strategy. The mTOR pathway, widely recognised for its central role in essential cellular processes like synthesising proteins, facilitating autophagy, and modulating immune responses, has implications in various neurological disorders. Drawing parallels between these disorders and the observed neurological complications in Covid-19, we present a comprehensive review on the current understanding of mTOR signalling in the context of severe acute respiratory syndrome coronavirus 2 infection and neuroinflammation.


Subject(s)
COVID-19 , Nervous System Diseases , TOR Serine-Threonine Kinases , Humans , COVID-19/complications , Nervous System Diseases/etiology , Signal Transduction , TOR Serine-Threonine Kinases/metabolism
4.
Article in English | MEDLINE | ID: mdl-38290438

ABSTRACT

Objective: To explore the experience, role, and needs of medical nursing assistants during hospitalization in patients with incapacitated fecal incontinence. Methods: Qualitative study using reflexive thematic analysis. Semi-structured interviews were conducted with 21 medical nursing assistants from three hospitals in Southern China. Results: Four themes were constructed from the data: (1) Role perception. All participants described the multiple roles they played during care and knowledge and familiarity with the roles were seen as providing high-quality care to patients. (2) Career cognition. Overall, participants had a positive view of nurse assistants as a career. They believed that nursing experience was more important than training. (3) emotional belonging. The multiple roles of medical nursing assistants give them very mixed emotions. (4) Potential needs. Participants reported that the fatigue of repeatedly scrubbing and cleaning stools, the negative emotions that could not be faced and resolved, and their special status made them overwhelmed, potentially reflecting that they needed more support. Conclusions: This study highlights the roles, experiences, confusions, and needs of nursing assistants in caring for patients with disabling fecal incontinence. Suggested areas for improvement include the development of more intelligent fecal incontinence collection devices and the development of management and training strategies by health managers based on the specific context of medical nursing assistants to emphasize the role of medical nursing assistants and improve the quality of clinical care.

5.
Toxicol Sci ; 198(1): 86-100, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38059598

ABSTRACT

Drug-induced proximal tubule (PT) injury remains a serious safety concern throughout drug development. Traditional in vitro 2-dimensional (2D) and preclinical in vivo models often fail to predict drug-related injuries presented in clinical trials. Various 3-dimensional (3D) microphysiological systems (MPSs) have been developed to mimic physiologically relevant properties, enabling them to be more predictive toward nephrotoxicity. To explore the capabilities of an MPS across species, we compared cytotoxicity in hRPTEC/TERT1s and rat primary proximal tubular epithelial cells (rPPTECs) following exposure to zoledronic acid and ibandronate (62.5-500 µM), and antibiotic polymyxin B (PMB) (50 and 250 µM, respectively). For comparison, we investigated cytotoxicity using 2D cultured hRPTEC/TERT1s and rPPTECs following exposure to the same drugs, including overlapping concentrations, as their 3D counterparts. Regardless of the in vitro model, bisphosphonate-exposed rPPTECs exhibited cytotoxicity quicker than hRPTEC/TERT1s. PMB was less sensitive toward nephrotoxicity in rPPTECs than hRPTEC/TERT1s, demonstrating differences in species sensitivity within both 3D and 2D models. Generally, 2D cultured cells experienced faster drug-induced cytotoxicity compared to the MPSs, suggesting that MPSs can be advantageous for longer-term drug-exposure studies, if warranted. Furthermore, ibandronate-exposed hRPTEC/TERT1s and rPPTECs produced higher levels of inflammatory and kidney injury biomarkers compared to zoledronic acid, indicating that ibandronate induces acute kidney injury, but also a potential protective response since ibandronate is less toxic than zoledronic acid. Our study suggests that the MPS model can be used for preclinical screening of compounds prior to animal studies and human clinical trials.


