The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic ...or therapeutic measures against EHS are nonexistent.
The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed.
TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28.
Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.
•We investigated whether miRNA-let-7d or miRNA-107 serve as biomarkers of ADHD in diagnosis and therapy.•There were significant differences of miRNA-let-7d between ADHD and healthy children after ...rTMS or ATX treatment.•MiRNA-107 had no obvious changes ADHD patients and healthy children after rTMS or ATX treatment.•Our results suggest serum miRNA-let-7d may serve as a potential biomarker for children with ADHD.
We aimed to investigate whether microRNA-let-7d (miRNA-let-7d) and miRNA-107 may serve as diagnostic and therapeutic biomarkers of attention deficit hyperactivity disorder (ADHD). The relative expression level of miRNA-let-7d and miRNA-107 in patients with ADHD and in a healthy control group was detected by real-time polymerase chain reaction. The blood samples were collected at 6 weeks after repetitive transcranial magnetic stimulation (rTMS) or atomoxetine (ATX) in ADHD patients, and the relative expression levels of the two miRNAs before and after treatments were compared. There were significant differences in the expression level of miRNA-let-7d between ADHD patients and healthy children, as well as before and after rTMS or ATX treatment in ADHD patients. However, the expression of miRNA-107 showed no significant difference between ADHD patients and healthy children or before and after rTMS (or ATX treatment). These results suggest that serum miRNA-let-7d may serve as a potential diagnostic and therapeutic biomarker for children with ADHD.
Liver transplantation (LT) is the best choice for patients with end-stage liver diseases. In order to better understand pathophysiological alterations in LT, we aimed to identify potential hub genes ...and inhibitory compounds involved in the LT process. Four pairs of peripheral blood mononuclear cell (PBMC) samples of the LT recipients before and after surgery were collected and taken for transcriptome sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for the screened differentially expressed genes (DEGs) between pre- and post-operation groups. Common DEGs were obtained from GO and KEGG enriched pathways, followed by protein-protein interaction (PPI) network construction, hub gene identification, module analysis, and structure-based virtual screening process (SBVS). Compared to the pre-operation stage, 4745 genes were down-regulated and 798 up-regulated after LT. GO analysis showed that the DEGs were enriched in ribosome-related translation regulation, and KEGG analysis indicated that infection and immune-related pathways and diseases were largely enriched. A large number of down-regulated DEGs were not only associated with ribosome-related pathways but also with the alterations of epigenetic modifications, in particular ubiquitination. Moreover, through the PPI network of 29 common genes from GO and KEGG-enriched pathways, 7 hub genes were identified, including PTEN, MYC, EIF2S1, EIF4EBP1, HSP90AB1, TP53, and HSPA8, which were mainly involved in the PI3K-AKT signaling pathway. SBVS of the seed molecule PTEN (PDB code: 1D5R) predicted top hits compounds that may serve as potential inhibitors of PTEN, of which the compound ZINC4235331 had the lowest binding affinity of -10 kcal/mol. The significance of screened hub genes and potential inhibitors involved in the process of LT provides novel therapeutic strategies for improving the outcomes of LT recipients during surgery.
•The number of downregulated DEGs is nearly 6 times that of upregulated DEGs after LT.•DEGs are enriched in ribosome-related translation regulation.•DEGs are also enriched in infection and immune-related pathways.•PTEN-led seven hub genes and potential inhibitors are identified during LT.
Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated ...encephalopathy.
GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms.
Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses.
The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus.
Introduction
Repetitive transcranial magnetic stimulation has been widely used for the treatment of neurological and psychiatric diseases. Rodent animals including mice and rats are often used to ...investigate the potential cellular and molecular mechanisms for the therapeutic effects of repetitive transcranial magnetic stimulation. So far there is no report about an easy‐to‐use device to restrain rodent animals for repetitive transcranial magnetic stimulation.
