Publications by authors named "Rui Tian"

413 Publications

Hub Gene Screening Associated with Early Glaucoma: An Integrated Bioinformatics Analysis.

Comput Math Methods Med 2022 15;2022:8030243. Epub 2022 Jul 15.

Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, 130041 Jilin Province, China.

Background: Primary open-angle glaucoma (POAG) is the most common type of glaucoma. The potential influence of some DEGs on the progression of POAG was still incomplete. In this study, we integrated transcriptome data with clinical data to investigate the relationship between them in POAG patients.

Methods: The gene expression profile (GSE27276) from Gene Expression Omnibus (GEO) was used to identify DEGs. The LIMMA package of R was used to identify the DEGs (Diboun et al., 2006). The adjusted values (adj value) were calculated instead to avoid the appearance of false-positive results. Genes with |log fold change (FC)| larger than 1 and adj value < 0.01 were taken as DEGs between PH and PC samples. GO (Gene Ontology) function and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses of the DEGs were performed. Protein-protein interactions (PPIs) of the DEGs were constructed.

Results: A total of 182 DEGs were identified through our analysis, of which 119 genes were upregulated and 63 genes were downregulated. GO enrichment analysis illustrated that these DEGs were mostly enriched into haptoglobin binding, antioxidant activity, and organic acid binding. KEGG enrichment analysis illustrated that these DEGs were mostly enriched into infection. The most significant module was identified by MCODE consists of 8 DEGs, and BCL11A is the seeded gene. The second most significant module consists of 5 DEGs, and IL1RN is the seeded gene.

Conclusion: Our results demonstrate the potential influence of some DEGs on the progression of POAG, providing a comprehensive bioinformatics analysis of the pathogenesis, which may contribute to future investigation into the molecular mechanisms and biomarkers.
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http://dx.doi.org/10.1155/2022/8030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307363PMC
July 2022

Fluorescence monitoring of the degradation evolution of aliphatic polyesters.

Chem Commun (Camb) 2022 Aug 4;58(63):8818-8821. Epub 2022 Aug 4.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 10029, China.

To provide lifecycle monitoring for degradable polymers, we have proposed a three-dimensional fluorescence monitoring and quantification method to simultaneously study the thermal and photothermal degradation by combining the intrinsic conjugation and probe-labelled carboxyl of poly(butylene adipate--terephthalate) (PBAT).
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http://dx.doi.org/10.1039/d2cc02150aDOI Listing
August 2022

Super-stable [email protected] fluorophore for enhanced NIR-II bioimaging.

Theranostics 2022 26;12(10):4536-4547. Epub 2022 May 26.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P.R. China.

Near-infrared-II (NIR-II) dyes could be encapsulated by either exogenous or endogenous albumin to form stable complexes for deep tissue bioimaging. However, we still lack a complete understanding of the interaction mechanism of the [email protected] complex. Studying this principle is essential to guide efficient dye synthesis and develop NIR-II probes with improved brightness, photostability, . Here, we screen and test the optical and chemical properties of [email protected] fluorophores, and systematically investigate the binding sites and the relationship between dye structures and binding degree. Super-stable cyanine [email protected] fluorophores are rationally obtained, and we also evaluate their pharmacokinetics and long-lasting NIR-II imaging abilities. We identify several key parameters of cyanine dyes governing the supramolecular/covalent binding to albumin, including a six-membered ring with chlorine (Cl), the small size of side groups, and relatively high hydrophobicity. The tailored fluorophore ([email protected]) exhibits much-improved photostability, serving as a long-lasting imaging probe for NIR-II bioimaging. Our study reveals that the chloride-containing cyanine dyes with the above-screened chemical structure (e.g. IR-780) could be lodged into albumin more efficiently, producing a much more stable fluorescent probe. Our finding partly solves the photobleaching issue of clinically-available cyanine dyes, enriching the probe library for NIR-II bioimaging and imaging-guided surgery.
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http://dx.doi.org/10.7150/thno.71443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254253PMC
May 2022

A Validation Study of the Hong Kong Brief Cognitive Test for Screening Patients with Mild Cognitive Impairment and Alzheimer's Disease.

J Alzheimers Dis 2022 Jul 4. Epub 2022 Jul 4.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.

Background: The Hong Kong Brief Cognitive Test (HKBC), a brief instrument designed to screen for cognitive impairment in older adults, has been validated in Cantonese-speaking populations and has shown better performance than the Mini-Mental State Examination (MMSE) in detecting both mild and major neurocognitive disorder (NCD).

Objective: This study aimed to validate the HKBC for detecting patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) in a Mandarin-speaking Chinese population.

Methods: Two hundred forty-eight patients with aMCI, 67 patients with mild AD and 306 healthy controls (HCs) were recruited for this study and completed both the HKBC and the MMSE. The performance of the HKBC and MMSE in distinguishing patients with aMCI from HCs and distinguishing patients with AD from patients with aMCI was compared in the whole population and in age- and education-stratified subgroups.

Results: The optimal HKBC cutoff score for distinguishing patients with aMCI from HCs was 23, and the optimal cutoff for distinguishing patients with AD from patients with aMCI was 17. The HKBC significantly outperformed the MMSE at differentiating patients with aMCI from HCs in the whole population (z = 12.38, p <  0.01) and all subgroups stratified by age or education. Regarding the discrimination of patients with AD from patients with aMCI, the HKBC showed better performance than the MMSE in the oldest subgroup (z = 2.18, p = 0.03).

Conclusion: The HKBC is a sensitive and specific screening tool for detecting aMCI and AD in the Chinese population across age groups and educational levels.
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http://dx.doi.org/10.3233/JAD-220417DOI Listing
July 2022

Antitumour effects of apatinib in progressive, metastatic differentiated thyroid cancer (DTC).

Endocrine 2022 Jun 29. Epub 2022 Jun 29.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.

Purpose: Management of progressive, metastatic radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has been a great challenge due to its poor prognosis and limited treatment options. Recently, apatinib, an orally anti-angiogenic tyrosine kinase inhibitor (TKI) is reported to be useful for treatment of progressive RAIR-DIC. The aim of this study was to evaluate the antitumour effect of apatinib and the combination therapy with radioactive iodine (RAI) in patients with progressive metastatic DTC.

