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1.
Sci Rep ; 14(1): 11423, 2024 05 19.
Article in English | MEDLINE | ID: mdl-38763922

ABSTRACT

Negative pressure wound therapy with instillation and dwell time (NPWTi-d) is increasingly used for a diverse range of wounds. Meanwhile, the topical wound irrigation solution consisting of polyhexamethylene biguanide and betaine (PHMB-B) has shown efficacy in managing wound infections. However, the effectiveness of this solution as a topical instillation solution for NPWTi-d in patients with diabetic foot infections (DFIs) has not been thoroughly studied. The objective of this retrospective study was to evaluate the impact of using PHMB-B as the instillation solution during NPWTi-d on reducing bioburden and improving clinical outcomes in patients with DFIs. Between January 2017 and December 2022, a series of patients with DFIs received treatment with NPWTi-d, using either PHMB-B or normal saline as the instillation solution. Data collected retrospectively included demographic information, baseline wound characteristics, and treatment outcomes. The study included 61 patients in the PHMB-B group and 73 patients in the normal saline group, all diagnosed with DFIs. In comparison to patients treated with normal saline, patients with PHMB-B exhibited no significant differences in terms of wound bed preparation time (P = 0.5034), length of hospital stay (P = 0.6783), NPWTi-d application times (P = 0.1458), duration of systematic antimicrobial administration (P = 0.3567), or overall cost of hospitalization (P = 0.6713). The findings of the study suggest that the use of either PHMB-B or normal saline as an instillation solution in NPWTi-d for DFIs shows promise and effectiveness, yet no clinical distinction was observed between the two solutions.


Subject(s)
Anti-Infective Agents, Local , Biguanides , Diabetic Foot , Negative-Pressure Wound Therapy , Saline Solution , Wound Healing , Humans , Diabetic Foot/therapy , Diabetic Foot/drug therapy , Male , Female , Negative-Pressure Wound Therapy/methods , Middle Aged , Saline Solution/administration & dosage , Saline Solution/therapeutic use , Retrospective Studies , Anti-Infective Agents, Local/administration & dosage , Anti-Infective Agents, Local/therapeutic use , Aged , Biguanides/therapeutic use , Biguanides/administration & dosage , Wound Healing/drug effects , Wound Infection/drug therapy , Wound Infection/therapy , Therapeutic Irrigation/methods , Betaine/administration & dosage , Betaine/therapeutic use , Treatment Outcome
2.
Anal Chim Acta ; 1308: 342649, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38740457

ABSTRACT

BACKGROUND: Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a-powered biosensor with a G-quadruplex (G4) reporter offer the benefits of simplicity and sensitivity, making them extensively utilized in detection applications. However, these biosensors used for monitoring pollutants in environmental water samples may face the problem of high background signal and easy interference due to the "signal-off" output. It is obvious that a biosensor based on the CRISPR/Cas12a system and G4 with a "signal on" output mode needs to be designed for detecting environmental pollutants. RESULTS: By using phosphorothioate-modified G4 as a reporter and catalytic hairpin assembly (CHA) integrated with Cas12a as an amplification strategy, a "signal-on" colorimetric/photothermal biosensor (psG4-CHA/Cas) for portable detection of environmental pollutants was developed. With the help of functional nucleotides, the target pollutant (kanamycin or Pb2+) triggers a CHA reaction to produce numerous double-strand DNA, which can activate Cas12a's trans-cleavage activity. The active Cas12a cleaves locked DNA to release caged psG-rich sequences. Upon binding hemin, the psG-rich sequence forms a psG4/hemin complex, facilitating the oxidation of the colorless 3,3',5,5'-tetramethylbenzidine (TMB) into the blue photothermal agent (oxTMB). The smartphone was employed for portable colorimetric detection of kanamycin and Pb2+. The detection limits were found to be 100 pM for kanamycin and 50 pM for Pb2+. Detection of kanamycin and Pb2+ was also carried out using a portable thermometer with a detection limit of 10 pM for kanamycin and 8 pM for Pb2+. SIGNIFICANCE: Sensitive, selective, simple and robust detection of kanamycin and Pb2+ in environmental water samples is achieved with the psG4-CHA/Cas system. This system not only provides a new perspective on the development of efficient CRISPR/Cas12a-based "signal-on" designs, but also has a promising application for safeguarding human health and environmental monitoring.