Methods and Results
We introduced the design and use of the restraint device for mice or rats. In the mouse device, western blot and real‐time PCR analysis showed that，in stimulated mouse frontal cortex, 10 Hz high frequency stimulation for 10 sessions resulted in enhanced expression of NR2B‐containing N‐methyl‐D‐aspartic acid receptors and reduced α1 subunit of inhibitory GABAA receptors, whereas 0.5 Hz low frequency stimulation for 10 sessions caused decreased expression of NR2B subunit and increased α1 subunit of GABAA receptors. In the rat device, measures of motor evoke potentials indicated that 10 Hz stimulation for 10 sessions increased the excitability of stimulated cortex, whereas 0.5 Hz for 10 sessions reduced it.
Conclusions
These results suggested the effectiveness of the devices. Thus, the two devices are practical and easy‐to‐use to investigate the mechanisms of repetitive transcranial magnetic stimulation.
The two devices were designed to restrain the mice and rats for repetitive transcranial magnetic stimulation. The two devices were verified by real‐time PCR，western blot and electrophysiological methods. The two devices are practical and easy‐to‐use to investigate the mechanisms of repetitive transcranial magnetic stimulation.
Aims To investigate the indicators affecting the early outcome of patients with sepsis and to explore its prognostic efficacy for sepsis. Methods We collected clinical data from 201 patients with ...sepsis admitted to the emergency department of Xijing Hospital between June 2019 and June 2022. The patients were categorized into groups (survival or fatality) based on their 28-day prognosis. The clinical characteristics, biochemical indexes, organ function-related indicators, and disease scores of the patients were analyzed for both groups. Risk factor analysis was conducted for the indicators with significant differences. Results Among the indicators with significant differences between the deceased and survival groups, D-dimer (D-DI), Sequential Organ Failure Assessment (SOFA) score, platelet (PLT), international normalized ratio (INR), and D-DI/PLT were identified as independent risk factors affecting the prognosis of sepsis patients. Receiver operating characteristic (ROC) curves showed that D-DI/PLT (area under the curve (AUC) = 93.9), D-DI (AUC = 89.6), PLT (AUC = 81.3), and SOFA (AUC = 78.4) had good judgment efficacy. Further, Kaplan Meier (K-M) survival analysis indicated that the 28-day survival rates of sepsis patients were significantly decreased when they had high levels of D-DI/PLT, D-DI, and SOFA as well as low PLTs. The hazard ratio (HR) of D-DI/PLT between the two groups was the largest (HR = 16.19). Conclusions D-DI/PLT may be an independent risk factor for poor prognosis in sepsis as well as a clinical predictor of patient prognosis.
This study compared the clinical efficacy of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in previously untreated non-small cell lung cancer (NSCLC) patients harboring ...uncommon epidermal growth factor receptor (EGFR) exon 19delins variants.
We retrospectively analyzed the clinical outcomes of NSCLC patients with EGFR exon 19delins mutations who were treated with third- and first-generation EGFR TKIs. In vitro and in vivo studies were conducted to verify the sensitivity of these mutations to distinct generations of TKIs. Molecular simulation was used to investigate the structural characteristics of the EGFR mutant molecules.
In a multicenter cohort of 1,526 patients, 37 (2.4 %) had uncommon EGFR 19delins mutations. Twenty-four patients were treated with first-generation EGFR TKIs, and third-generation TKIs were administered to ten patients as frontline therapy. Patients carrying EGFR exon 19delins mutations who were given third-generation TKIs exhibited comparatively shorter progression-free survival (PFS) and overall survival (OS) in relation to those who received first-generation EGFR inhibitors; median PFS: 6.9 months vs. 19.1 months (p < 0.001), Median OS: 19.1 months vs. 32.6 months (p < 0.001). In vivo and in vitro studies revealed that uncommon EGFR 19delins variants exhibit limited sensitivity to third-generation EGFR inhibitors in contrast to first- and second-generation EGFR inhibitors. The molecular binding affinity of third-generation EGFR TKIs toward uncommon EGFR 19delins mutations was less than that of first- and second-generation EGFR inhibitors.
