Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 2.007
Filter
1.
Stem Cell Res Ther ; 15(1): 350, 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39380045

ABSTRACT

BACKGROUND: The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear. METHODS: We established a SMYD1 knockout pluripotent stem cell line and a doxycycline-inducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model. RESULTS: Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation capacity of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome sequencing and small molecule inhibitor intervention suggested that the GSK3ß/ß-catenin&ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3ß through histone H3 lysine 4 trimethylation. Additionally, dual-luciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3ß, thereby augmenting its transcriptional activity. Moreover, administering insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells. CONCLUSIONS: Our research indicated that the participation of SMYD1 in the GSK3ß/ß-catenin&ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3ß. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease.


Subject(s)
Cell Differentiation , Cell Proliferation , Glycogen Synthase Kinase 3 beta , Histone-Lysine N-Methyltransferase , Myocytes, Cardiac , beta Catenin , Humans , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/genetics , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/genetics , beta Catenin/metabolism , beta Catenin/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/cytology , MAP Kinase Signaling System , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/cytology , Histones/metabolism , Muscle Proteins/metabolism , Muscle Proteins/genetics , Multipotent Stem Cells/metabolism , Multipotent Stem Cells/cytology , Multipotent Stem Cells/drug effects , Cell Line , DNA-Binding Proteins , Transcription Factors
2.
Integr Zool ; 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39350470

ABSTRACT

Many bird species in montane regions display altitudinal migration, but so far, the underlying ecological driving mechanisms are not clear. We studied the altitudinal migration behavior patterns and factors influencing altitudinal migration in the Xiling Snow Mountains, which are part of the Hengduan mountain range in southwest China. We recorded the local bird diversity, the seasonal change of: the average temperature (AT), the average humidity (AH), the average invertebrate biomass (AIB), and the amount of plant food sources (PFS) at two study sites (∼1300 and ∼2100 m a.s.l.) during two migration seasons from September 2022 to May 2023. During our surveys, we recorded 96 bird species in total. Among these, 15 altitudinal migrants were identified. The most common family among altitudinal migrants was Leiothrichidae. AT, AIB, and PFS had a significant positive correlation with the monthly number of individuals (MNI) several bird species, implying that increasing temperatures and an increasing abundance of invertebrates and PFS possibly induced upward migration of altitudinal migrants and vice versa. AH possibly only played a minor role in influencing altitudinal migration, since it exhibited no significant correlation with the MNI. Furthermore, we found that the upward migration temperature range of altitudinal migrants ranged between 9.8°C and 13.9°C during spring and the downward migration temperature range ranged between 12.2°C and 7.9°C during autumn. In conclusion, our study and several other studies revealed that the same environmental factors influenced the altitudinal migration patterns of birds in the Hengduan Mountains.

3.
Comput Inform Nurs ; 2024 Oct 02.
Article in English | MEDLINE | ID: mdl-39356834

ABSTRACT

Fall is a common adverse event among older adults. This study aimed to identify essential fall factors and develop a machine learning-based prediction model to predict the fall risk category among community-dwelling older adults, leading to earlier intervention and better outcomes. Three prediction models (logistic regression, random forest, and naive Bayes) were constructed and evaluated. A total of 459 people were involved, including 156 participants (34.0%) with high fall risk. Seven independent predictors (frail status, age, smoking, heart attack, cerebrovascular disease, arthritis, and osteoporosis) were selected to develop the models. Among the three machine learning models, the logistic regression model had the best model fit, with the highest area under the curve (0.856) and accuracy (0.797) and sensitivity (0.735) in the test set. The logistic regression model had excellent discrimination, calibration, and clinical decision-making ability, which could aid in accurately identifying the high-risk groups and taking early intervention with the model.