Subject(s)
Biosensing Techniques , CRISPR-Cas Systems , G-Quadruplexes , Biosensing Techniques/methods , CRISPR-Cas Systems/genetics , Colorimetry , Lead/analysis , Environmental Pollutants/analysis , Limit of Detection , CRISPR-Associated Proteins/chemistry , CRISPR-Associated Proteins/genetics , Water Pollutants, Chemical/analysis , Bacterial Proteins , Endodeoxyribonucleases
3.
Cancer Med ; 13(10): e7233, 2024 May.
Article in English | MEDLINE | ID: mdl-38752474

ABSTRACT

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. METHODS: We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. RESULTS: Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). CONCLUSIONS: Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.


Subject(s)
Immune Checkpoint Inhibitors , Myocarditis , Humans , Male , Retrospective Studies , Female , Immune Checkpoint Inhibitors/adverse effects , Myocarditis/chemically induced , Myocarditis/epidemiology , Myocarditis/diagnosis , Middle Aged , Aged , Risk Factors , Biomarkers/blood , Neoplasms/drug therapy , Troponin I/blood , ROC Curve , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Creatine Kinase, MB Form/blood , Natriuretic Peptide, Brain/blood , Heart Failure/chemically induced
4.
J Investig Med ; : 10815589241248073, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38594222

ABSTRACT

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

5.
Article in English | MEDLINE | ID: mdl-38657744

ABSTRACT

Patients with cancer have elevated cardiovascular risks compared to those without cancer. As cancer incidence increases and cancer-related mortality decreases, cardiovascular diseases in patients with a history of cancer will become increasingly important. This in turn is reflected by the exponentially increasing amount of cardio-oncology research in recent years. This narrative review aims to summarize the key existing literature in several main areas of cardio-oncology, including the epidemiology, natural history, prevention, management, and determinants of the cardiovascular health of patients with cancer, and identify relevant gaps in evidence for further research.

6.
Int J Cardiol ; 407: 132029, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38583590

ABSTRACT

BACKGROUND: Programmed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. METHODS: We conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. RESULTS: A total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70-14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431-61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276-72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879-26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. CONCLUSIONS: In cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.


Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Pericardial Effusion , Humans , Pericardial Effusion/epidemiology , Pericardial Effusion/chemically induced , Male , Female , Retrospective Studies , Middle Aged , Risk Factors , Neoplasms/drug therapy , Neoplasms/epidemiology , Aged , Immune Checkpoint Inhibitors/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Survival Rate/trends , Treatment Outcome
7.
Acta Otolaryngol ; 144(2): 130-135, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38634540

ABSTRACT

BACKGROUND: Deaf children with cochlear nerve canal stenosis (CNCs) are always considered poor candidates for cochlear implantation. OBJECTIVES: To investigate the function of the peripheral auditory pathway in deaf children with CNCs, as revealed by the electrically evoked auditory brainstem response (EABR), and postoperative cochlear implants (CIs) outcomes. MATERIALS AND METHODS: Thirteen children with CNCs and 13 children with no inner ear malformations (IEMs) who received CIs were recruited. The EABR evoked by electrical stimulation from the CI electrode was recorded. Postoperative CI outcomes were assessed using Categories of Auditory Performance (CAP) and Speech Intelligibility Rate (SIR). RESULTS: Compared with children with no IEMs, children with CNCs showed lower EABR extraction rates, higher thresholds, a longer wave V (eV) latency and lower CAP and SIR scores. The auditory and speech performance was positively correlated with the diameter of the cochlear nerve canal and the number of channels showing wave III (eIII) and eV in children with CNCs. CONCLUSIONS AND SIGNIFICANCE: The physiological function of the peripheral auditory pathway in children with CNCs is poorer than that in children with no IEMs. Postoperative auditory and speech abilities may depend on the severity of cochlear nerve malformation and auditory conduction function.


Subject(s)
Cochlear Nerve , Deafness , Evoked Potentials, Auditory, Brain Stem , Humans , Evoked Potentials, Auditory, Brain Stem/physiology , Male , Female , Child, Preschool , Cochlear Nerve/physiopathology , Cochlear Nerve/abnormalities , Deafness/physiopathology , Deafness/congenital , Deafness/surgery , Child , Constriction, Pathologic , Cochlear Implantation/methods
8.
Ann Med Surg (Lond) ; 86(4): 1843-1849, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38576988