Subject(s)
Acute Kidney Injury , Drug-Related Side Effects and Adverse Reactions , Humans , Rats , Animals , Zoledronic Acid/toxicity , Ibandronic Acid/toxicity , Diphosphonates/toxicity , Diphosphonates/therapeutic use , Kidney Tubules, Proximal
6.
Article in English | MEDLINE | ID: mdl-38083177

ABSTRACT

Cervical cell detection is crucial to cervical cytology screening at early stage. Currently most cervical cell detection methods use anchor-based pipeline to achieve the localization and classification of cells, e.g. faster R-CNN and YOLOv3. However, the anchors generally need to be pre-defined before training and the detection performance is inevitably sensitive to these pre-defined hyperparameters (e.g. number of anchors, anchor size and aspect ratios). More importantly, these preset anchors fail to conform to the cells with different morphology at inference phase. In this paper, we present a key-points based anchor-free cervical cell detector based on YOLOv3. Compared with the conventional YOLOv3, the proposed method applies a key-points based anchor-free strategy to represent the cells in the initial prediction phase instead of the preset anchors. Therefore, it can generate more desirable cell localization effect through refinement. Furthermore, PAFPN is applied to enhance the feature hierarchy. GIoU loss is also introduced to optimize the small cell localization in addition to focal loss and smooth L1 loss. Experimental results on cervical cytology ROI datasets demonstrate the effectiveness of our method for cervical cell detection and the robustness to different liquid-based preparation styles (i.e. drop-slide, membrane-based and sedimentation).


Subject(s)
Cervix Uteri , Uterine Cervical Neoplasms , Humans , Female , Vaginal Smears/methods , Uterine Cervical Neoplasms/diagnosis
7.
Cancer Imaging ; 23(1): 98, 2023 Oct 12.
Article in English | MEDLINE | ID: mdl-37828560

ABSTRACT

BACKGROUND: Accurate assessment of programmed death-ligand 1 (PD-L1) expression status in nasopharyngeal carcinoma (NPC) before immunotherapy is crucial. We aimed to explore the reproducibility and usefulness of the quantitative apparent diffusion coefficient (ADC) measurements for predicting PD-L1expression status in NPC. METHODS: We retrospectively recruited 134 NPC patients who underwent MRI scans and PD-L1 detection. A PD-L1 combined positive score (CPS) ≥ 20 was identified as high expression status. Patients were divide into two cohorts based on the MRI scanning devices, including a 1.5-T MRI cohort (n = 85, 44 PD-L1 high expression) and a 3.0-T MRI cohort (n = 49, 24 PD-L1 high expression). The mean ADC (ADCmean), minimum ADC (ADCmin) and maximal ADC (ADCmax) values were independently measured by two observers. The ADC measurement reproducibility was assessed by interclass correlation coefficients (ICC). The correlations between ADC parameters and CPS were analyzed by spearman's correlation coefficient (r), and the performance for PD-L1expression status prediction was assessed by the area under receiver operating characteristic curve (AUC). RESULTS: The measurement reproducibility of ADCmean, ADCmin and ADCmax was good in the 1.5-T MRI cohort (ICC: 0.843-0.930) and 3.0-T MRI cohort (ICC: 0.929-0.960). The ADCmean, ADCmin, and ADCmax tended to inversely correlate with the CPS (r:-0.37 - -0.52 in the 1.5-T MRI cohort, and - 0.52 - -0.60 in the 3.0-T MRI cohort; P all < 0.01). The ADCmean, ADCmin and ADCmax yielded the AUC of 0.756 (95% CI: 0.651, 0.861), 0.689 (95% CI: 0.576, 0.802), and 0.733 (95%CI: 0.626, 0.839) in the 1.5-T MRI cohort and 0.820 (95%CI: 0.703, 0.937), 0.755 (95% CI: 0.616, 0.894), and 0.760 (95%CI: 0.627, 0.893) in the 3.0-T MRI cohort for predicting PD-L1 high expression status, respectively. CONCLUSION: ADC measurements may act as a reproducible and feasible method to predict PD-L1 expression status in NPC.