4.
RSC Adv ; 14(43): 31768-31776, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-39380652

ABSTRACT

The unique capacity of certain plant endophytes to degrade organic pollutants has garnered considerable interest in recent years. However, it remains uncertain whether endophytes can maintain high degradation activity after in vitro culture and whether they can be used directly in the remediation of contaminated soils. This study reveals that resveratrol, a plant secondary metabolite, selectively boosts the degradation of polycyclic aromatic hydrocarbons (PAHs) by endophytic Methylobacterium extorquens C1 (C1) in vitro, while exerting negligible effects on the activity of indigenous soil bacteria. For the first time, a combined application of C1 and resveratrol was employed in the remediation of polycyclic aromatic hydrocarbon (PAH)-contaminated soil. The findings indicate that the sole use of resveratrol failed to promote the removal of PAHs by indigenous soil microorganisms, whereas sole application of C1 boosted Methylobacterium-related PAH-degrading bacterial abundance, enhancing PAH removal, yet concurrently reduced overall soil microbial diversity. The combination of resveratrol and C1 not only stimulated the PAH removal but also mitigated the impact of C1 on the soil microbial community structure when C1 was applied individually. Specifically, the optimal removal efficacy was achieved with a treatment combination of 5 mg kg-1 resveratrol and 1.2 × 107 CFU kg-1 of C1, leading to a 130% and 231% increase in the removal of phenanthrene and acenaphthene, respectively, over a 15 days period. This study proposes a novel approach for the bioremediation of organic-contaminated soil by using the specific biological response of plant endophytic bacteria to secondary metabolites.

5.
Biol Res ; 57(1): 71, 2024 Oct 05.
Article in English | MEDLINE | ID: mdl-39367424

ABSTRACT

BACKGROUND: Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. METHODS: Hydrogen peroxide (H2O2) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. RESULTS: The findings demonstrated that ozone mitigated H2O2-induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H2O2. Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. CONCLUSIONS: These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.


Subject(s)
Disease Models, Animal , Ischemic Stroke , Oxidative Stress , Ozone , Reactive Oxygen Species , Ozone/pharmacology , Ozone/therapeutic use , Animals , Ischemic Stroke/drug therapy , Mice , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Reperfusion Injury , Male , Hydrogen Peroxide/metabolism , Humans , NF-E2-Related Factor 2/metabolism , Apoptosis/drug effects , Mice, Inbred C57BL , Calcium/metabolism
6.
J Med Chem ; 2024 Oct 03.
Article in English | MEDLINE | ID: mdl-39361006

ABSTRACT

Currently, there are no specific drugs for treating acute pancreatitis. Soluble epoxide hydrolase (sEH) inhibitors show promise, but face challenges like low blood drug concentrations and potential adverse effects on CYP enzymes and the human ether-a-go-go-related gene (hERG). In this study, an approach involving scaffold hopping and structure-activity guided optimization was employed to design a series of phenylquinoline-based sEH inhibitors. Among these compounds, DJ-53 exhibited potent in vitro and in vivo effects in alleviating pain and reducing inflammation. The in vivo mechanism of action involved inhibiting sEH enzyme activity, thereby increasing levels of anti-inflammatory epoxyeicosatrienoic acids (EETs) and decreasing levels of proinflammatory dihydroxyeicosatrienoic acids (DHETs). Importantly, DJ-53 showed exceptional oral bioavailability and pharmacokinetics, while avoiding inhibition of CYP enzymes or the hERG channel. These results highlight DJ-53's potential as a new lead compound for anti-inflammatory and analgesic applications and provide a safe and effective scaffold for developing sEH inhibitors.

7.
Front Pediatr ; 12: 1380985, 2024.
Article in English | MEDLINE | ID: mdl-39376677

ABSTRACT

Background: Laparoscopic pyeloplasty is a minimally invasive approach for the therapy of infant ureteropelvic junction obstruction (UPJO), reliant on CO2 pneumoperitoneum insufflation. While the impact of CO2 insufflation on adult and older pediatric populations has been studied, its effects on infants remain less explored. Methods: This prospective randomized controlled trial included infants with UPJO undergoing laparoscopic pyeloplasty. Patients were allocated to low pneumoperitoneum pressure (LPP, 5 mmHg) or high pneumoperitoneum pressure (HPP, 8 mmHg) groups. Surgical parameters, postoperative complications, acid-base balance, stress markers, inflammatory cytokines, and oxidative stress markers were evaluated and compared. Results: A total of 116 infants were analyzed. Preoperative characteristics were comparable between LPP and HPP groups. No significant differences in blood loss, operation time, or hospitalization time were observed. Postoperative complications were similar between groups. Acid-base balance analysis revealed a decrease in pH after pneumoperitoneum in both groups, with greater reductions in actual base excess and standard base excess in the HPP group. Stress markers, cytokines, and oxidative stress markers increased postoperatively in both groups, with higher levels in the HPP group. Conclusion: HPP leads to more pronounced physiological responses, including acid-base alterations, stress reactions, and inflammatory cytokine elevations.