ABSTRACT

Background: The dimensionless Rajan's heart failure (R-hf) risk score was proposed to predict all-cause mortality in patients hospitalized with chronic heart failure (HF) and reduced ejection fraction (EF) (HFrEF). Purpose: To examine the association between the modified R-hf risk score and all-cause mortality in patients with HFrEF. Methods: Retrospective cohort study included adults hospitalized with HFrEF, as defined by clinical symptoms of HF with biplane EF less than 40% on transthoracic echocardiography, at a tertiary centre in Dalian, China, between 1 November 2015, and 31 October 2019. All patients were followed up until 31 October 2020. A modified R-hf risk score was calculated by substituting brain natriuretic peptide (BNP) for N-terminal prohormone of BNP (NT-proBNP) using EF× estimated glomerular filtration rate (eGFR)× haemoglobin (Hb))/BNP. The patients were stratified into tertiles according to the R-hf risk score. The measured outcome was all-cause mortality. The score performance was assessed using C-statistics. Results: A total of 840 patients were analyzed (70.2% males; mean age, 64±14 years; median (interquartile range) follow-up 37.0 (27.8) months). A lower modified R-hf risk score predicted a higher risk of all-cause mortality, independent of sex and age [1st tertile vs. 3rd tertile: adjusted hazard ratio (aHR), 3.46; 95% CI: 2.11-5.67; P<0.001]. Multivariate Cox regression analysis indicated that a lower modified R-hf risk score was associated with increased cumulative all-cause mortality [univariate: (1st tertile vs. 3rd tertile: aHR, 3.45; 95% CI: 2.11-5.65; P<0.001) and multivariate: (1st tertile vs. 3rd tertile: aHR 2.21, 95% CI: 1.29-3.79; P=0.004)]. The performance of the model, as reported by C-statistic was 0.67 (95% CI: 0.62-0.72). Conclusion: The modified R-hf risk score predicted all-cause mortality in patients hospitalized with HFrEF. Further validation of the modified R-hf risk score in other cohorts of patients with HFrEF is needed before clinical application.

9.
Bioorg Med Chem Lett ; 105: 129743, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38608962

ABSTRACT

Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC50 = 0.13 µM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC50 = 0.44 µM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.


Subject(s)
Antiviral Agents , Enzyme Inhibitors , Neuraminidase , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Structure-Activity Relationship , Hydrazones/chemistry , Hydrazones/pharmacology , Hydrazones/chemical synthesis , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/enzymology , Drug Discovery , Molecular Docking Simulation , Molecular Structure , Humans , Molecular Dynamics Simulation , Dose-Response Relationship, Drug
10.
Nat Commun ; 15(1): 2899, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38575572

ABSTRACT

Electrocatalytic conversion of organic small molecules is a promising technique for value-added chemical productions but suffers from high precious metal consumption, poor stability of electrocatalysts and tedious product separation. Here, a Pd/NiMoO4/NF electrocatalyst with much lowered Pd loading amount (3.5 wt.%) has been developed for efficient, economic, and ultra-stable glycolate synthesis, which shows high Faradaic efficiency (98.9%), yield (98.8%), and ultrahigh stability (1500 h) towards electrocatalytic ethylene glycol oxidation. Moreover, the obtained glycolic acid has been converted to value-added sodium glycolate by in-situ acid-base reaction in the NaOH electrolyte, which is atomic efficient and needs no additional acid addition for product separation. Moreover, the weak adsorption of sodium glycolate on the catalyst surface plays a significant role in avoiding excessive oxidation and achieving high selectivity. This work may provide instructions for the electrocatalyst design as well as product separation for the electrocatalytic conversions of alcohols.

11.
J Tissue Viability ; 33(2): 185-189, 2024 May.
Article in English | MEDLINE | ID: mdl-38521680

ABSTRACT

BACKGROUND: Pediatric burn patients are an essential part of burn populations. However, there is limited publicly available data on the epidemiological impact of COVID-19 on pediatric burns in China. OBJECTIVE: In this paper, pediatric burn patients admitted to the Department of Burn Surgery of the First Hospital of Jilin University before and during COVID-19 were retrospectively investigated to determine the impact of COVID-19 on pediatric burn inpatients. METHODS: The information of inpatients from July 2017 to December 2019 (pre-COVID-19 group) and from January 2020 to June 2022 (COVID-19 group) in the Department of Burn Surgery at the First Hospital of Jilin University was retrospectively investigated. Demographic information of patients, length of hospital stay, total body surface area (TBSA) of burn injury, post-injury visit time, comorbidity, surgical methods, etc., were statistically analyzed. RESULTS: The COVID-19 group included 154 (10.2%) patients, and the pre-COVID-19 group included 335 (19.4%) patients (P<0.001). There were no differences in gender, age, length of hospital stay, or etiology of burns between the two groups. Compared to the pre-COVID-19 group, patients in the pre-COVID-19 group experienced a significant delay in presentation (P<0.001), had a larger TBSA of burn wound (P < 0.001), were more prone to sustaining major burns (P < 0.001), a higher likelihood of undergoing operations (P = 0.03), higher cost (P<0.001) and more complications (P<0.001). Additionally, upper extremities were the most commonly part involved in both groups (P = 0.004), with the lower extremities showed a significant increase to be involved in burn injury during COVID-19 pandemic (P = 0.007). Furthermore, the majority of guardians did not take first aid measures in both groups following burn injury (P = 0.102). CONCLUSIONS: During the COVID-19 pandemic period, scalds remained the main reason for hospitalization. The number of hospitalized patients has decreased dramatically, while the severity of burns has significantly increased, with a notable delay in hospital visits and an increased occurrence of complications.