Methods: Five patients (all female, mean age 62 ± 8 years, ranged from 51 to 69 years) with distant metastatic DTC (dmDTC) after total thyroidectomy (TTE) and neck lymph node dissection were treated with apatinib at a dose 500 mg per day after F-Fluorodeoxyglucose (F-FDG) PET/CT. The effects of apatinib on DTC were evaluated at 4 ± 1 months after treatment with apatinib. RAI therapy was then initiated. The response to apatinib and the combination therapy with RAI treatment was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) and metabolic activity using serum thyroglobulin (Tg) and F-FDG PET/CT.

Results: Positive F-FDG PET/CT results were found in all patients before apatinib therapy. The immunohistochemical analysis of primary tumour tissues showed high expression of vascular endothelial growth factor receptor-2 (VEGFR-2). Four patients with follicular thyroid carcinoma (FTC) showed partial response (PR) with significant decrease in tumour size and maximum standardized uptake value (SUVmax) after 4 ± 1 month's treatment with apatinib. Further significant reduction of tumour size and SUVmax were observed in three patients after combination therapy with apatinib and RAI. Only one patient with both FTC and papillary thyroid cancer (PTC) demonstrated progressive disease (PD) after treatment with apatinib alone, however, a decrease in tumour size and SUVmax as well as serum Tg levels was achieved after the combination with RAI therapy and apatinib.

Conclusions: Apatinib had significant antitumour effects on progressive distant metastatic DTC. Moreover, beneficial synergistic and complementary effects were shown when apatinib combined with RAI therapy.

Clinical Trial Registration: NCT04180007, Registered November 26, 2019.
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http://dx.doi.org/10.1007/s12020-022-03113-9DOI Listing
June 2022

[Relationship between blood electrolytes and prognosis of patients with severe coronavirus disease 2019].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2022 May;34(5):502-508

Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (original named "Shanghai First People's Hospital"), Shanghai 201620, China.

Objective: To analyze the relationship between blood electrolytes and the prognosis of patients with severe coronavirus disease 2019 (COVID-19) and to provide assistance for clinical decision-making.

Methods: The clinical data of patients with severe COVID-19 admitted to intensive care unit (ICU) of the Wuhan Third Hospital by the Shanghai aid-Hubei medical team from January 21 to March 4, 2020 were collected. Excluding ineligible patients, 110 patients were finally enrolled. The patients' gender, age, temperature, heart rate, systolic and diastolic blood pressure, clinical symptoms at admission, time of symptom onset, duration of fever, and relevant indicators at admission to ICU (including blood potassium, chloride, sodium, calcium, phosphorus, and magnesium, etc.) and prognosis were analyzed. The patients were grouped by blood potassium or calcium levels or blood potassium/calcium ratio. The Kaplan-Meier survival curves were used to analyze the survival of patients in each group. The relationship between the potassium/calcium ratio and the prognosis was analyzed using restricted cubic spline plots. The relationship between each index in the different models and the prognosis was analyzed using Cox regression models.

Results: Among 110 severe COVID-19 patients, 78 cases survived, and 32 cases died. Compared with the surviving group, patients in the death group had higher blood potassium levels [mmol/L: 4.25 (3.80, 4.65) vs. 3.90 (3.60, 4.20), P < 0.05] and lower blood calcium levels (mmol/L: 2.00±0.14 vs. 2.19±0.18, P < 0.05). The Kaplan-Meier survival curves showed that patients in the potassium > 4.2 mmol/L group had a worse prognosis than the potassium < 3.8 mmol/L group and the potassium 3.8-4.2 mmol/L group (P = 0.011), patients in the calcium > 2.23 mmol/L group had a better prognosis than the calcium < 2.03 mmol/L group and the calcium 2.03-2.23 mmol/L group, and the lower calcium group had a worse prognosis (P = 0.000 15). Cox regression analysis showed that the hazard ratio (HR) of blood potassium and calcium were 2.08 and 0.01, respectively, in model 1 (single blood potassium or calcium) and in model 2 (model 1 plus age and gender), the HR of blood potassium and calcium were 1.98 and 0.01 respectively, which were significantly associated with patient prognosis (all P < 0.05). Patients in the group with the potassium/calcium ratio > 1.9 had higher blood potassium levels and a higher proportion of mechanical ventilation, lower calcium levels and lower proportion of survival, and longer time of ICU admission compared with the groups with the potassium/calcium ratio < 1.7 and 1.7-1.9. The Kaplan-Meier survival curves showed that the survival rate of the potassium/calcium ratio > 1.9 group was the lowest (P < 0.000 1), and there was no statistically significant difference in survival between the potassium/calcium ratio < 1.7 group and the potassium/calcium ratio 1.7-1.9 group. A restricted cubic spline plot corrected for age and gender showed that patients in the potassium/calcium ratio > 1.8 group had HR values > 1. Cox regression analysis corrected for other indicators showed that the potassium/calcium ratio was still associated with patient prognosis (HR = 4.85, P = 0.033).

Conclusion: Blood potassium, calcium, and the potassium/calcium ratio at ICU admission are related to the prognosis of patients with severe COVID-19, and the potassium/calcium ratio is an independent risk factor for the death of patients. The higher the potassium/calcium ratio, the worse the prognosis of patients.
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http://dx.doi.org/10.3760/cma.j.cn121430-20211013-01474DOI Listing
May 2022

[Comparative analysis of clinical features between severe coronavirus disease 2019 and severe community acquired pneumonia].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2022 May;34(5):485-491

Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (originally named "Shanghai First People's Hospital"), Shanghai 201620, China.

Objective: To compare and analyze the clinical features of patients with severe coronavirus disease 2019 (sCOVID-19) and severe community acquired pneumonia (sCAP) who meet the diagnostic criteria for severe pneumonia of the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS).

Methods: A retrospective comparative analysis of the clinical records of 116 patients with sCOVID-19 admitted to the department of critical care medicine of Wuhan Third Hospital from January 1, 2020 to March 31, 2020 and 135 patients with sCAP admitted to the department of critical care medicine of Shanghai First People's Hospital from January 1, 2010 to December 31, 2017 was conducted. The basic information, diagnosis and comorbidities, laboratory data, etiology and imaging results, treatment, prognosis and outcome of the patients were collected. The differences in clinical data between sCOVID-19 and sCAP patients were compared, and the risk factors of death were analyzed.