8.
Microbiol Spectr ; : e0082624, 2024 Oct 09.
Article in English | MEDLINE | ID: mdl-39382281

ABSTRACT

Bombyx mori cypovirus (BmCPV), a member of the Reoviridae family, is a well-established research model for double-stranded RNA (dsRNA) viruses with segmented genomes. Despite its small genome size, the coding potential of BmCPV remains largely unexplored. In this study, we identified a novel small open reading frame within the S10 dsRNA genome, encoding a small viral peptide (VSP59) with 59 amino acid residues. Functional characterization revealed that VSP59 acts as a negative regulator of viral replication. VSP59 predominantly localizes to the cytoplasm, where it interacts with prohibitin 2 (PHB2), an inner membrane mitophagy receptor. This interaction targets mitochondria and triggers caspase 3-dependent apoptosis. Transient expression of vsp59 in BmN cells suppressed viral replication, an effect that was reversed by silencing PHB2 expression. Moreover, recombinant BmCPV with a mutated vsp59 exhibited reduced replication. Our findings demonstrate that VSP59 interacts with PHB2 on mitochondria, inducing apoptosis and thereby diminishing viral replication. This study expands our understanding of the genetic information encoded by the BmCPV genome and highlights the role of novel small peptides in host-virus interactions. IMPORTANCE: A novel small open reading frame (sORF) from the viral genome was identified and characterized. The sORF could encode a small viral peptide (VSP59) that targeted mitochondria and induced prohibitin 2-related apoptosis, further attenuating Bombyx mori cypovirus replication.

10.
Int J Biol Macromol ; : 136314, 2024 Oct 04.
Article in English | MEDLINE | ID: mdl-39370064

ABSTRACT

Viral circRNAs play important roles in host-virus interactions. Previous reports showed that grass carp reovirus (GCRV) encodes 32 circRNAs, and circ_20 from the negative strand of GCRV genome segment 7 has the potential to regulate GCRV replication. However, the regulatory mechanism of circ_20 on GCRV remains unknown. In this study, circ_20 was further validated, and circ_20 negatively regulated ERS, the PERK pathway, and ROS production in GCRV-infected cells. Furthermore, circ_20 inhibited the PERK pathway by forming a ternary complex with BIP and PERK, resulting in delaying GCRV replication. RNA pull-down results indicated that the 51-102 nt region of circ_20 interacts with BIP, while the 451-502 and 514-565 nt regions interact with PERK. After the deletion of these interaction regions, the ability of circ_20 to promote BIP-PERK interaction decreases, leading to a decrease in the ability to inhibit GCRV proliferation. These findings uncovered new insights into the complex interplay between viruses and host cells and provided a novel understanding of the significance of viral circRNAs in virus-host interactions.