Subject(s)
Burn Units , Burns , COVID-19 , Humans , COVID-19/epidemiology , Retrospective Studies , Burns/epidemiology , Burns/therapy , China/epidemiology , Male , Female , Child , Burn Units/statistics & numerical data , Burn Units/organization & administration , Child, Preschool , Length of Stay/statistics & numerical data , Adolescent , Infant , Pandemics , SARS-CoV-2
12.
J Allergy Clin Immunol Glob ; 3(2): 100225, 2024 May.
Article in English | MEDLINE | ID: mdl-38524787

ABSTRACT

Background: Increasing frequency of intermittent oral corticosteroid (OCS) prescription and cumulative OCS exposure increase the risk of OCS-related adverse outcomes. Objective: We sought to describe the evolution and trajectory of intermittent OCS prescription patterns in patients with asthma and investigate risk factors independently associated with transitioning to a frequent prescription pattern. Methods: This historical cohort study included patients with active asthma managed in UK primary care and included in the Optimum Patient Care Research Database (OPCRD; opcrd.co.uk). Intermittent OCS prescription patterns were categorized as sporadic, infrequent, moderately frequent, or frequent. Prescription pattern sequences were described for those who had a frequent sequence in their final year of prescribing. We examined associations between OCS prescription pattern and the hazard of transitioning into a frequent intermittent OCS prescription pattern using multivariable Cox regression with a 10-year look-back period. Results: Of 105,229 patients with intermittent OCS prescriptions, 57.1% (n = 60,083) had a frequent OCS prescription pattern at some point. Irrespective of baseline pattern, most patients transitioned to frequent prescription during the look back. The strongest risk factors were a more frequent prescription pattern at the start of look-back period, a lower percentage peak expiratory flow rate, and higher Global Initiative for Asthma treatment step. Older age, female sex, obesity, and active smoking were also associated with a higher risk of transitioning. Conclusion: Our findings help identify those most at risk of transitioning to frequent intermittent OCS receipt and encourage earlier intervention with OCS-sparing treatments.

13.
Int J Mol Sci ; 25(6)2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38542518

ABSTRACT

Mitochondria are essential organelles that generate energy via oxidative phosphorylation. Plant mitochondrial genome encodes some of the respiratory complex subunits, and these transcripts require accurate processing, including C-to-U RNA editing and intron splicing. Pentatricopeptide repeats (PPR) proteins are involved in various organellar RNA processing events. PPR596, a P-type PPR protein, was previously identified to function in the C-to-U editing of mitochondrial rps3 transcripts in Arabidopsis. Here, we demonstrate that PPR596 functions in the cis-splicing of nad2 intron 3 in mitochondria. Loss of the PPR596 function affects the editing at rps3eU1344SS, impairs nad2 intron 3 splicing and reduces the mitochondrial complex I's assembly and activity, while inducing alternative oxidase (AOX) gene expression. This defect in nad2 intron splicing provides a plausible explanation for the slow growth of the ppr595 mutants. Although a few P-type PPR proteins are involved in RNA C-to-U editing, our results suggest that the primary function of PPR596 is intron splicing.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Gene Expression Regulation, Plant , Introns/genetics , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Plant Proteins/genetics , RNA Splicing
14.
Org Biomol Chem ; 22(13): 2562-2565, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38451158

ABSTRACT

A radical initiator-free defunctionalization reaction of alkyl isocyanides with a hydrosilane has been established through C-N bond cleavage under catalyst-free visible light irradiation. Various alkyl isocyanides participated in the defunctionalization with tris(trimethylsilyl)silane under blue light irradiation at room temperature, delivering the reduced products in good yields with high chemoselectivity.