Subject(s)
B7-H1 Antigen , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma , Retrospective Studies , Reproducibility of Results , Diffusion Magnetic Resonance Imaging/methods , Nasopharyngeal Neoplasms/diagnostic imaging
8.
Clin Exp Med ; 23(7): 3349-3359, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37743424

ABSTRACT

One of the most crucial T cell subsets in a variety of autoimmune and chronic inflammatory illnesses is T helper (Th) 17 cells. Th17 cells appear to have an essential role in the clearance of extracellular pathogens during infections. However, Th17 cells are also involved in inflammation and have been implicated in the pathogenesis of several autoimmune diseases and human inflammatory conditions. Due to the involvement of Th17 cells in the onset of Th17-associated diseases, understanding molecular mechanisms of Th17 cell functions may open the door to developing tailored therapies to address these difficult disorders. However, the molecular mechanisms governing Th17 differentiation in various diseases are still not well understood. The JAK/STAT signaling pathway plays a critical role in immune responses and has been linked to various aspects of Th17 cell differentiation and function. In this article, we conducted a comprehensive review of various molecular mechanisms (JAK/STAT, microRNAs, etc.), that can affect the differentiation of Th17 cells in various Th17-associated diseases.


Subject(s)
Autoimmune Diseases , RNA, Long Noncoding , Humans , Th17 Cells , Cell Differentiation , Signal Transduction
9.
Neurourol Urodyn ; 42(8): 1756-1768, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37723922

ABSTRACT

OBJECTIVE: This study aimed to develop and validate a Decision-Making Ability Scale (DMA-S) for postpartum urinary incontinence (PPUI) women engaging in pelvic floor physical therapy (PFPT). METHODS: Items were created in line with a review of the literature and exploratory qualitative study with 22 women. The items were submitted for expert opinion and a pilot implementation was made with 58 women with PPUI. Furthermore, the construct validity of the scale was tested with exploratory factor analysis (EFA) (n = 220) and confirmatory factor analysis (CFA) (n = 240). Internal consistency for the Chronbach's α and test-retest reliability for the intraclass correlation coefficient (ICC) were also investigated for the DMA-S in the study. RESULTS: The results of the EFA indicated a Kaiser-Meyer-Olkin value of 0.85 and Bartlett's test of sphericity showed a χ2 value of 8352.101, p < 0.001. After removing one item with factor loading values below 0.50, the resulting factor structure accounted for 83.38% of the total variance. The fit indices of the scale model tested in the CFA were determined as χ2 /df = 1.08 < 3, root mean square error of approximation = 0.018 < 0.08, comparative fit index = 0.996 > 0.90, Tucker-Lewis index = 0.995 > 0.90, goodness-of-fit index (GFI) = 0.933 > 0.90, adjusted GFI = 0.916 > 0.90, and incremental fit index = 0.996 > 0.90. The Cronbach's α values were 0.95-0.97 for the subdimensions of the scale and 0.93 for the total scale. Data also showed a good test-retest stability (ICC = 0.984). CONCLUSION: The DMA-S is a reliable and valid tool for assessing the decision-making ability for PPUI women engaging in PFPT.


Subject(s)
Pelvic Floor , Humans , Female , Reproducibility of Results , Surveys and Questionnaires , Factor Analysis, Statistical , Psychometrics
10.
Nutrients ; 15(15)2023 Aug 07.
Article in English | MEDLINE | ID: mdl-37571425