12.
J Mech Behav Biomed Mater ; 160: 106742, 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39284273

ABSTRACT

Spider silk is a type of natural protein fiber with excellent toughness and tensile strength. The mechanical properties of chimeric silk have been improved by integrating the spider silk protein gene into the silkworm (Bombyx mori) genome, but this strategy requires a long time to produce genetically modified silkworms. In this study, to rapidly produce chimeric silkworms/spider silk with improved toughness and tensile strength, recombinant Autographa californica multiple nucleopolyhedrovirus (AcMNPV), AcMNPV-FHP-MaSp-G, harboring a full-length Trichonephila clavipes major ampullate spidroin G (MaSp-G) gene driven by the silkworm fibroin heavy chain (Fib-H) promoter, was constructed, in which the signal peptide sequence of the MaSp-G gene was replaced by the signal peptide sequence of the Fib-H gene. Western blot and LC-MS/MS results showed that MaSp-G was successfully expressed in the posterior silk gland of silkworm larvae infected with AcMNPV-FHP-MaSp-G and secreted into the cocoon. Mechanical property tests revealed that the average maximum breaking stress and the average maximum elastic strain of chimeric silkworms/spider silk were 497.867 MPa and 14.824%, respectively, which were 36.53% and 23.55% greater than those of silk produced by normal silkworms. Fourier transform infrared (FTIR) spectroscopy revealed that the proportions of ß-sheets, α-helices, and ß-turns in the chimeric silk increased by 18.22%, 16.92%, and 18.72%, respectively. These results indicate that the mechanical properties of the chimeric silk produced by silkworms infected with AcMNPV-FHP-MaSp-G were significantly improved, which provides a new method for rapid production of chimeric silk in a genetically modified/genome-edited silkworm-independent manner.

13.
Emerg Microbes Infect ; 13(1): 2400546, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39221898

ABSTRACT

The vast majority of data obtained from sequence analysis of influenza A viruses (IAVs) have revealed that nonstructural 1 (NS1) proteins from H1N1 swine, H3N8 equine, H3N2 avian and the correspondent subtypes from dogs have a conserved four C-terminal amino acid motif when independent cross-species transmission occurs between these species. To test the influence of the C-terminal amino acid motifs of NS1 protein on the replication and virulence of IAVs, we systematically generated 7 recombinants, which carried naturally truncated NS1 proteins, and their last four C-terminal residues were replaced with PEQK and SEQK (for H1N1), EPEV and KPEI (for H3N8) and ESEV and ESEI (for H3N2) IAVs. Another recombinant was generated by removing the C-terminal residues by reverse genetics. Remarkably, the ESEI and KPEI motifs circulating in canines largely contributed efficient replication in cultured cells and these had enhanced virulence. In contrast, the avian ESEV motif was only responsible for high pathogenicity in mice. We examined the effects of these motifs upon interferon (IFN) induction. The 7 mutant viruses replicated in vitro in an IFN-independent manner, and the canine SEQK motif was able to induced higher levels of IFN-ß in human cell lines. These findings shed further new light on the role of the four C-terminal residues in replication and virulence of IAVs and suggest that these motifs can modulate viral replication in a species-specific manner.


Subject(s)
Amino Acid Motifs , Influenza A Virus, H1N1 Subtype , Orthomyxoviridae Infections , Viral Nonstructural Proteins , Virus Replication , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/chemistry , Animals , Dogs , Virulence , Mice , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza A Virus, H1N1 Subtype/physiology , Orthomyxoviridae Infections/virology , Humans , Madin Darby Canine Kidney Cells , Mice, Inbred BALB C , Dog Diseases/virology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/pathogenicity , Influenza A Virus, H3N2 Subtype/physiology , Influenza A Virus, H3N8 Subtype/genetics , Influenza A Virus, H3N8 Subtype/pathogenicity , Female
14.
J Hazard Mater ; 479: 135717, 2024 Nov 05.
Article in English | MEDLINE | ID: mdl-39241362

ABSTRACT

Chlorinated organophosphorus flame retardants (Cl-OPFRs) and microplastics (MPs) are emerging pollutants in landfills, but their synergistic behaviors and triggering risks were rarely focused on, impeding the resource utilization of landfill soils. This study systematically investigated the adsorption/desorption behaviors, bioaccessibility and human health risks of Cl-OPFRs in landfill soil particle-size fractions coexisted with MPs under simulated gastrointestinal conditions. The results showed that the adsorption capacity and bioaccessibility of Cl-OPFRs in humus soil were higher than that in subsoil. MPs promoted the adsorption of tris(1-chloro-2-methylethyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) in landfill soils by up to 34.6 % and 34.1 % respectively, but inhibited the adsorption of tris(2-chloroethyl) phosphate (TCEP) by up to 43.6 %. The bioaccessibility of Cl-OPFRs in landfill soils was positively correlated with MPs addition ratio but negatively correlated with the KOW of Cl-OPFRs, soil organic matter and particle size. MPs addition increased the residual concentration of Cl-OPFRs and significantly increased the bioaccessibility of TCEP and TDCPP by up to 33.1 % in landfill soils, resulting in higher carcinogenic and noncarcinogenic risks. The study presents the first series of the combined behavior and effects of MPs and Cl-OPFRs in landfill soils, and provides a theoretical reference for landfill risk management.

