Category: Nevin Manimala

Transl Psychiatry. 2023 Feb 1;13(1):31. doi: 10.1038/s41398-023-02320-w.

ABSTRACT

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14⁺ monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology.

PMID:36720844 | DOI:10.1038/s41398-023-02320-w

Methods Mol Biol. 2023;2545:325-348. doi: 10.1007/978-1-0716-2561-3_17.

ABSTRACT

Genomic patterns of diversity and divergence are impacted by certain life history traits, reproductive systems, and demographic history. The latter is characterized by fluctuations in population sizes over time, as well as by temporal patterns of introgression. For a given organism, identifying a demographic history that deviates from the standard neutral model allows a better understanding of its evolution but also helps to reduce the risk of false positives when screening for molecular targets of natural selection. Tetraploid organisms and beyond have demographic histories that are complicated by the mode of polyploidization, the mode of inheritance, and different scenarios of gene flow between sub-genomes and diploid parental species. Here we provide guidelines for experimenters wishing to address these issues through a flexible statistical framework: approximate Bayesian computation (ABC). The emphasis is on the general philosophy of the approach to encourage future users to exploit the enormous flexibility of ABC beyond the limitations imposed by generalist data analysis pipelines.

PMID:36720821 | DOI:10.1007/978-1-0716-2561-3_17

Methods Mol Biol. 2023;2545:209-225. doi: 10.1007/978-1-0716-2561-3_11.

ABSTRACT

Whole-genome duplications (WGDs) are important in shaping the evolution of complex genomes, including rewiring of genome regulation. To address key questions about how WGDs impact the evolution of genome regulation, we need to understand the relative importance of selection versus drift and temporal evolutionary dynamics. One promising class of statistical models that can help address such questions are phylogenetic Ornstein-Uhlenbeck (OU) models.Here we present a computational pipeline for the comparative phylogenetic analyses of genome regulation using an OU model. We have implemented this model in R and provide a step-by-step protocol for the use of this model, including example scripts and simulated test data. We provide the nonspecialist a brief overview of how this model works and how to perform tests for signatures of selection on genome regulation as well as power simulations to aid in experimental design and interpretation of results. We believe that these resources could help polyploidy research move forward in an era of rapidly increasing functional genomics data across the tree of life.

PMID:36720815 | DOI:10.1007/978-1-0716-2561-3_11

Mol Biol Rep. 2023 Jan 31. doi: 10.1007/s11033-023-08247-1. Online ahead of print.

ABSTRACT

INTRODUCTION: The purpose of the current study was to evaluate the effect of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) on the production of cytokines and expression of genes, which are corresponded to the subsets of T helper cells.

MATERIALS AND METHODS: The supernatant of the second passage of MSCs that had been isolated from C57BL/6 mice abdominal adipose tissue was used to collect the MSC-EV. Splenocytes of healthy mice were activated using anti-CD3 and anti-CD28 antibodies and simultaneously were treated using the MSC-EVs. The proliferation rate of lymphocytes and the frequency of regulatory T cells were measured using flow cytometry. In addition, the expressions of T helper cell subset-specific transcription factors were evaluated using a real-time PCR assay. To appraise the effects of MSC-EV on splenocytes, the levels of IFN-γ, IL-17A, IL-10, and TGF-β were measured using ELISA.

RESULTS: The results showed that the treatment of the CD3/CD28-activated splenocytes with MSC-EV did not statistically change the proliferation of CD3⁺ splenocytes. However, after the treatment, the mRNA levels of Foxp3 and Elf4 as well as the frequency of regulatory T cells was significantly higher when compared to the control group. The expression levels of Gata3, Rorc, and Tbx21 were down-regulated while, the corresponding cytokines levels did not alter.

CONCLUSION: The results revealed that the in vitro treatment of MSC-EV was associated with the increase in the frequency of CD4⁺CD25⁺FOXP3⁺ T cells and upregulation of Foxp3 mRNA level.

PMID:36720794 | DOI:10.1007/s11033-023-08247-1

Int Urol Nephrol. 2023 Jan 31. doi: 10.1007/s11255-023-03470-y. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic kidney disease (CKD) has become a major public health problem across the globe, leading to various complications. This study aimed to construct a nomogram to predict the 4-year risk of CKD among Chinese adults.

METHODS: The study was based on the China Health and Retirement Longitudinal Study (CHARLS). A total of 3562 participants with complete information in CHARLS2011 and CHARLS2015 were included, and further divided into the training cohort and the validation cohort by a ratio of 7:3. Univariate and multivariate logistic regression analyses were used to select variables of the nomogram. The nomogram was evaluated by receiver-operating characteristic curve, calibration plots, and decision curve analysis (DCA).

RESULTS: In all, 2494 and 1068 participants were included in the training cohort and the validation cohort, respectively. A total of 413 participants developed CKD in the following 4 years. Five variables selected by multivariate logistic regression were incorporated in the nomogram, consisting of gender, hypertension, the estimated glomerular filtration rate (eGFR), hemoglobin, and Cystatin C. The area under curve was 0.809 and 0.837 in the training cohort and the validation cohort, respectively. The calibration plots showed agreement between the nomogram-predicted probability and the observed probability. DCA indicated that the nomogram had potential clinical use.

CONCLUSIONS: A predictive nomogram was established and internally validated in aid of identifying individuals at increased risk of CKD.

PMID:36720744 | DOI:10.1007/s11255-023-03470-y

Herz. 2023 Jan 31. doi: 10.1007/s00059-023-05163-9. Online ahead of print.

