High Metabolism Research Articles

Distribution of CYP3A4 and CYP3A5 Polymorphisms and Genotype Combination Implicated in Tacrolimus Metabolism.

Human cytochrome P450 (CYP), particularly CYP3A4 and CYP3A5 is mainly responsible for the metabolism of several drugs including tacrolimus. Significant interracial/interethnic variation in the expression and function of CYP3A5 and CYP3A4 is caused by Single Nucleotide Polymorphisms (SNPs) of genes encoding these proteins. The present study investigated the genetic polymorphisms CYP3A4*1B, CYP3A4*22, and CYP3A5*3 in the Tunisian population. We included in this study, Tunisian healthy subjects and renal transplant recipients receiving tacrolimus. CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). According to the genotypic combination of the three CYP polymorphisms, we have identified for the first time four metabolizers statuses: slow metabolizers (SM), intermediate metabolizers (IM), high metabolizers (HM), and extensive metabolizers (EM). A total of 101 renal transplant patients and 102 healthy subjects were included. Our results showed that the predominant alleles in the Tunisian population are a wild type of CYP3A4*1B (0.87), likewise CYP3A4*22 (0.975) and CYP3A5*3 (0.82). The genotype frequencies of CYP3A4*1B, CYP3A4*22, and CYP3A5*3 were found to be 3.9%, 0.0%, and 69.5%, respectively. Also, we found a significant linkage disequilibrium between CYP3A4*1B and CYP3A5*3. We approved that the IM is the predominant phenotype in our population with 124 patients followed by and EM with 41 patients, HM in 29 patients and SM in 9 patients. These results showed that Tunisians are most similar to Caucasians. The genetic background of these enzymes CYP3A4*1B, CYP3A4*22, and CYP3A5*3 in this study are important in the prescription of personalized medicine.

Comparative genomics reveals convergent signals associated with the high metabolism and longevity in birds and bats.

Birds and bats have long lifespans relative to their body size compared with non-flying animals. However, the genomic basis associated with longer lifespan of flying species despite their higher metabolism was unclear. In this study, we hypothesized that genes involved in the regulation of metabolism and lifespan changed with the acquisition of flight and searched for genes that show specific evolutionary patterns in flying species. As a result, we identified several genes that show different evolutionary rates in bird and bat lineages. Genes in pathways involved in lifespan regulation were conserved in birds, while they evolved at an accelerated rate in bats. We also searched for genes in which convergent amino acid substitutions occurred in birds and bats and found such substitutions in genes involved in cancer, reactive oxygen species control and immunity. Our study revealed genomic changes associated with the acquisition of flight in birds and bats and suggested that multiple genes involved in the regulation of lifespan and metabolism support both high metabolism and longevity in flying species.

The influence of temperature on the impacts of caffeine in mussels: Evaluating subcellular impacts and model predictions

In aquatic ecosystems, the presence of pharmaceuticals, particularly caffeine (CAF), has been linked to wastewater discharge, hospital waste, and the disposal of expired pharmaceutical products containing CAF. Additionally, rising temperatures due to climate change are anticipated in aquatic environments. This study aimed to assess the toxicity of various CAF concentrations under current (17 °C) and projected (21 °C) temperature conditions, using the mussel Mytilus galloprovincialis as a bioindicator species. Subcellular impacts were evaluated following 28 days of exposure to four CAF concentrations (0.5; 1.0; 5.0; 10.0 μg/L) at the control temperature (17 °C). Only effects at an environmentally relevant CAF concentration (5.0 μg/L) were assessed at the highest temperature (21 °C). The overall biochemical response of mussels was evaluated using non-metric Multidimensional Scaling (MDS) and the Integrated Biomarker Response (IBR) index, while the Independent Action (IA) model was used to compare observed and predicted responses. Results showed that at 17 °C, increased CAF concentrations were associated with higher metabolism and biotransformation capacity, accompanied by cellular damage at the highest concentration. Conversely, under warming conditions (21 °C), the induction of antioxidant enzymes was observed, although insufficient to prevent cellular damage compared to the control temperature. Regarding neurotoxicity, at 17 °C, the activity of the acetylcholinesterase enzyme was inhibited up to 5.0 μg/L; however, at 10.0 μg/L, activity increased, possibly due to CAF competition for adenosine receptors. The IA model identified a synergistic response for most parameters when CAF and warming acted together, aligning with observed results, albeit with slightly lower magnitudes.