15.
Mycoses ; 67(9): e13785, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39245647

ABSTRACT

Antifungal-resistant dermatophytes (ARD) infection is a hotspot issue in clinical microbiology and the dermatology field. Trichophyton indotineae as the dominant species of dermatophyte with terbinafine-resistance or multidrug resistance, is easy to be missed detection clinically, which brings severe challenges to diagnosis and treatment. ARD infection cases have emerged in China, and it predicts a risk of transmission among human. Based on the existing medical evidence and research data, the Mycology Group of Combination of Traditional and Western Medicine Dermatology and Chinese Antifungal⁃Resistant Dermatophytoses Expert Consensus Group organized experts to make consensus on the management of the infection. Here, the consensus formulated diagnosis and treatment recommendations, to raise attention to dermatophytes drug resistance problem, and expect to provide reference information for the clinical diagnosis, treatment, prevention and control.


Subject(s)
Antifungal Agents , Consensus , Drug Resistance, Fungal , Tinea , Humans , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Arthrodermataceae/drug effects , China , Tinea/drug therapy , Tinea/microbiology , Tinea/diagnosis , Trichophyton/drug effects , Trichophyton/isolation & purification
16.
Eur J Neurol ; : e16488, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39331367

ABSTRACT

BACKGROUND AND PURPOSE: Emerging evidence has linked impaired kidney function with dementia in older adults, but the neuropathological pathways underlying their association remain poorly understood. We sought to examine the relationships of kidney function with dementia and plasma biomarkers in a Chinese rural population. METHODS: This population-based study used data from the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) cohort (March-September 2018; n = 5715). Kidney function was assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine level. Dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were diagnosed according to the international criteria. Plasma biomarkers were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, general linear, and mediation models. RESULTS: Of the 5715 participants, 306 were diagnosed with dementia, including 195 with AD and 100 with VaD. Impaired kidney function (eGFR <60 vs. ≥90 mL/min/1.73 m2) was associated with multivariable-adjusted odds ratios of 2.24 (95% confidence interval [CI] 1.44-3.46) for all-cause dementia, 1.85 (1.07-3.18) for AD, and 2.49 (1.16-5.22) for VaD. In the biomarker subsample, impaired kidney function was significantly associated with higher plasma amyloid-ß (Aß)40 (ß-coefficient = 54.36, 95% CI 43.34-65.39), Aß42 (ß-coefficient = 3.14, 95% CI 2.42-3.86), neurofilament light chain (ß-coefficient = 10.62, 95% CI 5.62-15.62), and total tau (ß-coefficient = 0.68, 95% CI 0.44-0.91), and a lower Aß42/Aß40 ratio (ß-coefficient = -4.11, 95% CI -8.08 to -0.14). The mediation analysis showed that plasma total tau significantly mediated 21.76% of the association between impaired kidney function and AD (p < 0.05). CONCLUSION: Impaired kidney function is associated with dementia and plasma biomarkers among rural-dwelling older Chinese adults, and the association with AD is partly mediated by plasma biomarkers for neurodegeneration.

17.
Clin Pharmacol Ther ; 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39295563

ABSTRACT

T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.