Results: The 28-day mortality of sCOVID-19 and sCAP patients were 50.9% (59/116) and 37.0% (50/135), respectively. The proportion of arterial partial pressure of oxygen/fraction of inspired oxygen (PaO/FiO) ≤ 250 mmHg (1 mmHg ≈ 0.133 kPa) in sCOVID-19 patients was significantly higher than that of sCAP [62.1% (72/116) vs. 34.8% (47/135), P < 0.01]. The possible reason was that the proportion of multiple lung lobe infiltration in sCOVID-19 was significantly higher than that caused by sCAP [94.0% (109/116) vs. 40.0% (54/135), P < 0.01], but the proportion of sCOVID-19 patients requiring mechanical ventilation was significantly lower than that of sCAP [45.7% (53/116) vs. 60.0% (81/135), P < 0.05]. Further analysis of clinical indicators related to patient death found that for sCOVID-19 patients PaO/FiO, white blood cell count (WBC), neutrophils (NEU), neutrophil percentage (NEU%), neutrophil/lymphocyte ratio (NLR), total bilirubin (TBil), blood urea nitrogen (BUN), albumin (ALB), Ca, prothrombin time (PT), D-dimer, C-reactive protein (CRP) and other indicators were significantly different between the death group and the survival group, in addition, the proportion of receiving mechanical ventilation, gamma globulin, steroid hormones and fluid resuscitation in death group were higher than survival group. Logistic regression analysis showed that the need for mechanical ventilation, NLR > 10, TBil > 10 μmol/L, lactate dehydrogenase (LDH) > 250 U/L were risk factors for death at 28 days. For sCAP patients, there were significant differences in age, BUN, ALB, blood glucose (GLU), Ca and D-dimer between the death group and the survival group, but there was no significant difference in treatment. Logistic regression analysis showed that BUN > 7.14 mmol/L and ALB < 30 g/L were risk factors for 28-day death of sCAP patients.

Conclusions: The sCOVID-19 patients in this cohort have worse oxygen condition and symptoms than sCAP patients, which may be due to the high proportion of lesions involving the lungs. The indicators of the difference between the death group and the survival group were similar in sCOVID-19 and sCAP patients. It is suggested that the two diseases have similar effects on renal function, nutritional status and coagulation function. But there were still differences in risk factors affecting survival. It may be that sCOVID-19 has a greater impact on lung oxygenation function, inflammatory cascade response, and liver function, while sCAP has a greater impact on renal function and nutritional status.
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http://dx.doi.org/10.3760/cma.j.cn121430-20211013-01477DOI Listing
May 2022

Development of an Allostery Responsive Chromatographic Method for Screening Potential Allosteric Modulator of Beta2-adrenoceptor from a Natural Product-Derived DNA-Encoded Chemical Library.

Anal Chem 2022 06 13;94(25):9048-9057. Epub 2022 Jun 13.

College of Life Sciences, Northwest University, Xi'an 710069, China.

Allosteric ligands are promising drugs owing to their remote regulations of the orthosteric ligand signaling pathway. There are few allosteric ligands due to the lack of handy and efficacious method for the screening. Herein, we developed an affinity chromatographic method for allosteric ligand screening by immobilizing purified beta2 adrenoceptor (β-AR) onto macroporous silica gel by a two-point tethering method. The method relies on the occupation of the orthosteric site by an antagonist and the chelation of N-terminal His-tag of the receptor and Ni coated on the gel. The immobilized β-AR demonstrated the greatest allosteric responsive feature when Cmpd-15 (0.25 μM) was included in the mobile phase. Under the same conditions, the association constants of three agonists (salbutamol, terbutaline, and tulobuterol) reduced to 47%, 19%, and 27% compared with the data without the inclusion of Cmpd-15 in the mobile phase. APF was screened as a potential allosteric modulator of β-AR by applying the immobilized receptor in a natural product-derived DNA-encoded chemical library (DEL). Relying on these results, we reasoned that the current method has potential in screening allosteric ligands of the receptor. We expect that it is applicable for the discovery of new allosteric binding sites of a target protein and screening allosteric modulators of the other receptors from complex samples.
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http://dx.doi.org/10.1021/acs.analchem.2c01210DOI Listing
June 2022

Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade.

J Immunother Cancer 2022 06;10(6)

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China

Background: Oncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.

Methods: A tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).

Results: The identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8 T cell activity by augmenting the tumor infiltration of effector CD8 T cells and establishment of memory CD8 T cells and reducing associated CD8 T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8 T cells and high levels of CTLA-4 Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.

Conclusion: Localized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.
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http://dx.doi.org/10.1136/jitc-2022-004762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189843PMC
June 2022

A genetic engineering strategy for editing near-infrared-II fluorophores.

Nat Commun 2022 05 23;13(1):2853. Epub 2022 May 23.

Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, 117597, Singapore, Singapore.

The second near-infrared (NIR-II) window is a fundamental modality for deep-tissue in vivo imaging. However, it is challenging to synthesize NIR-II probes with high quantum yields (QYs), good biocompatibility, satisfactory pharmacokinetics, and tunable biological properties. Conventional long-wavelength probes, such as inorganic probes (which often contain heavy metal atoms in their scaffolds) and organic dyes (which contain large π-conjugated groups), exhibit poor biosafety, low QYs, and/or uncontrollable pharmacokinetic properties. Herein, we present a bioengineering strategy that can replace the conventional chemical synthesis methods for generating NIR-II contrast agents. We use a genetic engineering technique to obtain a series of albumin fragments and recombinant proteins containing one or multiple domains that form covalent bonds with chloro-containing cyanine dyes. These albumin variants protect the inserted dyes and remarkably enhance their brightness. The albumin variants can also be genetically edited to develop size-tunable complexes with precisely tailored pharmacokinetics. The proteins can also be conjugated to biofunctional molecules without impacting the complexed dyes. This combination of albumin mutants and clinically-used cyanine dyes can help widen the clinical application prospects of NIR-II fluorophores.
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http://dx.doi.org/10.1038/s41467-022-30304-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127093PMC
May 2022

Detection and typing of dengue virus by one-step RT-PCR-based high-resolution melting assay.