Association of β-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia.

Plasma β-amyloid42 (Aβ42)/Aβ40 levels have shown promise in identifying Aβ-PET positive individuals. This study explored the concordance and discordance of plasma Aβ42/Aβ40 positivity (Plasma±) with CSF Aβ42/Aβ40 positivity (CSF±) and Aβ-PET positivity (PET±) in older adults without dementia. Associations of Aβ deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. We selected participants without dementia who had concurrent plasma Aβ42/Aβ40 and Aβ-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite 18F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aβ42/Aβ40 ≤0.1218. Aβ-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aβ42/Aβ40 ≤0.138), and the concordance and discordance of Aβ42/Aβ40 in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma±/PET± groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in Aβ-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aβ accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS Aβ accumulation (standardized β (βstd) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. These findings suggest that plasma Aβ42/Aβ40 abnormalities may predate CSF Aβ42/Aβ40 and Aβ-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aβ accumulation primarily at relatively advanced stages.

Abstract 4715: Azathioprine and Z36 induced cell death in human colorectal cancer HCT-116 and HCT-15 cells

Abstract Rationale and Objectives: Cancer accounts for a huge global health burden and is the third highest cause of death across the globe. Cancer cells are known to have higher basal reactive oxygen species (ROS) levels, owing to their higher metabolism and proliferation. Higher basal ROS in cancer cells made them susceptible to exogenous ROS stimuli that lead to cell death. Therefore, in the present study, we have analyzed the effects of Azathioprine, a glutathione (GSH) inhibitor and an intracellular ROS producer. The effect of Azathioprine was analyzed alone or in combination with a BCL-2 family protein inhibitor Z36, on human colorectal cancer cell lines HCT-116 and HCT-15. Methods: The effects of the drugs have been investigated using various methods including cell viability assay, DNA fragmentation assay, and Annexin V-FITC/PI apoptosis assay. In addition, morphological changes evident in cell death were detected by Giemsa staining. Combination dosage for drug synergistic effects was computed through the use of CompuSyn software. Western blot was performed to detect changes in the expression of cell death-related proteins following drug treatments. Results and conclusion: Azathioprine at a dose of 5 µM has been demonstrated to induce cell death in both HCT116 and HCT15 cells in a concentration and time-dependent manner. On the contrary, Z36, a novel BCLXL inhibitor, has demonstrated similar cell viability results at an even lower dose of 2.5 µM. When both drugs were combined at lower doses, no significant effects were observed on the cell viability of either cell line, demonstrating that the combined treatment has no synergistic or additive effects. This suggests that both drugs do not augment each other and might induce cell death via upregulation of ROS using a similar mechanism. Citation Format: Yousuf Tahir Ali, Mahwish Fatima, Muhammad Areeb Ahmed, Hasan Salman Siddiqi, Azhar Hussain, Mati Ur Rehman. Azathioprine and Z36 induced cell death in human colorectal cancer HCT-116 and HCT-15 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4715.

Bulk and single-cell transcriptome reveal the immuno-prognostic subtypes and tumour microenvironment heterogeneity in HCC.

Accumulating evidences suggest tumour microenvironment (TME) profoundly influence clinical outcome in hepatocellular carcinoma (HCC). Existing immune subtypes are susceptible to batch effects, and integrative analysis of bulk and single-cell transcriptome is helpful to recognize immune subtypes and TME in HCC. Based on the relative expression ordering (REO) of 1259 immune-related genes, an immuno-prognostic signature was developed and validated in 907 HCC samples from five bulk transcriptomic cohorts, including 72 in-house samples. The machine learning models based on subtype-specific gene pairs with stable REOs were constructed to jointly predict immuno-prognostic subtypes in single-cell RNA-seq data and validated in another single-cell data. Then, cancer characteristics, immune landscape, underlying mechanism and therapeutic benefits between subtypes were analysed. An immune-related signature with 29 gene pairs stratified HCC samples individually into two risk subgroups (C1 and C2), which was an independent prognostic factor for overall survival. The machine learning models verified the immune subtypes from five bulk cohorts to two single-cell transcriptomic data. Integrative analysis revealed that C1 had poorer outcomes, higher CNV burden and malignant scores, higher sensitivity to sorafenib, and exhibited an immunosuppressive phenotype with more regulators, e.g., myeloid-derived suppressor cells (MDSCs), Mø_SPP1, while C2 was characterized with better outcomes, higher metabolism, more benefit from immunotherapy, and displayed active immune with more effectors, e.g., tumour infiltrating lymphocyte and dendritic cell. Moreover, both two single-cell data revealed the crosstalk of SPP1-related L-R pairs between cancer and immune cells, especially SPP1-CD44, might lead to immunosuppression in C1. The REO-based immuno-prognostic subtypes were conducive to individualized prognosis prediction and treatment options for HCC. This study paved the way for understanding TME heterogeneity between immuno-prognostic subtypes of HCC.