ABSTRACT

This study focused on the development and validation of a nutrition literacy assessment instrument for Chinese lactating women (NLAI-L). A comprehensive literature review and group discussion by experts in relevant fields were adopted to determine the dimension, topics and questions of NLAI-L. Content validity was evaluated by a panel of experts. The exploratory factor analyses (EFA) and confirmatory factor analyses (CFA) were used to evaluate the construct validity. Cronbach's α and split-half reliability were applied to examine the reliability of NLAI-L. The final NLAI-L consisted of 38 questions covering three dimensions: knowledge, behavior and skill. The EFA revealed four sub-domains for knowledge, one sub-domain for behavior and four sub-domains for skill. The results showed that NLAI-L had satisfactory content validity (CVI = 0.98, CVR = 0.96), good reliability (Cronbach's α coefficient = 0.84) and acceptable construct validity (χ2/df = 2.28, GFI = 2.81, AGFI = 0.79, RMSEA = 0.057). In the application part, the average NL score was 46.0 ± 9.3. In multivariate linear regression, education level, age, postnatal period and occupation were the potential influencing factors of NL for Chinese lactating women. The study established an effective and reliable assessment instrument for Chinese lactating women (NLAI-L) through qualitative and quantitative methods. The establishment of NLAI-L will provide an effective tool for exploring the role of NL in health or disease and provide a basis for the formulation of targeted nutrition interventions.


Subject(s)
East Asian People , Health Literacy , Nutrition Surveys , Female , Humans , Lactation , Psychometrics/methods , Reproducibility of Results , Surveys and Questionnaires
11.
Sci Adv ; 9(27): eadg7943, 2023 07 07.
Article in English | MEDLINE | ID: mdl-37406110

ABSTRACT

An understanding of protein conformational ensembles is essential for revealing the underlying mechanisms of interpeptide recognition and association. However, experimentally resolving multiple simultaneously existing conformational substates remains challenging. Here, we report the use of scanning tunneling microscopy (STM) to analyze the conformational substate ensembles of ß sheet peptides with a submolecular resolution (in-plane <2.6 Å). We observed ensembles of more than 10 conformational substates (with free energy fluctuations between several kBTs) in peptide homoassemblies of keratin (KRT) and amyloidal peptides (-5Aß42 and TDP-43 341-357). Furthermore, STM reveals a change in the conformational ensemble of peptide mutants, which is correlated with the macroscopic properties of peptide assemblies. Our results demonstrate that the STM-based single-molecule imaging can capture a thorough picture of the conformational substates with which to build an energetic landscape of interconformational interactions and can rapidly screen conformational ensembles, which can complement conventional characterization techniques.


Subject(s)
Amyloid , Peptides , Protein Conformation, beta-Strand , Peptides/chemistry , Protein Conformation , Entropy
12.
ACS Cent Sci ; 9(7): 1480-1487, 2023 Jul 26.
Article in English | MEDLINE | ID: mdl-37521785

ABSTRACT

Deciphering the conformations and interactions of peptides in their assemblies offers a basis for guiding the rational design of peptide-assembled materials. Here we report the use of scanning tunneling microscopy (STM), a single-molecule imaging method with a submolecular resolution, to distinguish 18 types of coexisting conformational substates of the ß-strand of the 8-37 segment of human islet amyloid polypeptide (hIAPP 8-37). We analyzed the pairwise peptide-peptide interactions in the hIAPP 8-37 assembly and found 82 interconformation interactions within a free energy difference of 3.40 kBT. Besides hIAPP 8-37, this STM method validates the existence of multiple conformations of other ß-sheet peptide assemblies, including mutated hIAPP 8-37 and amyloid-ß 42. Overall, the results reported in this work provide single-molecule experimental insights into the conformational ensemble and interpeptide interactions in the ß-sheet peptide assembly.

13.
Nano Lett ; 23(6): 2370-2378, 2023 03 22.
Article in English | MEDLINE | ID: mdl-36897606

ABSTRACT

Transferring structural information from amino acid sequence to macroscale assembly is a challenging approach for designing protein quaternary structure. However, the pathway by which the slight variations in sequence result in a global perturbation effect on the assembled structure is unknown. Herein, we design two synthetic peptides, QNL-His and QNL-Arg, with one amino acid substitution and use scanning tunneling microscopy (STM) to image individual peptides in the assembled state. The submolecular resolution of STM enables us to determine the folding structure and ß-sheet supramolecular organization of peptides. QNL-His and QNL-Arg differ in their ß-strand length distribution in pleated ß-sheet association. These structural variations lead to distinguishable outcomes in their ß-sheet assembled fibrils and phase transitions. The comparison of QNL-His versus QNL-Arg structures and macroscopic properties unveils the role of assembly to amplify the structural variations associated with a single-site mutation from a single-molecule scale to a macroscopic scale.