Virus Genes 2022 Aug 10;58(4):319-326. Epub 2022 May 10.

Shangcheng District Center for Disease Control and Prevention, Hangzhou, China.

Dengue is a rapidly spreading arboviral disease that can be transmitted through any of the four types of dengue virus (DENV) serotypes. Previous studies have observed that individuals who have a pre-existing secondary infection due to a different dengue serotype, experience severe forms of this disease. During a DENV outbreak, a time-sensitive preliminary diagnosis of the origin of DENV might be useful in controlling the epidemic. Here, we developed a rapid and accurate one-step TB Green RT-PCR-based high-resolution melting (HRM) assay to identify and serotype DENV using serotyping primers based on the alignment with the E gene. This assay had a detection limit of 7.7 × 10 (DENV 1), 3.8 × 10 (DENV 2), 6.2 × 10 (DENV 3), and 1.2 × 10 (DENV 4) RNA copies/mL. No cross-reactivity with the Chikungunya, Zika, and Japanese encephalitis viruses was observed. The feasibility of using this assay for clinical diagnosis was evaluated in DENV-positive patient sera. The HRM assay and the RT-qPCR had complete matched results derived from DENV detection, including 51 serum positive and 20 serum negative. Additionally, eight DENV 2 strains in the same serotype were successfully differentiated by an HRM assay. Thus, this assay facilitated accurate detection and serotyping of DENV, along with the time-sensitive identification of the infectious focus of different DENVs.
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http://dx.doi.org/10.1007/s11262-022-01906-8DOI Listing
August 2022

Development and Validation of a Nomogram for Predicting the Risk of Coronavirus-Associated Acute Respiratory Distress Syndrome: A Retrospective Cohort Study.

Infect Drug Resist 2022 2;15:2371-2381. Epub 2022 May 2.

Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Background: Since the outbreak of coronavirus disease (COVID-19) in December 2019 in Wuhan, it has spread rapidly worldwide. We aimed to establish and validate a nomogram that predicts the probability of coronavirus-associated acute respiratory distress syndrome (CARDS).

Methods: In this single-centre, retrospective study, 261 patients with COVID-19 were recruited using positive reverse transcription-polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2 in Tongji Hospital at Huazhong University of Science and Technology (Wuhan, China). These patients were randomly distributed into the training cohort (75%) and the validation cohort (25%). The factors included in the nomogram were determined using univariate and multivariate logistic regression analyses based on the training cohort. The area under the receiver operating characteristic curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA) were used to evaluate the efficiency of the nomogram in the training and validation cohorts.

Results: Independent predictive factors, including fasting plasma glucose, platelet, D-dimer, and cTnI, were determined using the nomogram. In the training cohort, the AUC and concordance index were 0.93. Similarly, in the validation cohort, the nomogram still showed great distinction (AUC: 0.92) and better calibration. The calibration plot also showed a high degree of agreement between the predicted and actual probabilities of CARDS. In addition, the DCA proved that the nomogram was clinically beneficial.

Conclusion: Based on the results of laboratory tests, we established a predictive model for acute respiratory distress syndrome in patients with COVID-19. This model shows good performance and can be used clinically to identify CARDS early.

Trial Registration: Ethics committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (No.:(2020) Linlun-34th).
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http://dx.doi.org/10.2147/IDR.S348278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075028PMC
May 2022

Construction of Petal-Like Ag [email protected] with Three-Dimensional Core-Shell Structure for Overall Water Splitting.

Nanomaterials (Basel) 2022 Apr 4;12(7). Epub 2022 Apr 4.

State Key Laboratory of Silicon Materials, School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China.

High-efficiency, good electrical conductivity and excellent performance electrocatalysts are attracting growing attention in the field of overall water splitting. In order to achieve the desirable qualities, rational construction of the structure and chemical composition of electrocatalysts is of fundamental importance. Herein, petal-like structure NiCoP shells grown on conductive silver nanowires (Ag NWs) cores as bifunctional electrocatalysts for overall water splitting were synthesized through a facile hydrothermal method and phosphorization. The resultant three-dimensional core-shell petal-like structure Ag [email protected] possesses excellent catalytic activities in alkaline conditions with the overpotential of 259 mV for the oxygen evolution reaction (OER), 121 mV for the hydrogen evolution reaction (HER) and a full cell voltage of 1.64 V to reach the current density of 10 mA cm. Highly conductive Ag NWs as cores and high surface area petal-like NiCoP as shells can endow outstanding catalytic performance for the bifunctional electrocatalyst. Thus, the synthetic strategy of the three-dimensional core-shell structure Ag [email protected] considerably advances the practice of Ag NWs toward electrocatalysts.
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http://dx.doi.org/10.3390/nano12071205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000666PMC
April 2022

A Pharmacoinformatics Analysis of Artemisinin Targets and Design of Hits for Treating Ulcerative Colitis.

Front Pharmacol 2022 18;13:843043. Epub 2022 Mar 18.

Department of Anoenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Ulcerative colitis (UC), as an intractably treated disease, seriously affects the quality of life of patients and has an increase in terms of incidence and prevalence annually. However, due to the lack of a direct etiology and drug-induced side effects, the medical treatment of UC falls into a bottleneck. There are many natural phytochemicals with the potential to regulate immune function in nature. Herein, a potential mechanism of artemisinin in the treatment of UC and potential druggability compounds with an artemisinin peroxide bond were discussed and predicted based on computer-aided drug design (CADD) technology by using the methods of network pharmacology, molecular docking, drug structure design and molecular dynamics through the integration of artemisinin related targets from TCMSP, ChEMBL and HERB databases. The networks were constructed based on 50 artemisinin-disease intersection targets related to inflammation, cytokines, proliferation and apoptosis, showing the importance of GALNT2, BMP7 and TGFBR2 in the treatment of disease, which may be due to the occupation of the ricin B-type lectin domain of GALNT2 by artemisinin compounds or designed candidates. This result could guide the direction of experiments and actual case studies in the future. This study provides a new route for the application of artemisinin and the development of drugs.
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http://dx.doi.org/10.3389/fphar.2022.843043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971781PMC
March 2022

Immune response gene 1 deficiency impairs Nrf2 activation and aggravates liver fibrosis in mice.