Cognitive Reserve in Parkinson's Disease without Dementia: β-Amyloid and Metabolic Assessment.

Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown. To evaluate the effect of CR on β-amyloid burden and brain metabolism in non-demented PD subjects. Participants with PD (n = 53) underwent a clinical evaluation, [18 F]-fluorodeoxyglucose and [18 F]-flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects. The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior-CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low-medium-CR subjects (n = 31). Higher CR in non-demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of β-amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.

Integrated PET/MRI With 11C-CFT and 18F-FDG for levodopa response difference in Parkinson’s disease

AimParkinson's disease is one of the most common neurodegenerative diseases. Excellent levodopa responsiveness has been proposed as a characteristic supporting feature in substantiating the PD diagnosis. However, a small portion of clinically established PD patients shows poor levodopa response. This study aims to investigate brain function alterations of PD patients with poor levodopa responsiveness by PET/MRI. MethodA total of 46 PD patients were recruited. They all completed 11C-CFT PET/MRI scans and the acute levodopa challenge test. Among these 46 PD patients, 42 participants further underwent 18F-FDG PET/MRI scans. Clinical variables regarding demographic data, disease features and cognition scales were also collected. Based on the improvement rate of UPDRS‐III, PD patients were divided into non-responders (improvement rate < 33 %) and responders (improvement rate ≥ 33 %). Statistical parametric zapping was performed to analyze molecular imaging. Dopaminergic uptake and metabolism of 70 brain regions were converted to quantitative values and expressed as standard uptake value (SUV). SUV was further normalized by the cerebellum. The resulting SUV ratios and clinical variables were then compared by SPSS. ResultsThe difference between levodopa non-responders (n = 17) and responders (n = 29) in the UPDRS III baseline was statistically significant and the former had a lower UPDRS III baseline (19 (10, 32), p＜0.05). In contrast, no statistical difference between these two groups was found in age, gender, disease duration, cognition, motor subtype and Hoehn-Yahr stage. Dopaminergic uptake differences between levodopa non-responders (n = 17) and responders (n = 29) were shown in the left inferior frontal cortex (1.00 ± 0.09 vs 1.07 ± 0.08, p < 0.05 and FDR < 0.2), the right posterior cingulum (1.10 ± 0.10 vs 1.20 ± 0.13, p < 0.05 and FDR < 0.2) and the right insula (1.21 ± 0.12 vs 1.30 ± 0.10, p < 0.05 and FDR < 0.2). The metabolic alterations between levodopa non-responders (n = 16) and responders (n = 26) were shown in the right supplementary motor area (1.30 (1.18, 1.39) vs 1.41 (1.31, 1.53), p < 0.05 and FDR < 0.2), right precuneus (1.37 ± 0.10 vs 1.47 ± 0.18, p < 0.05 and FDR < 0.2), right parietal cortex (1.14 ± 0.15 vs 1.27 ± 0.21, p < 0.05 and FDR < 0.2), right supramarginal gyrus (1.16 (1.12, 1.26) vs 1.25 (1.14, 1.46), p < 0.05 and FDR < 0.2), right postcentral gyrus (1.15 (1.08, 1.32) vs 1.24 (1.17, 1.39), p < 0.05 and FDR < 0.2), medulla (0.75 ± 0.07 vs 0.80 ± 0.07, p < 0.05 and FDR < 0.2), right rolandic operculum (1.25 (1.18, 1.32) vs 1.33 (1.25, 1.50), p < 0.05 and FDR < 0.2), right olfactory (0.95 (0.91, 1.01) vs 1.01 (0.95, 1.15), p < 0.05 and FDR < 0.2), the right insula (1.15 (1.06, 1.22) vs 1.21 (1.12, 1.35), p < 0.05 and FDR < 0.2) and the left cerebellum crus (0.96 (0.91, 1.01) vs 0.92 (0.86, 0.96), p < 0.05 and FDR < 0.2). ConclusionsPD patients with poor response to levodopa showed less severe impairment of baseline motor symptoms, more severe dopaminergic deficits in the left inferior frontal, right posterior cingulate cortex and the right insula, and lower metabolism in the right supplementary motor area, right precuneus, right parietal cortex, right supramarginal gyrus, right postcentral gyrus, medulla, right rolandic operculum, right olfactory, the right insula and higher metabolism in the left cerebellum crus.