18.
Plant Dis ; 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39295135

ABSTRACT

Phytoplasmas are minute phytopathogenic bacteria that induce excessive vegetative growth, known as witches'-broom (WB), in many infected plant species during the later stages of infection. The WB structure is characterized by densely clustered little (small) leaves, which are frequently accompanied by chlorosis (yellowing). The mechanisms behind the formation of little leaves within WB structures (LL-WB) are poorly understood. To address this gap, the LL-WB formation was extensively studied using sweet cherry virescence (SCV) phytoplasma-infected sweet cherry plants. Based on morphological examinations, signs of premature leaf senescence were observed in LL-WB samples, including reduced leaf size, chlorosis, and alterations in shape. Subsequent physiological analyses indicated decreased sucrose and glucose levels and changes in hormone concentrations in LL-WB samples. Additionally, the transcriptomic analysis revealed impaired ribosome biogenesis and DNA replication. As an essential process in protein production, the compromised ribosome biogenesis and the inhibited DNA replication led to cell cycle arrest, thus affecting leaf morphogenesis and further plant development. Moreover, the expression of marker genes involved in premature leaf senescence was significantly altered. These results indicate a complicated interplay between the development of leaves, premature leaf senescence, and the pathogen-induced stress responses in SCV phytoplasma-infected sweet cherry trees. The results of this study provide insight into understanding the underlying molecular mechanisms driving the formation of little leaves and interactions between plants and pathogens. The findings might help control phytoplasma diseases in sweet cherry cultivation.

19.
Int J Mol Sci ; 25(17)2024 Aug 23.
Article in English | MEDLINE | ID: mdl-39273103

ABSTRACT

Understanding the mechanisms that regulate plant root growth under soil drying is an important challenge in root biology. We observed that moderate soil drying promotes wheat root growth. To understand whether metabolic and hormonic changes are involved in this regulation, we performed transcriptome sequencing on wheat roots under well-watered and moderate soil drying conditions. The genes upregulated in wheat roots under soil drying were mainly involved in starch and sucrose metabolism and benzoxazinoid biosynthesis. Various plant hormone-related genes were differentially expressed during soil drying. Quantification of the plant hormones under these conditions showed that the concentrations of abscisic acid (ABA), cis-zeatin (CZ), and indole-3-acetic acid (IAA) significantly increased during soil drying, whereas the concentrations of salicylic (SA), jasmonic (JA), and glycosylated salicylic (SAG) acids significantly decreased. Correlation analysis of total root length and phytohormones indicated that CZ, ABA, and IAA are positively associated with wheat root length. These results suggest that changes in metabolic pathways and plant hormones caused by moderate soil drying help wheat roots grow into deeper soil layers.


Subject(s)
Gene Expression Regulation, Plant , Plant Growth Regulators , Plant Roots , Soil , Transcriptome , Triticum , Triticum/metabolism , Triticum/growth & development , Triticum/genetics , Plant Roots/growth & development , Plant Roots/metabolism , Plant Roots/genetics , Plant Growth Regulators/metabolism , Soil/chemistry , Indoleacetic Acids/metabolism , Abscisic Acid/metabolism , Gene Expression Profiling/methods , Desiccation
20.
J Hazard Mater ; 480: 135820, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39298960

ABSTRACT

Since December 2019, the COVID-19 pandemic has rapidly disseminated globally, posing significant threats to the world. The dining spaces are high-risk indoor environments for the transmission of SARS-CoV-2, posing challenges for intervention and control. This study, based on surveillance videos from two COVID-19 outbreak cases in restaurants, obtained real data on human behaviors of close contact and surface touch. A respiratory infectious disease transmission model was developed, incorporating four transmission routes: short-range airborne, long-range airborne, fomite and large droplet. The results indicate that diners and staff spent 21.9 %-28.7 % and 17.5 %-27.8 % of their time on speaking, respectively, while spending 85.9 %-90.7 % and 83.4 %-87.6 % of their time on surface touching. The primary transmission routes were short-range (contributing 5.8 %-70.9 %) and long-range airborne (contributing 28.4 %-93.0 %), with fomite and large droplet routes contributing less than 12.0 %. Staff-only mask wearing reduced infection risk by 12.8 %-31.8 %. It is recommended that mandatory mask wearing for staff is necessary, while diners should wear masks as much as possible, and that the equivalent ventilation rate of clean fresh air is suggested to 30.0 m3/ (h·person). This study provides a scientific support to make non-pharmaceutical interventions in dinning spaces.

SELECTION OF CITATIONS
SEARCH DETAIL