Biochem Biophys Res Commun 2022 06 24;607:103-109. Epub 2022 Mar 24.

Department of Pathophysiology, Chongqing Medical University, Chongqing, China; Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China. Electronic address:

A growing body of evidence suggests that metabolic events play essential roles in the development of liver fibrosis. Immune response gene 1 (IRG1) catalyzes the generation of itaconate, which function as a metabolic checkpoint under several pathological circumstances. In the present study, the hepatic level of IRG1 was determined in mice with carbon tetrachloride (CCl)-induced liver fibrosis. And then the pathological significance of IRG1 and the pharmacological potential of 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, in liver fibrosis were investigated in mice. The results indicated that the hepatic level of IRG1 was upregulated in mice with liver fibrosis. CCl-induced formation of fibrotic septa and deposition of collagen was aggravated in IRG1 KO mice. IRG1 deletion also resulted in increased expression of transforming growth factor beta 1 (TGF-β1), enhanced phosphorylation of Smad3, elevated level of alpha smooth muscle actin (α-SMA) and hydroxyproline, which were associated with compromised activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant system and exacerbated oxidative stress. Interestingly, supplementation with 4-OI activated Nrf2 pathway, suppressed TGF-β1 signaling and attenuated fibrogenesis. Our data indicated that upregulation of IRG1 might function as a protective response during the development of liver fibrosis, and 4-OI might have potential value for the pharmacological intervention of liver fibrosis.
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http://dx.doi.org/10.1016/j.bbrc.2022.03.110DOI Listing
June 2022

A potent neutralizing and protective antibody against a conserved continuous epitope on HSV glycoprotein D.

Antiviral Res 2022 05 24;201:105298. Epub 2022 Mar 24.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address:

Infections caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) remain a serious global health issue, and the medical countermeasures available thus far are limited. Virus-neutralizing monoclonal antibodies (NAbs) are crucial tools for studying host-virus interactions and designing effective vaccines, and the discovery and development of these NAbs could be one approach to treat or prevent HSV infection. Here, we report the isolation of five HSV NAbs from mice immunized with both HSV-1 and HSV-2. Among these were two antibodies that potently cross-neutralized both HSV-1 and HSV-2 with the 50% virus-inhibitory concentrations (IC) below 200 ng/ml, one of which (4A3) exhibited high potency against HSV-2, with an IC of 59.88 ng/ml. 4A3 neutralized HSV at the prebinding stage and prevented HSV infection and cell-to-cell spread. Significantly, administration of 4A3 completely prevented weight loss and improved survival of mice challenged with a lethal dose of HSV-2. Using structure-guided molecular modeling combined with alanine-scanning mutagenesis, we observed that 4A3 bound to a highly conserved continuous epitope (residues 216 to 220) within the receptor-binding domain of glycoprotein D (gD) that is essential for viral infection and the triggering of membrane fusion. Our results provide guidance for developing NAb drugs and vaccines against HSV.
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http://dx.doi.org/10.1016/j.antiviral.2022.105298DOI Listing
May 2022

Recycling of autophagosomal components from autolysosomes by the recycler complex.

Nat Cell Biol 2022 04 24;24(4):497-512. Epub 2022 Mar 24.

School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Autolysosomes contain components from autophagosomes and lysosomes. The contents inside the autolysosomal lumen are degraded during autophagy, while the fate of autophagosomal components on the autolysosomal membrane remains unknown. Here we report that the autophagosomal membrane components are not degraded, but recycled from autolysosomes through a process coined in this study as autophagosomal components recycling (ACR). We further identified a multiprotein complex composed of SNX4, SNX5 and SNX17 essential for ACR, which we termed 'recycler'. In this, SNX4 and SNX5 form a heterodimer that recognizes autophagosomal membrane proteins and is required for generating membrane curvature on autolysosomes, both via their BAR domains, to mediate the cargo sorting process. SNX17 interacts with both the dynein-dynactin complex and the SNX4-SNX5 dimer to facilitate the retrieval of autophagosomal membrane components. Our discovery of ACR and identification of the recycler reveal an important retrieval and recycling pathway on autolysosomes.
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http://dx.doi.org/10.1038/s41556-022-00861-8DOI Listing
April 2022

Decreased accuracy of erythrocyte sedimentation rate in diagnosing osteomyelitis in diabetic foot infection patients with severe renal impairment: A retrospective cross-sectional study.

PLoS One 2022 23;17(3):e0265769. Epub 2022 Mar 23.

Department of Surgery of Traditional Chinese Medicine, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Rapid diagnosis and treatment of diabetic foot osteomyelitis (DFO) could reduce the risk of amputation and death in patients with diabetic foot infection (DFI). Erythrocyte sedimentation rate (ESR) is considered the most useful serum inflammatory marker for the diagnosis of DFO. However, whether severe renal impairment (SRI) affects its diagnostic accuracy has not been reported previously.

Objective: To investigate the accuracy of ESR in diagnosing DFO in DFI patients with and without SRI.

Methods: This was a retrospective cross-sectional study. From the inpatient electronic medical record system, the investigators extracted demographic information, diagnostic information, and laboratory test results of patients with DFI who had been hospitalized in Longhua Hospital from January 1, 2016 to September 30, 2021. Logistic regression was performed to analyze the interaction between ESR and SRI with adjustment for potential confounders. The area under the curve (AUC), cutoff point, sensitivity, specificity, prevalence, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were analyzed by receiver operating characteristic (ROC) curve analysis and VassarStats.