Subject(s)
Microscopy, Scanning Tunneling , Peptides , Protein Conformation, beta-Strand , Protein Structure, Secondary , Peptides/chemistry , Amino Acid Sequence
14.
Food Chem ; 416: 135863, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-36898340

ABSTRACT

A new analytical technique involving protein precipitation, heating, lipid degreasing, and SPE procedures combined with HPLC-UV and HPLC-MS/MS has been developed for the determination of neotame in a variety of food samples. This method is applicable for high-protein, high-lipid, or gum-based solid samples. The limit of detection of the HPLC-UV method was 0.5 µg/mL, while that of the HPLC-MS/MS method was 3.3 ng/mL. The spiked recoveries of neotame in 73 kinds of foods were in the range of 81.1-107.2 % with UV detection. The spiked recoveries obtained by HPLC-MS/MS in 14 kinds of foods ranged from 81.6 % to 105.8 %. This technique was successfully used to determine the contents of neotame in two positive samples, indicating its applicability in food analysis.


Subject(s)
Solid Phase Extraction , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid/methods , Solid Phase Extraction/methods , Lipids
15.
Adv Sci (Weinh) ; 10(2): e2204041, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36442852

ABSTRACT

Constructing faradaic electrode with superior desalination performance is important for expanding the applications of capacitive deionization (CDI). Herein, a simple one-step alkalized treatment for in situ synthesis of 1D TiO2 nanowires on the surface of 2D Ti3 C2 nanosheets, forming a Ti3 C2 -MXene partially derived hierarchical 1D/2D TiO2 /Ti3 C2 heterostructure as the cathode electrode is reported. Cross-linked TiO2 nanowires on the surface help avoid layer stacking while acting as the protective layer against contact of internal Ti3 C2 with dissolved oxygen in water. The inner Ti3 C2 MXene nanosheets cross over the TiO2 nanowires can provide abundant active adsorption sites and short ion/electron diffusion pathways. . Density functional theory calculations demonstrated that Ti3 C2 can consecutively inject electrons into TiO2 , indicating the high electrochemical activity of the TiO2 /Ti3 C2 . Benefiting from the 1D/2D hierarchical structure and synergistic effect of TiO2 and Ti3 C2 , TiO2 /Ti3 C2 heterostructure presents a favorable hybrid CDI performance, with a superior desalination capacity (75.62 mg g-1 ), fast salt adsorption rate (1.3 mg g-1 min-1 ), and satisfactory cycling stability, which is better than that of most published MXene-based electrodes. This study provides a feasible partial derivative strategy for construction of a hierarchical 1D/2D heterostructure to overcome the restrictions of 2D MXene nanosheets in CDI.

16.
Talanta ; 255: 124219, 2023 Apr 01.
Article in English | MEDLINE | ID: mdl-36580809

ABSTRACT

Nanozyme with the merit of excellent and adjustable catalytic activity, outstanding stability and low cost is a promising alternative for natural enzymes widely applied in a variety of fields. In the present study, a new two-dimensional cobalt-based MOF nanocomposite designated as MVCM@ß-CD was synthesized. Combined with the strategies of increasing the ratio of Co(Ⅲ)/Co(Ⅱ) and modifying with small molecule ß-cyclodextrin (ß-CD), MVCM@ß-CD displayed remarkably enhanced oxidase-mimicking activity, which was attributed to synergistic effect from large surface area of two dimensional Co-MOF nanosheet, numerous exposed active sites, high-proportioned trivalence of cobalt and regulating action of ß-cyclodextrin. The addition of aminophenol isomers inhibited the catalytic oxidation process, resulting in different color change of the solution and UV-Vis absorption behaviors, based on which a sensitive ratiometric colorimetry for m-aminophenol (m-Ap) and a simple colorimetric p-aminophenol (p-Ap) detection method were developed with the detection limit of 0.16 µM and 1.01 µM, respectively. This method realized the colorimetric differentiation of aminophenol isomers, which provided a simple, accurate and low-cost approach for visual discrimination without complicated instrument and procedure, especially appropriate for on-site detection.