Formulation and Characterization of Herbal Cleansing Gel from Turmeric Extract Loaded Nanostructured Lipid Carriers

The herbal cleansing gel from turmeric extract is a natural skin care product with antioxidant, antimicrobial, and anti-inflammatory properties. Despite its advantages, turmeric extract has a higher metabolism, a low absorption rate, stability, and solubility. Encapsulation of turmeric extract had been developed to increase the bioavailability of turmeric extract for topical drug delivery. Hence, turmeric extract is encapsulated via nanostructured lipid carriers (NLCs) to produce turmeric extract-loaded nanostructured lipid carriers (T-NLCs). This project highlights the formulation and characterization of an herbal cleansing gel from encapsulated turmeric extract. To produce T-NLCs, medium-chain triglycerides (MCT) as liquid lipid and glycerol monostearate (GMS) as solid lipid generated an imperfect matrix incorporating turmeric extract. The T-NLCs were then characterized in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and stability. The T-NLCs exhibited particle size 129.407 ± 1.278 nm, polydispersity index 15.067 ± 2.105%, zeta potential -44.7 ± 1.8 mV, encapsulation efficiency 98.04 ± 9.19 % and remained stable over 30 days. The herbal cleansing gel was formulated with T-NLCs and characterized in term sensory test. The formulation is believed to improve the turmeric extract's phytochemical stability, biocompatibility, skin permeability, and dermo-cosmetic efficiency. In conclusion, developing turmeric in an innovative encapsulated formulation has aided in developing herbal-based cosmetic products for a wide range of skin care systems.

O-205 Poor mitochondrial metabolism impairs meiosis and contributes to reduced oocyte maturation rates in patients with advanced maternal age