Results: A total of 364 DFI patients were included in the analysis. The logistic regression analysis results showed that elevated ESR increased the probability of diagnosing DFO (adjusted odds ratio [OR], 2.40; 95% confidence interval [CI], 1.75-3.28; adjusted P < 0.001); SRI was not associated with the diagnosis of DFO (adjusted OR, 3.20; 95% CI, 0.40-25.32; adjusted P = 0.271), but it had an obstructive effect on the diagnosis of DFO by ESR (adjusted OR, 0.48; 95% CI, 0.23-0.99; adjusted P = 0.048). ROC analysis in DFI patients without SRI revealed that the AUC of ESR to diagnose DFO was 0.76 (95% CI, 0.71-0.81), with the cutoff value of 45 mm/h (sensitivity, 67.8%; specificity, 78.0%; prevalence, 44.7%; PPV, 71.3%; NPV, 75.0%; LR+, 3.08; LR-, 0.41). In contrast, in patients with SRI, the AUC of ESR to diagnose DFO was 0.57 (95% CI, 0.40-0.75), with the cutoff value of 42 mm/h (sensitivity, 95.0%; specificity, 29.2%; prevalence, 45.5%; PPV, 52.8%; NPV, 87.5%; LR+, 1.34; LR-, 0.17).

Conclusions: The accuracy of ESR in diagnosing DFO in DFI patients with SRI is reduced, and it may not have clinical diagnostic value in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942204PMC
May 2022

FrCas9 is a CRISPR/Cas9 system with high editing efficiency and fidelity.

Nat Commun 2022 03 17;13(1):1425. Epub 2022 Mar 17.

Department of Gynecological oncology, the First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2nd Road, Yuexiu, Guangzhou, 510080, Guangdong, China.

Genome editing technologies hold tremendous potential in biomedical research and drug development. Therefore, it is imperative to discover gene editing tools with superior cutting efficiency, good fidelity, and fewer genomic restrictions. Here, we report a CRISPR/Cas9 from Faecalibaculum rodentium, which is characterized by a simple PAM (5'-NNTA-3') and a guide RNA length of 21-22 bp. We find that FrCas9 could achieve comparable efficiency and specificity to SpCas9. Interestingly, the PAM of FrCas9 presents a palindromic sequence, which greatly expands its targeting scope. Due to the PAM sequence, FrCas9 possesses double editing-windows for base editor and could directly target the TATA-box in eukaryotic promoters for TATA-box related diseases. Together, our results broaden the understanding of CRISPR/Cas-mediated genome engineering and establish FrCas9 as a safe and efficient platform for wide applications in research, biotechnology and therapeutics.
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http://dx.doi.org/10.1038/s41467-022-29089-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931148PMC
March 2022

Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells.

Front Pharmacol 2021 16;12:788667. Epub 2022 Feb 16.

China-Japan Union Hospital, Jilin University, Changchun, China.

Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib are the pivotal resistant mechanism of HCC cells, but the specific regulatory mechanism remains unclear, which makes it difficult to increase drug sensitivity by targeting glycolysis. As a metabolic-recycling pathway, autophagy regulates multiple important pathways involved in cell survival and death. In this study, we found the expression of key autophagy proteins were closely related to the prognosis and progression of HCC patients. Based on experiments, our studies showed sorafenib induced autophagy in HCC cells. Inhibition of autophagy by chloroquine could significantly increase the sensitivity of HCC cells to sorafenib and reverse the enhancement of glycolysis. Furthermore, sorafenib-induced autophagy promoted the deacetylase activity of HDAC6 by degrading p62, which promoted the activity of PKM2 by regulating the acetylation of its critical substrate HSP90. In this study, we investigated the role of autophagy-induced HDAC6 in regulating the key glycolytic enzyme PKM2, which may be helpful to clarify the relationship between autophagy and glycolysis in a sorafenib-resistant mechanism. Targeting p62/HDAC6/HSP90 could herald a potential improvement in HCC therapy.
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http://dx.doi.org/10.3389/fphar.2021.788667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888828PMC
February 2022

Cationic Conjugated Polyelectrolytes with Aggregation-Induced Ratiometric Fluorescence.

Macromol Rapid Commun 2022 Mar 5:e2100899. Epub 2022 Mar 5.

Wuhan National Laboratory for Optoelectronics, School of Optical and Electronic Information, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China.

The molecular diversity of aggregation-induced emission remains a challenge due to the limitation of conventional synthesis methods. Here, a series of novel neutral and cationic conjugated polymers composed of various ratios of tetraarylethylene (TAE) containing a bridged oxygen (O) and fluorene (F) units is designed and synthesized via the geminal cross-coupling (GCC) of 1,1-dibromoolefins. The incorporation of TAE segments into the conjugated backbone of polyfluorene produces pronounced aggregation-induced ratiometric fluorescence, i.e., aggregation-induced emission (AIE) at 520-600 nm and grows synergistically with aggregations-caused quenching (ACQ) at 400-450 nm. The content of fluorene unit in the polymer backbones determines the intensity of the initial fluorescence in the blue light region. The huge distinction (about 150 nm) in dual emission wavelengths caused by the environment change makes these conjugated polyelectrolytes particularly suitable for ratiometric fluorescence sensing. Based on electrostatic interaction mechanism, the gradual addition of heparin into the cationic conjugated polymers aqueous solutions can induce dual-color fluorescence changes with a detection limit of 9 × 10 m. This work exhibits the great facility of using GCC reaction to synthesis the conjugated TAE polymers with superior AIE properties and special functions.
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http://dx.doi.org/10.1002/marc.202100899DOI Listing
March 2022

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis.

Crit Care 2022 01 28;26(1):29. Epub 2022 Jan 28.

Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.

Background: Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis.

Methods: Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated.

Results: Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs' chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs' chemotaxis and phagocytosis functions.

Conclusions: The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.
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http://dx.doi.org/10.1186/s13054-022-03893-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796568PMC
January 2022

Effects of hydrothermal pretreatment on the dissolution and structural evolution of hemicelluloses and lignin: A review.

Carbohydr Polym 2022 Apr 30;281:119050. Epub 2021 Dec 30.

Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, China. Electronic address:

Exploration of lignocellulosic biomass provides a sustainable and eco-friendly route for producing liquid fuels, materials, and chemicals. However, direct utilization of lignocelluloses is limited by the stable and complicated cross-linking structure of the plant cell wall. Hydrothermal pretreatment (HTP) is a green and cost-effective technology because it can disrupt lignin-carbohydrate complex (LCC) linkages, dissolve hemicelluloses and lignin, and redistribute lignin in the cell wall layers without utilization of any chemicals. Thus, HTP is expected to achieve industrial scale in second-generation biorefineries and circular bioeconomies. This review analyzed the deconstruction of lignocelluloses by HTP, with particular emphasis on the formation mechanism of hemicellulose degradation products and the structural evolution of hemicelluloses and lignin accompanying HTP. Meanwhile, the formation mechanism of pseudolignin and its effect on the enzymatic hydrolysis of cellulose as well as strategies for inhibiting lignin recondensation were discussed.
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http://dx.doi.org/10.1016/j.carbpol.2021.119050DOI Listing
April 2022

Sellar Region Lesions and Intracranial Aneurysms in the Era of Endoscopic Endonasal Approach.

Front Endocrinol (Lausanne) 2021 4;12:802426. Epub 2021 Jan 4.

Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.

In the clinical practice of neurosurgery, the endoscopic endonasal approach (EEA) has been the mainstream approach in the management of sellar region diseases. However, clinicians have come to realize that EEA procedure is associated with intraoperative hemorrhage. Due to the limited surgical field and poor proximal control under endoscope, massive hemorrhage always leads to severe complication or even perioperative death. Previously, intraoperative hemorrhage used to be attributed to endoscopic intervention of cavernous sinus or internal carotid artery, but our recent understanding of EEA indicated that preoperatively complicated intracranial aneurysms (IAs) may play a role. In this article, we retrospectively reviewed the baseline characteristics, treatment strategy, pathology, intraoperative findings, as well as radiological profiles of sellar region lesions complicated with IAs. With the focus put on the high comorbidity rate of sellar region lesions and IAs, we did further statistical analysis to sketch the outline of this coexisting circumstance and to emphasize the importance of computed tomography angiography (CTA) as routine EEA preoperative examination. Thorough patient-surgeon communication should be proceeded before the formulation of an individualized treatment strategy.
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http://dx.doi.org/10.3389/fendo.2021.802426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763682PMC
March 2022

Machine Learning-Based Approaches for Prediction of Patients' Functional Outcome and Mortality after Spontaneous Intracerebral Hemorrhage.

J Pers Med 2022 Jan 14;12(1). Epub 2022 Jan 14.

Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China.

Spontaneous intracerebral hemorrhage (SICH) has been common in China with high morbidity and mortality rates. This study aims to develop a machine learning (ML)-based predictive model for the 90-day evaluation after SICH. We retrospectively reviewed 751 patients with SICH diagnosis and analyzed clinical, radiographic, and laboratory data. A modified Rankin scale (mRS) of 0-2 was defined as a favorable functional outcome, while an mRS of 3-6 was defined as an unfavorable functional outcome. We evaluated 90-day functional outcome and mortality to develop six ML-based predictive models and compared their efficacy with a traditional risk stratification scale, the intracerebral hemorrhage (ICH) score. The predictive performance was evaluated by the areas under the receiver operating characteristic curves (AUC). A total of 553 patients (73.6%) reached the functional outcome at the 3rd month, with the 90-day mortality rate of 10.2%. Logistic regression (LR) and logistic regression CV (LRCV) showed the best predictive performance for functional outcome (AUC = 0.890 and 0.887, respectively), and category boosting presented the best predictive performance for the mortality (AUC = 0.841). Therefore, ML might be of potential assistance in the prediction of the prognosis of SICH.
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http://dx.doi.org/10.3390/jpm12010112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778760PMC
January 2022

Overexpression of apple Ma12, a mitochondrial pyrophosphatase pump gene, leads to malic acid accumulation and the upregulation of malate dehydrogenase in tomato and apple calli.

Hortic Res 2022 Jan 18. Epub 2022 Jan 18.

State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling 712100, Shaanxi, China.

Acidity is an important factor influencing the organoleptic quality of apple fruits. In this study, an apple pyrophosphate-energized proton pump (PEPP) gene was isolated and designated MdMa12. On the basis of a phylogenetic analysis in Rosaceae species, PEPP genes were divided into three groups, with apple PEPP genes most closely related to pear PEPP genes. Gene expression analysis revealed that high malic acid content was generally accompanied by high MdMa12 expression levels. Moreover, MdMa12 was mainly expressed in the fruit. A subcellular localization analysis suggested that MdMa12 is a mitochondrial protein. The ectopic expression and overexpression of MdMa12 in "Micro-Tom" tomato and apple calli, respectively, increased the malic acid content. One (MDH12) of four malate dehydrogenase genes highly expressed in transgenic apple calli was confirmed to encode a protein localized in mitochondria. The overexpression of MDH12 increased the malate content in apple calli. Furthermore, MdMa12 overexpression increased MdDTC1, MdMa1, and MdMa10 expression levels, which were identified to transport malate. These findings imply that MdMa12 has important functions related to apple fruit acidity. Our study explored the regulatory effects of mitochondria on the complex mechanism underlying apple fruit acidity.
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http://dx.doi.org/10.1093/hr/uhab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769031PMC
January 2022

Gene knock-out chain reaction enables high disruption efficiency of HPV18 / genes in cervical cancer cells.

Mol Ther Oncolytics 2022 Mar 18;24:171-179. Epub 2021 Dec 18.

Department of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, Hubei, China.

A genome editing tool targeting the high-risk human papillomavirus (HPV) oncogene is a promising therapeutic strategy to treat HPV-related cervical cancer. To improve gene knockout efficiency, we developed a gene knockout chain reaction (GKCR) method for continually generating mutagenic disruptions and used this method to disrupt the HPV18 and genes. We verified that the GKCR Cas9/guide RNA (gRNA) cassettes could integrated into the targeted loci via homology-independent targeted insertion (HITI). The qPCR results revealed that the GKCR method enabled a relatively higher Cas9/gRNA cassette insertion rate than a control method (the common CRISPR-Cas9 strategy). Tracking of Indels by DEcomposition (TIDE) assay results showed that the GKCR method produced a significantly higher percentage of insertions or deletions (indels) in the HPV18 and genes. Furthermore, by targeting the HPV18 oncogenes, we found that the GKCR method significantly upregulated the P53/RB proteins and inhibited the proliferation and motility of HeLa cells. The GKCR method significantly improved the gene knockout efficiency of the HPV18 / oncogenes, which might provide new insights into treatment of HPV infection and related cervical cancer.
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http://dx.doi.org/10.1016/j.omto.2021.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733033PMC
March 2022

Risk Assessment and Source Identification of Arsenic in Surface Sediments from Caohai Lake, China.