Subject(s)
Oxidoreductases , beta-Cyclodextrins , Oxidoreductases/chemistry , Colorimetry/methods , Aminophenols , Cobalt/chemistry
17.
Pharmacol Res ; 185: 106503, 2022 11.
Article in English | MEDLINE | ID: mdl-36241000

ABSTRACT

Acute myeloid leukemia (AML) is featured with poor prognosis and high mortality, because chemo-resistance, nonspecific distribution and dose-limiting toxicity lead to a high rate of relapse and a very low 5-year survival percentage of less than 25%. CXCR4 is a highly expressed chemokine receptor in multiple types of AML cells and closely associated with the drug resistance and relapse. In this work, we integrate a chemically synthesized CXCR4 antagonistic peptide and doxorubicin using DSPE-mPEG2000 micelles (referred to as M-E5-Dox) that is applied to a very challenging refractory AML mouse model as well as human AML cell lines. Results showed that M-E5-Dox can effectively bind to the CXCR4-expressing AML cells, downregulating the signaling proteins mediated by CXCR4/CXCL12 axis and increasing the cellular uptake of Dox. Importantly, M-E5-Dox remarkably decreases the leukemic cells in the peripheral blood and bone marrow, as well as their infiltration in the spleen and liver of the AML mice, which in turn prolongs the survival significantly. Meanwhile, M-E5-Dox did not increase the cardiotoxicity of Dox. In conclusion, M-E5-Dox harnesses the functions of CXCR4 specific binding and CXCR4 antagonism of the peptide and the tumor cell killing capacity of Dox, which displays significant therapeutic effects and promising translational potentials for the treatment of refractory AML.


Subject(s)
Leukemia, Myeloid, Acute , Humans , Mice , Animals , Leukemia, Myeloid, Acute/metabolism , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Signal Transduction , Peptides/pharmacology , Recurrence , Receptors, CXCR4
18.
Bioconjug Chem ; 33(10): 1837-1851, 2022 10 19.
Article in English | MEDLINE | ID: mdl-36153839

ABSTRACT

Here, we explore whether PEGylation of antibodies can modulate their biodistribution to the eye, an organ once thought to be immune privileged but has recently been shown to be accessible to IV-administered large molecules, such as antibodies. We chose to PEGylate an anti-MerTK antibody, a target with known potential for ocular toxicity, to minimize biodistribution to retinal pigment epithelial cells (RPEs) in the eye by increasing the hydrodynamic volume of the antibody. We used site-specific conjugation to an engineered cysteine on anti-MerTK antibody to chemically attach 40-kDa branched or linear PEG polymers. Despite reduced binding to MerTK on cells, site-specifically PEGylated anti-MerTK retained similar potency in inhibiting MerTK-mediated macrophage efferocytosis of apoptotic cells. Importantly, we found that PEGylation of anti-MerTK significantly reduced MerTK receptor occupancy in RPE cells in both naïve mice and MC-38 tumor-bearing mice, with the branched PEG exhibiting a greater effect than linear PEG. Furthermore, similar to unconjugated anti-MerTK, PEGylated anti-MerTK antibody triggered type I IFN response and exhibited antitumor effect in syngeneic mouse tumor studies. Our results demonstrate the potential of PEGylation to control ocular biodistribution of antibodies.