Abstract Study question Is there a relationship between poor mitochondrial metabolism and impaired meiotic progression of germinal vesicle (GVs) oocytes in women of advanced maternal age (AMA)? Summary answer Poor mitochondrial metabolism impairs meiotic progression in human oocytes, contributing to a lower oocyte maturation capacity in women of AMA. What is known already High aneuploidy rates and impaired metabolism are characteristic features of AMA oocytes. Studies in mouse suggest that successful meiotic maturation and metabolic competency may be functionally linked, however this relationship has not been clearly established in human. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using Fluorescence Lifetime Imaging Microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. We performed an extensive characterization of oocyte metabolism in maturing GVs, obtained from both young and AMA patients, to establish the importance of mitochondrial metabolism during meiosis. Study design, size, duration A total of 401 GVs from young (≤30 years, n = 264) and AMA (&amp;gt;37 years, n = 137) women were included in the study. GVs were matured in vitro in G2-plus medium for 30 hours. Maturation was determined by the presence of an extruded polar body. Oocytes were used for FLIM (n = 175) and immunofluorescence (IF) analysis (n = 226). Further, mitochondrial metabolism loss of function studies (n = 64) were performed by treating young GVs with 1μM Trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 minutes. Participants/materials, setting, methods The proteins Dihydrolipoamide-S-Acetyltransferase (D-LAT) and Translocase-of-outer mitochondrial-membrane (TOMM20) were analysed in young and AMA oocytes by IF (Arbitrary-Unit, AU) to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities were quantified with ImageJ and compared by t-test; maturation rates were compared by Chi-squared test. FLIM comprehensive metabolism (NADH; FAD+) were taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short/long lifetime) were evaluated individually and combined into the Redox ratio (NADH intensity/FAD+ intensity). Main results and the role of chance Mitochondrial staining showed a common pattern in young and AMA GV oocytes, with a uniform localization of mitochondria in the ooplasm (TOMM20) and a subcortical localization of active organelles (D-LAT). These patterns were confirmed by in-live FLIM analysis. The total mitochondria abundance was comparable between AMA and young GV oocytes (intensity of 61674±24322 AU in young, 32186±33414 AU in AMA, p = 0.195), however, active mitochondria were diminished in AMA compared to young GVs both by IF and FLIM (intensity of 78614±58534 AU in young, 12517±10187 AU in AMA, p = 0.003; Redox ratio in young 2e+00±0.15, in AMA 1e+00 ± 0.16, p = 2.969e-05). Notably, young oocytes matured at a significantly higher rate (86.3%; 63/73) than AMA oocytes (62.3%; 38/61; p = 0.002). Moreover, FLIM imaging revealed that GVs with a higher metabolism were more likely to complete meiosis to MII (Redox ratio 2e+00±0.17 in GVs matured to MII, 1e+00±0.18 in non-matured, p = 1.054e-06). Following treatment with FCCP, young GVs showed a similar phenotype to AMA oocytes, with a significant decrease in mitochondrial activity (intensity of 78614±58534 IU in untreated and 11554±16131 IU in treated GVs, p = 0.019), and an associated drop-in maturation rate. Ultimately, only 39.5% (17/43) of the young treated GVs were able to accomplish meiotic maturation. Limitations, reasons for caution Maturation rates were assessed by the presence of an extruded PB and variations in spindle assembly timings may have been overlooked. The quantification of mitochondrial activity in loss of function studies was assessed only by IF staining. Wider implications of the findings Our findings demonstrate the presence of a functional link between oocyte metabolism and impaired meiosis, which may contribute to the decline of oocyte quality with age. Given that live-metabolic imaging is able to discern GVs that progress through meiosis, this approach may represent a valuable non-invasive tool in oocyte selection. Trial registration number not applicable

Inspiratory pressure waveform influences time to failure, respiratory muscle fatigue, and metabolism during resistive breathing.

Increased ventilatory work beyond working capacity of the respiratory muscles can induce fatigue, resulting in limited respiratory muscle endurance (Tlim ). Previous resistive breathing investigations all applied square wave inspiratory pressure as fatigue-inducing pattern. Spontaneous breathing pressure pattern more closely approximate a triangle waveform. This study aimed at comparing Tlim , maximal inspiratory pressure (PImax ), and metabolism between square and triangle wave breathing. Eight healthy subjects (Wei = 76 ± 10 kg, H = 181 ± 7.9 cm, age = 33.5 ± 4.8 years, sex [F/M] = 1/7) completed the study, comprising two randomized matched load resistive breathing trials with square and triangle wave inspiratory pressure waveform. Tlim decreased with a mean difference of 8 ± 7.2 min (p = 0.01) between square and triangle wave breathing. PImax was reduced following square wave (p = 0.04) but not for triangle wave breathing (p = 0.88). Higher VO2 was observed in the beginning and end for the triangle wave breathing compared with the square wave breathing (p = 0.036 and p = 0.048). Despite higher metabolism, Tlim was significantly longer in triangle wave breathing compared with square wave breathing, showing that the pressure waveform has an impact on the function and endurance of the respiratory muscles.

The Age of Absorptive Roots Impacts Root-Adjacent Microbial Composition in Grapevines

In grapevine, metabolic activity of absorptive roots changes rapidly as roots age but it is unclear whether nearby microbial assemblages shift as well. Here, we investigated whether first-order root age affects bacterial and fungal variation adjacent to the root surface, and whether root age should be integrated into future studies on root functional traits and associated microbes. We hypothesized that microbial diversity and composition would differ between young (≤11 days old) and old (11.5 to 40 days old) first-order roots due to expected differences in metabolism over the root lifespan (i.e., higher metabolism in young roots). Overall, we found that microbial composition was distinct between young and old absorptive roots, with stronger evidence at the phylum and amplicon sequence variant (ASV) taxonomic levels for fungi ( P = 0.003 and P = 0.038, respectively) than bacteria ( P = 0.082 and P = 0.129, respectively). Furthermore, we identified differentially abundant fungal and bacterial ASVs in young and old roots that related to expected differences in root function, including instances of microbes previously described as copiotrophs more abundant adjacent to young roots and microbes described as oligotrophs and saprotrophs more abundant adjacent to old roots. In contrast to the distinct shifts in microbial composition, there was little evidence of shifts in α diversity (i.e., observed ASVs and Shannon diversity) between young and old roots. Our study suggests that future work on the impacts of root functional traits on localized microbial composition may improve results interpretation and reduce some variation by accounting for root age at sampling.