Uncommon EGFR 19delins variants respond poorly to third-generation EGFR inhibitors in NSCLC. Uncommon EGFR 19delins mutations may serve as an unfavorable predictive factor for the efficacy of third-generation EGFR TKI therapy, offering potential guidance for future clinical decision-making.
Background
Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our ...study was to identify potent EGFR inhibitors effective against the
T790M/C797S/L858R
mutant, a key player in resistance mechanisms.
Methods
Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination.
Results
Kinase assays identified three compounds to which the T790M/C797S/L858R mutant exhibited increased sensitivity compared to the T790M/L858R mutant, highlighting the potential efficacy of these compounds against resistance mechanisms. Among them,
T001-10027877
exhibited dual inhibitory effects, with IC
50
values of 4.34 µM against EGFR
T790M/C797S/L858R
and 1.27 µM against EGFR
T790M/L858R
. Further investigations into the antiproliferative effects in H1975, A549, H460 and Ba/F3-EGFR
L858/T790M/C797S
cancer cells revealed that
T001-10027877
was the most potent anticancer agent among the tested compounds. Additionally, the induction of H1975 cell apoptosis and cell cycle arrest by
T001-10027877
were confirmed, elucidating its mechanism of action.
Conclusions
This study highlights the efficacy of combining computational techniques with bioactivity assessments in the quest for novel antiproliferative agents targeting complex EGFR mutations. In particular,
T001-10027877
has great potential for overcoming EGFR-mediated resistance and merits further in vivo exploration. Our findings contribute valuable insights into the development of next-generation anticancer therapies, demonstrating the power of an integrated drug discovery approach.
When language program administrators consider changing a placement test, there are many issues to address. Will the scores help us place students into our curriculum? Will the scores reflect real ...differences in students' abilities? Will the administration of the test be feasible? This article describes one program's deliberations between keeping an in-house test or adopting a commercial test for speaking. Two speaking tests were compared according to curricular coverage, statistical distributions, and practicality. One test, PIE Speaking, was developed in-house. The other test, Versant English, was developed by Pearson Knowledge Technologies. Both covered many but not all curricular objectives. Internal consistency estimates were higher for Versant English than for PIE Speaking. The comparison of distribution patterns suggested that PIE Speaking better discriminated between mid-level students, but Versant English better discriminated between low and high ability students. PIE Speaking took approximately 60 staff hours, costing about $1200. Versant English took about 10 staff hours at an estimated cost of $6500. Cost weighed most heavily in the decision to keep the in-house speaking test. Modeling the steps taken to answer specific questions may provide structure for other language programs when evaluating their placement tests.
•Two speaking tests compared to determine appropriateness as basis for placement decisions.•One test, PIE Speaking, was developed in-house; the other, Versant English, a commercial product.•PIE Speaking was better at distinguishing students at intermediate levels, Versant English at high levels.•In terms of time, the fully automated computerized test, Versant English, was more efficient.•The in-house test, PIE Speaking, was much, much less expensive in terms of financial costs.
DNA-damage tolerance (DDT) is employed by eukaryotic cells to bypass replication-blocking lesions induced by DNA-damaging agents. In budding yeast Saccharomyces cerevisiae, DDT is mediated by RAD6 ...epistatic group genes and the central event for DDT is sequential ubiquitination of proliferating cell nuclear antigen (PCNA), a DNA clamp required for replication and DNA repair. DDT consists of two parallel pathways: error-prone DDT is mediated by PCNA monoubiquitination, which recruits translesion synthesis DNA polymerases to bypass lesions with decreased fidelity; and error-free DDT is mediated by K63-linked polyubiquitination of PCNA at the same residue of monoubiquitination, which facilitates homologous recombination-mediated template switch. Interestingly, the same PCNA residue is also subjected to sumoylation, which leads to inhibition of unwanted recombination at replication forks. All three types of PCNA posttranslational modifications require dedicated conjugating and ligation enzymes, and these enzymes are highly conserved in eukaryotes, from yeast to human.
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