Bull Environ Contam Toxicol 2022 Jan 6. Epub 2022 Jan 6.

Chongqing Key Laboratory of Soil Multi-Scale Interfacial Process, Department of Soil Science, College of Resources and Environment, Southwest University, Chongqing, 400715, China.

Urban freshwaters containing arsenic are facing an increasing problem of eutrophication. This study evaluated the spatial distribution, ecological risk, and origin of As in surface sediments obtained from Caohai Lake, a typical hypertrophic urban lake in China. It revealed that the total As concentration in surface sediments decreased gradually from north to south, consisted with the lake eutrophication status. The average As level was 161 mg/kg, dominated by reducible and oxidisable fractions. The analyses of geoaccumulation index and enrichment factor indicated that As ranged between moderately-to-heavily and heavily contamination, was severely influenced by anthropogenic factors, i.e. industrial discharges and agricultural activities. Risk assessment code and potential ecological risk index results showed moderate to high potential ecological risk could be observed although the current As risk was low, supporting by the experimentally quantified As release data.
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http://dx.doi.org/10.1007/s00128-021-03418-xDOI Listing
January 2022

Feasibility and Accuracy of Menstrual Blood Testing for High-risk Human Papillomavirus Detection With Capture Sequencing.

JAMA Netw Open 2021 12 1;4(12):e2140644. Epub 2021 Dec 1.

Department of Obstetrics and Gynecology, Academician Expert Workstation, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Importance: High-risk human papillomavirus (hrHPV) persistent infection is the major etiology of cervical precancer and cancer. Noninvasive self-sampling HPV testing is a promising alternative cervical cancer screening for avoiding stigma and improving patient willingness to participate.

Objective: To investigate the feasibility and accuracy of menstrual blood (MB) hrHPV capture sequencing in hrHPV detection.

Design, Setting, And Participants: This cohort study collected 137 sanitary pads from 120 women who were premenopausal and had hrHPV as detected by cervical HPV GenoArray testing. Patients were recruited from September 1, 2020, to April 1, 2021, at Central Hospital of Wuhan, China. Target capture sequencing was performed to determine hrHPV genotypes in MB. Sanger sequencing was performed as the criterion standard for detecting hrHPV genotypes among enrolled women. Data were analyzed from April 1 through June 1, 2021.

Main Outcomes And Measures: Complete concordance, incomplete concordance, and discordance of MB hrHPV capture sequencing and conventional HPV testing were defined according to genotype overlapping levels. Concordance of the 2 detection methods and comparative power of MB hrHPV capture sequencing during different menstrual cycle days (MCDs) were the main outcomes.

Results: A total of 120 enrolled women with hrHPV (mean [SD; range] age, 33.9 [6.9; 20.0 -52.0] years) provided 137 sanitary pads. The overall concordance rate of MB hrHPV capture sequencing and cervical HPV testing was 92.7% (95% CI, 88.3%-97.1%), with a κ value of 0.763 (P < .001). Among 24 samples with incomplete concordance or discordant results, 11 samples with additional hrHPV genotypes (45.8%), 5 true-negative samples (20.8%), and the correct hrHPV genotypes of 2 samples (8.3%) were correctly identified by MB hrHPV capture sequencing. MB hrHPV detection of hrHPV was equivalent on different MCDs, with an MB hrHPV-positive rate of 27 of 28 patients (96.4%) for MCD 1, 52 of 57 patients (91.2%) for MCD 2, 27 of 28 patients for MCD 3, 4 of 4 patients (100%) for MCD 4, and 3 of 3 patients (100%) for MCD 5 (P = .76). The sensitivity of the MB hrHPV capture sequencing was 97.7% (95% CI, 95.0%-100%).

Conclusions And Relevance: These findings suggest that MB hrHPV capture sequencing is a feasible and accurate self-collected approach for cervical cancer screening. This study found that this method is associated with superior performance in identification of HPV genotypes and true-negative events compared with cervical HPV testing.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.40644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703251PMC
December 2021

The comparison of ZFNs, TALENs, and SpCas9 by GUIDE-seq in HPV-targeted gene therapy.

Mol Ther Nucleic Acids 2021 Dec 19;26:1466-1478. Epub 2021 Aug 19.

Department of Gynecological Oncology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2nd Road, Yuexiu, Guangzhou 510080, Guangdong, China.

Zinc-finger nucleases (ZFNs), transcription activator-like endonucleases (TALENs), and CRISPR-associated Cas9 endonucleases are three major generations of genome editing tools. However, no parallel comparison about the efficiencies and off-target activity of the three nucleases has been reported, which is critical for the final clinical decision. We for the first time developed the genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) method in ZFNs and TALENs with novel bioinformatics algorithms to evaluate the off-targets. By targeting human papillomavirus 16 (HPV16), we compared the performance of ZFNs, TALENs, and SpCas9 . Our data showed that ZFNs with similar targets could generate distinct massive off-targets (287-1,856), and the specificity could be reversely correlated with the counts of middle "G" in zinc finger proteins (ZFPs). We also compared the TALENs with different N-terminal domains (wild-type [WT]/αN/βN) and G recognition modules (NN/NH) and found the design (αN or NN) to improve the efficiency of TALEN inevitably increased off-targets. Finally, our results showed that SpCas9 was more efficient and specific than ZFNs and TALENs. Specifically, SpCas9 had fewer off-target counts in URR (SpCas9, n = 0; TALEN, n = 1; ZFN, n = 287), E6 (SpCas9, n = 0; TALEN, n = 7), and E7 (SpCas9, n = 4; TALEN, n = 36). Taken together, we suggest that for HPV gene therapies, SpCas9 is a more efficient and safer genome editing tool. Our off-target data could be used to improve the design of ZFNs and TALENs, and the universal off-target detection pipeline for three generations of artificial nucleases provided useful tools for genome engineering-based gene therapy.
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http://dx.doi.org/10.1016/j.omtn.2021.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655392PMC
December 2021
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