15.
Alzheimers Dement ; 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38506634

ABSTRACT

BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

16.
Alzheimers Dement ; 20(4): 2922-2942, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38460121

ABSTRACT

INTRODUCTION: The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. METHODS: To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. RESULTS: The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant. DISCUSSION: The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. HIGHLIGHTS: BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.


Subject(s)
Alzheimer Disease , Animals , Mice , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides , Disease Models, Animal , Mice, Transgenic , Neuroglia/pathology , Plaque, Amyloid/pathology , Humans
17.
ChemSusChem ; : e202301911, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38477175

ABSTRACT

The multifunctional derivatization of alcohols has been achieved by the bipyridinium-based conjugated small molecule photocatalysts with redox center and Lewis acid site. Besides exhibiting high activity in the selective generation of aldehydes/ketones, acids from alcohols through solvent modulation, this system renders the first selective synthesis of esters via an attractive cross-coupling pattern, whose reaction route is significantly different from the traditional condensation of alcohols and acids or esterification from hemiacetals. Following the oxidization of alcohol to aldehyde via bipyridinium-mediated electron and energy transfer, the Lewis acid site of bipyridinium then activates the aldehyde and methanol to obtain the acetal, which further reacts with methanol to generate ester. This method not only demonstrates a clear advantage of bipyridinium in diverse catalytic activities, but also paves the way for designing efficient multifunctional small molecule photocatalysts. This metal- and additive-free photocatalytic esterification reaction marks a significant advancement towards a more environmentally friendly, cost-effective and green sustainable approach, attributed to the utilization of renewable substrate alcohol and the abundant, low-cost air as the oxidant. The mildness of this esterification reaction condition provides a more suitable alternative for large-scale industrial production of esters.

18.
Plant Physiol ; 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38447060

ABSTRACT

Global climate change is accompanied by carbon dioxide (CO2) enrichment and high-temperature stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. Here, we show that elevated CO2 alleviated plant sensitivity to high-temperature stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to high-temperature stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-Luc assays revealed that Glc bound to tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. Transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.

19.
J Org Chem ; 89(6): 4085-4097, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38394366

ABSTRACT

A palladium-catalyzed annulative π-extension reaction of bay-iodinated triphenylenes with aryl iodides/o-chloroaromatic carboxylic acids was developed. This approach enabled the synthesis of diverse polycyclic aromatic compounds, including dibenzo[fg,op]tetracenes, azadibenzo[fg,op]tetracenes, and tribenzo[a,g,m]coronenes. Initial studies indicate that the resulting product, 2,3,8,9,14,15-hexakis(decyloxy)tribenzo[a,g,m]coronene, exhibits good liquid-crystalline properties.

20.
Mol Plant ; 17(4): 598-613, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38341757

ABSTRACT

Jasmonates (JAs), a class of lipid-derived stress hormones, play a crucial role across an array of plant physiological processes and stress responses. Although JA signaling is thought to rely predominantly on the degradation of specific JAZ proteins by SCFCOI1, it remains unclear whether other pathways are involved in the regulation of JAZ protein stability. Here, we report that PUB22, a plant U-box type E3 ubiquitin ligase, plays a critical role in the regulation of plant resistance against Helicoverpa armigera and other JA responses in tomato. Whereas COI1 physically interacts with JAZ1/2/5/7, PUB22 physically interacts with JAZ1/3/4/6. PUB22 ubiquitinates JAZ4 to promote its degradation via the 26S proteasome pathway. Importantly, we observed that pub22 mutants showreduced resistance to H. armigera, whereas jaz4 single mutants and jaz1 jaz3 jaz4 jaz6 quadruple mutants have enhanced resistance. The hypersensitivity of pub22 mutants to herbivores could be partially rescued by JAZ4 mutation. Moreover, we found that expression of PUB22 can be transcriptionally activated by MYC2, thus forming a positive feedback circuit in JA signaling. We noticed that the PUB22-JAZ4 module also regulates other JA responses, including defense against B. cinerea, inhibition of root elongation, and anthocyanin accumulation. Taken together, these results indicate that PUB22 plays a crucial role in plant growth and defense responses, together with COI1-regulated JA signaling, by targeting specific JAZs.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Solanum lycopersicum , Arabidopsis Proteins/metabolism , Arabidopsis/metabolism , Repressor Proteins/metabolism , Solanum lycopersicum/genetics , Cyclopentanes/metabolism , Oxylipins/metabolism , Plants/metabolism , Gene Expression Regulation, Plant , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism
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