Integrating multiple machine learning algorithms for prognostic prediction of gastric cancer based on immune-related lncRNAs.

Background: Long non-coding RNAs (lncRNAs) play an important role in the immune regulation of gastric cancer (GC). However, the clinical application value of immune-related lncRNAs has not been fully developed. It is of great significance to overcome the challenges of prognostic prediction and classification of gastric cancer patients based on the current study. Methods: In this study, the R package ImmLnc was used to obtain immune-related lncRNAs of The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) project, and univariate Cox regression analysis was performed to find prognostic immune-related lncRNAs. A total of 117 combinations based on 10 algorithms were integrated to determine the immune-related lncRNA prognostic model (ILPM). According to the ILPM, the least absolute shrinkage and selection operator (LASSO) regression was employed to find the major lncRNAs and develop the risk model. ssGSEA, CIBERSORT algorithm, the R package maftools, pRRophetic, and clusterProfiler were employed for measuring the proportion of immune cells among risk groups, genomic mutation difference, drug sensitivity analysis, and pathway enrichment score. Results: A total of 321 immune-related lncRNAs were found, and there were 26 prognostic immune-related lncRNAs. According to the ILPM, 18 of 26 lncRNAs were selected and the risk score (RS) developed by the 18-lncRNA signature had good strength in the TCGA training set and Gene Expression Omnibus (GEO) validation datasets. Patients were divided into high- and low-risk groups according to the median RS, and the low-risk group had a better prognosis, tumor immune microenvironment, and tumor signature enrichment score and a higher metabolism, frequency of genomic mutations, proportion of immune cell infiltration, and antitumor drug resistance. Furthermore, 86 differentially expressed genes (DEGs) between high- and low-risk groups were mainly enriched in immune-related pathways. Conclusion: The ILPM developed based on 26 prognostic immune-related lncRNAs can help in predicting the prognosis of patients suffering from gastric cancer. Precision medicine can be effectively carried out by dividing patients into high- and low-risk groups according to the RS.

Brain glucose metabolism and nigrostriatal degeneration in isolated rapid eye movement sleep behaviour disorder.

Alterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer's Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson's disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson's correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

How do ectotherms perform in cold environments? Physiological and life-history traits in an Andean viviparous lizard

Both the mean and the variation in environmental temperature are increasing globally. Indeed, the predicted increases in temperature range from 2 to 4°C in the next 50 years. Ectotherms control body temperature by means of behavior selecting microsites with different temperatures, which makes them more susceptible to changes in climate. Nevertheless, lizards living in high mountain environments have developed several mechanisms to inhabit and colonize variable environments with extreme temperatures. These mechanisms include a high metabolism to be active at lower temperatures and viviparity to improve embryonic development. Despite behavioral thermoregulation acting as a buffer to changes in environmental temperature, other traits such as life-history traits may be less flexible. Consequently, in an attempt to understand how lizards cope with harsh habitats, we evaluated some physiological traits and responses of females of Liolaemus bellii from two contrasting slope sites with differences in environmental temperature and humidity, but at the same altitude in the southern Andes range. We collected pregnant females from opposite slopes and maintained them until parturition in a common-garden experiment. Females from the south-facing slope (S-slope) had higher preferred body temperature (Tpref) values before and after parturition and exhibited higher daily energy expenditure before parturition. Nevertheless, no difference in Tpref was shown by their offspring, suggesting a developmental plastic response or adaptation to lower environmental temperature. For instance, the higher metabolism during pregnancy could be associated with a shorter activity period on the snowy S-slope. Additionally, females from the S-slope had larger kidneys and gave birth later than N-slope females, likely due to developmental plasticity or genetic differentiation. How fixed these traits are, in individuals from the contrasting slopes, will determine the response capacity of the L. bellii population to climate change.