Subject(s)
Cysteine , Neoplasms , Mice , Animals , c-Mer Tyrosine Kinase/metabolism , Tissue Distribution , Cysteine/metabolism , Phagocytosis/physiology , Antibodies/metabolism , Neoplasms/metabolism , Polyethylene Glycols/chemistry , Polymers/metabolism , Retinal Pigments/metabolism
19.
Comput Math Methods Med ; 2022: 2645607, 2022.
Article in English | MEDLINE | ID: mdl-35664646

ABSTRACT

The aim of this study was to explore the application value of transvaginal color Doppler ultrasound based on the improved mean shift algorithm in the diagnosis of idiopathic premature ovarian failure (POF). In this study, 80 patients with idiopathic POF were selected and included in the experimental group, and 40 volunteers who underwent health examinations during the same period were selected and included in the control group, who underwent transvaginal Doppler ultrasound examination. At the same time, an improved mean shift algorithm was proposed based on artificial intelligence technology and applied to ultrasound image processing. In addition, the ovarian artery parameters of patients were compared in two groups, including peak systolic flow rate (PSV), diastolic flow rate (EDV), resistance index (RI), and pulsatile index (PI). The results showed that the relative difference degree (RDD) of the segmentation results of the algorithm in this study was significantly lower than that of Snake, Live_wire, and the traditional mean shift algorithm, while the relative overlap degree (ROD) and Dice coefficient were opposite, and the differences were significant (P<0.05). The mediolateral diameter of control group was 2.87±0.31cm, and the anteroposterior diameter was 1.86±0.28 cm; while those were 2.11±0.36 cm and 1.13±0.34 cm, respectively, in the experimental group, showing significant differences between the groups (P<0.05). Of the 80 patients in the experimental group, 132 cases with ovarian arteries were found; among 40 patients in the experimental group, 76 cases were found with ovarian arteries, and the hemodynamic detection rate of the experimental group was significantly lower than that of the control group (P<0.05). The ovarian artery parameters PI, RI, and S/D of the experimental group were significantly higher than those of the control group, and the differences were statistically significant (P<0.05). The results showed that the segmentation results of the improved algorithm in this study were more superior to the segmentation results of other algorithms. The regional information loss of the segmentation results was not serious, and the resolution was higher and the definition was higher. The transvaginal color Doppler ultrasound based on the artificial intelligence segmentation algorithm can clearly show the functional status and hemodynamics of the patient's ovaries. The ovarian artery parameters PI and RI can be used as specific indicators for evaluating the POF.


Subject(s)
Primary Ovarian Insufficiency , Algorithms , Artificial Intelligence , Blood Flow Velocity , Female , Hemodynamics , Humans , Primary Ovarian Insufficiency/diagnostic imaging , Ultrasonography, Doppler, Color
20.
ACS Appl Mater Interfaces ; 14(25): 28527-28536, 2022 Jun 29.
Article in English | MEDLINE | ID: mdl-35713340

ABSTRACT

Rapid antigen detection tests are urgently needed for the early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The discovery of a binder with high affinity and selectivity for the biomarkers presented by SARS-CoV-2 is crucial to the development of the rapid antigen detection method. We utilized the surface biopanning to identify a peptide binder R1 from a phage-displayed peptide library consisting of 109 independent phage recombinants. The R1 peptide exhibited high-affinity for specific binding with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with a dissociation constant KD of (7.5 ± 1.9) × 10-10 M, which maintained high binding affinity with the RBD derived from Gamma, Lambda, Delta, and Omicron variants. The composition and sequence dependence of binding characteristics in R1-RBD interactions was revealed by the binding affinity fluctuations between RBD and the scrambled sequences or single-site mutants of R1. The R1-functionalized gold nanoparticles possessed concentration-dependent response to RBD and selectivity over bovine serum albumin and human serum albumin. The peptide binder R1 shows the potential to be used for constructing a rapid detection method for the early-stage diagnostics for SARS-CoV-2.


Subject(s)
COVID-19 , Metal Nanoparticles , Antibodies, Viral , Binding Sites , COVID-19/diagnosis , Gold , Humans , Peptide Library , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
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