Comprehensive qualitative characterization of linguistic performance profiles in primary progressive aphasia: a multivariate study with FDG-PET

Primary progressive aphasia (PPA) classification relies on profile characterization of quantitatively impaired/spared performance in language tasks. In this study, we coextracted 8 qualitative types of errors in 67 PPA patients submitted to a comprehensive language assessment. Canonical correlation analysis was applied to simultaneously correlate qualitative errors and brain metabolism, collected with FDG-PET. Results showed the contribution of semantic, syntactic and working memory errors associated with specific correlates of regional metabolic changes. Reduced metabolism in the left fusiform gyrus, anterior-middle and inferior-temporal gyri and middle-temporal pole correlated with an increase of semantic errors. Hypometabolism in the left inferior, middle, and superior frontal gyri, insula and right middle-occipital gyrus was related to syntactic errors. Higher metabolism in the bilateral pallidum, putamen, and left thalamus, as well as hypometabolism in the left angular and supramarginal gyri, inferior-parietal lobule, posterior-middle and inferior-temporal gyri and posterior cingulum predicted the increase of working memory errors. A relevant role of working memory subcomponents was associated with distinct neural systems. Patients’ profiles are easily represented in a qualitative multidimensional space, in which mixed PPA overlapped with different phenotypes.

Metabolism-Related Gene Pairs to Predict the Clinical Outcome and Molecular Characteristics of Early Hepatocellular Carcinoma.

Simple SummaryAfter surgery, about 60–70% of early hepatocellular carcinoma patients suffer from relapse within 5 years, hindering long-term survival. Clinical and pathologic features cannot provide an accurate evaluation. We aimed to construct a stratification model from the metabolic aspect to predict the clinical outcome and reveal the molecular characteristics of different prognostic subgroups. An individualized metabolic signature of 10 gene pairs was developed from 250 early HCCs and validated in 311 samples from different datasets. The signature stratified early HCC cases one-by-one into two risk groups with different survival rates. The molecular characteristics of the two risk groups were analyzed by multi-omics data. The relationships with proliferation, immunity, and drug benefits were summarized. The signature was further validated in 47 institutional transcriptomic HCC samples and 101 public proteomic samples.Recurrence is the main factor affecting the prognosis of early hepatocellular carcinoma (HCC), which is not accurately evaluated by clinical indicators. The metabolic heterogeneity of HCC hints at the possibility of constructing a stratification model to predict the clinical outcome. On the basis of the relative expression orderings of 2939 metabolism-related genes, an individualized signature with 10 metabolism-related gene pairs (10-GPS) was developed from 250 early HCC samples in the discovery datasets, which stratified HCC patients into the high- and low-risk subgroups with significantly different survival rates. The 10-GPS was validated in 311 public transcriptomic samples from two independent validation datasets. A nomogram that included the 10-GPS, age, gender, and stage was constructed for eventual clinical evaluation. The low-risk group was characterized by lower proliferation, higher metabolism, increased activated immune microenvironment, and lower TIDE scores, suggesting a better response to immunotherapy. The high-risk group displayed hypomethylation, higher copy number alterations, mutations, and more overexpression of immune-checkpoint genes, which might jointly lead to poor outcomes. The prognostic accuracy of the 10-GPS was further validated in 47 institutional transcriptomic samples and 101 public proteomic samples. In conclusion, the 10-GPS is a robust predictor of the clinical outcome for early HCC patients and could help evaluate prognosis and characterize molecular heterogeneity.

Altered Regional Brain Glucose Metabolism in Diffuse Large B-Cell Lymphoma Patients Treated With Cyclophosphamide, Epirubicin, Vincristine, and Prednisone: An Fluorodeoxyglucose Positron Emission Tomography Study of 205 Cases

BackgroundA growing number of neuroimaging studies reported that chemotherapy might impair brain functions, leading to persistent cognitive alterations in a subset of cancer patients. The present study aimed to investigate the regional brain glucose metabolism differences between diffuse large B cell lymphoma (DLBCL) patients treated with cyclophosphamide, epirubicin, vincristine, and prednisone and controls using positron emission tomography with 18F-labeled fluoro-2-deoxyglucose integrated with computed tomography (18F-FDG PET/CT) scanning.MethodsWe analyzed 18F-FDG PET data from 205 right-handed subjects (for avoiding the influence of handedness factors on brain function), including 105 post-chemotherapy DLBCL patients and 100 controls. The two groups had similar average age, gender ratio, and years of education. First, we compared the regional brain glucose metabolism using a voxel-based two-sample t-test. Second, we compared the interregional correlation. Finally, we investigated the correlations between the regional brain glucose metabolism and the number of chemotherapy cycles.ResultsCompared with the controls, the post-chemotherapy group showed higher metabolism in the right hippocampus and parahippocampal gyrus (region of interest (ROI) 1) and the left hippocampus (ROI 2), and lower metabolism in the left medial orbitofrontal gyrus (ROI 3), the left medial superior frontal gyrus (ROI 4), and the left superior frontal gyrus (ROI 5). The two groups had different interregional correlations between ROI 3 and ROI 5. In some brain regions—mainly located in the bilateral frontal gyrus—the number of chemotherapy cycles was positively correlated with the regional brain glucose metabolism. Meanwhile, in some bilateral hippocampus regions, these two parameters were negatively correlated.ConclusionThe present study provides solid data on the regional brain glucose metabolism differences between post-chemotherapy DLBCL patients and controls. These results should improve our understanding of human brain functions alterations in post-chemotherapy DLBCL patients and suggest that 18F-FDG PET/CT scanning is a valuable neuroimaging technology for studying chemotherapy-induced brain function changes.

The Influence of Urbanization on Mammal Diversity and their Population Patterns: A Case Study of Tashkent, Uzbekistan

Abstract The article provides a survey of the mammalian fauna and ecology in different habitats across the city of Tashkent that vary in the degree of urbanization. The current mammalian fauna of Tashkent is represented by 32 species; during the city’s development, 9 species have disappeared from the place, either through an anthropogenic impact or having been forced out by alien species. The urban mammalian fauna has increased through arrival of five new invasive species. With the ongoing urbanization, the species diversity of small-sized mammals is decreasing, while their numbers are growing, resulting in simplification of the structure of small mammals’ urban communities and lowering of their biodiversity. The urbanization does not impact the age and sex structure of the house mouse population noticeably. The urban population shows a productivity 1.7 times higher than the wild populations, which is a compensatory response to the relatively high embryonic mortality that is almost totally absent in natural populations. Differences in the morphophysiological indicators of the house mouse synanthropic population and those of populations in the wild are an adaptive response to anthropogenic impact, which appears in the form of more rapid growth, a higher metabolism, exchange of energies, and overall stress load on the rodents in urban biocoenoses. The study showed that the skulls of urban animals grow more rapidly than those of wild mice, while their proportions change following the development pattern of juvenile mice, which suggests that individuals from the Tashkent population can be referred to as rapidly growing animals, with outdoor individuals showing greater relative cranial parameters.

Intestinal flora characteristics of advanced non-small cell lung cancer in China and their role in chemotherapy based on metagenomics: A prospective exploratory cohort study.

BackgroundLung cancer has the highest mortality rate among malignant tumors, with non‐small cell lung cancer (NSCLC) being the most common type. As the main component of the human microflora, the intestinal flora interacts with the human body to affect immunity, metabolism, and the formation of diseases.MethodsForty‐five patients with advanced NSCLC who received platinum‐containing dual‐drug chemotherapy were enrolled in a prospective exploratory cohort study. The intestinal flora was dynamically collected at baseline and after two chemotherapy cycles. Next‐generation sequencing and metagenomics were then used to analyze the species and function of the intestinal flora at all levels.ResultsSignificant differences in the intestinal flora of patients with NSCLC were found according to sex and age. At the family level, the abundances of Streptococcaceae, Lactobacillaceae, and Leuconostocaceae after platinum‐containing dual‐drug chemotherapy were significantly higher compared to those before chemotherapy. At the family level, patients with chemotherapy‐induced gastrointestinal reactions had a significantly higher abundance of Leuconostocaceae than those without gastrointestinal responses. Meanwhile, patients with gastrointestinal reactions had higher metabolism, human diseases, cellular processes, and environmental information processing than those who did not. At the genus level, responders had higher abundances of Bacteroides compared to nonresponders. Moreover, nonresponders had higher levels of the six major metabolic pathways compared to responders.ConclusionsThe intestinal flora of Chinese patients with advanced NSCLC differed according to sex and age. Moreover, significant differences in the intestinal flora were noted after chemotherapy, which could be associated with chemotherapy‐induced gastrointestinal reactions and the efficacy of chemotherapy.