ABSTRACT

OBJECTIVE: Our aim was to determine the risk factors of postoperative systemic inflammatory response syndrome (SIRS) in patients with transcatheter aortic valve replacement (TAVR), identify those with a high risk of SIRS, and help reduce SIRS occurrence.

METHODS: A retrospective cohort study was conducted to collect the clinical data of patients who underwent TAVR from January 2014 to December 2019 at a tertiary hospital in Zhejiang Province. The study included 156 men and 94 women. Patients were divided into SIRS and non-SIRS groups. The pre-, intra-, and postoperative indices of the two groups were recorded. The data of the two groups were compared, and univariate analysis was performed. All statistically significant factors were assessed using binary logistic regression analysis to clarify the risk factors of SIRS after TAVR.

RESULTS: Overall, 30 patients developed SIRS after TAVR, with an incidence rate of 12%, an odds ratio (OR) of 0.571, and a 95% confidence interval (CI) of 0.469-0.694 (p = 0.000). There was a significant correlation between SIRS and glucose (OR: 0.823, 95% CI: 0.678-1.000, p = 0.049), albumin (OR: 0.938, 95% CI: 0.881-0.998, p = 0.044), brain natriuretic peptide (OR: 1.000, 95% CI: 1.000-1.000, p = 0.010), sex (OR: 0.412, 95% CI: 0.190-0.892, p = 0.025), and history of hypertension (OR: 0.375, 95% CI: 0.169-0.819, p = 0.014). Multivariate regression analysis demonstrated that age (OR: 1.190, 95%CI: 1.073-1.319, p = 0.001) and body mass index (BMI; OR: 0.559, 95% CI: 0.447-0.698, p = 0.000) were independent risk factors for postoperative SIRS in patients with TAVR.

CONCLUSION: The incidence of SIRS after TAVR was 12%. There was a significant correlation between SIRS and albumin, glucose, and hypertension. The independent risk factors for SIRS after TAVR were age and BMI.

PMID:36720725 | DOI:10.1007/s00059-023-05163-9

Orthop Surg. 2023 Jan 31. doi: 10.1111/os.13608. Online ahead of print.

ABSTRACT

OBJECTIVE: Wear particles induce inflammation and the further osteolysis around the prosthesis, has been proven to be the main cause of aseptic hip joint loosening. In this research, we aimed to clarify whether human umbilical cord mesenchymal stem cells (HUCMSCs) could inhibit the titanium particles-induced osteolysis and shed light upon its mechanism.

METHODS: The expression of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5) were examinjed in clinical specimens of aseptic hip prosthesis loosening patients. Local injection of lentivirus that knocked down CCL2 or CCL3 in a cranial osteolysis mice model were used to exam the effect of CCL2 and CCL3 on titanium particles-induced osteolysis in vivo. Transwell assay was used to examine the effect of CCL2 and CCL3 on titanium particles-induced activation of macrophage in vitro. Furthermore, the therapeutic effect of HUCMSCs, and exosomes from HUCMSCs were also examed in vivo and vitro. Immunohistochemical and real-time PCR were used to examine the expression of relative pathways. Analysis of variance (ANOVA) and Student-Newman-Keuls post hoc t test were used to analyze the results and determine the statistical significance of the differences.

RESULTS: Results showed that titanium particles caused the osteolysis at the mice cranial in vivo and a large number of macrophages that migrated, while local injection of HUCMSCs and exosomes did inhibit the cranial osteolysis and migration. An exosome inhibitor GW4869 significantly increased the osteolysis area in the mice cranium osteolysis model, and increased the number of migrated macrophages. Immunohistochemical results suggested that the expression of CCL2, CCL3 and CD68 in the cranial in Titanium particles mice increased significantly, but was significantly reduced by HUCMSCs or exosomes. HUCMSC and exosomes down-regulate the expression of CCL3 in vitro and in vivo.

CONCLUSION: HUCMSCs and HUCMSC-derived exosomes could suppress the titanium particles-induced osteolysis in mice through inhibiting chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 3.

PMID:36720704 | DOI:10.1111/os.13608

Arab J Gastroenterol. 2023 Jan 29:S1687-1979(23)00005-9. doi: 10.1016/j.ajg.2023.01.004. Online ahead of print.

ABSTRACT

BACKGROUND AND STUDY AIMS: Intestinal metaplasia (IM), and Helicobacter pylori (HP) infection can be shown as risk factors in the development of gastric cancer (GC). WNT signaling pathway plays a critical role in carcinogenesis. However, the literature studies are limited on the significance of this pathway for the transition from IM to GC.

PATIENTS AND METHODS: We aimed to investigate the importance of the genes of WNT signaling pathways diagnostic and prognostic markers in the presence and absence of HP in conversion from IM to GC. 104 patients, (GC group n = 35, IM group n = 45, control group n = 25) were included in this case-control study. Expression of genes in WNT signalling were searched in study groups with qRT-PCR array and qRT-PCR method. Data were analysed using PCR array data analysis software.

RESULTS: Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in the GC and IM groups compared to the control group (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was observed in patients with metastatic GC compared to patients with GC without metastasis (p < 0.05). It was found that the RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes were statistically significantly over-expressed in diffuse GC patients compared to non-diffuse GC patients (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in HP positive IM patients compared to HP negative IM patients (p < 0.05).

CONCLUSION: Overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes in IM may suggest that these genes are important markers in the development of IM and inflammation with HP. In addition, these genes are linked to tumor burden in the GC group. Consequently, we can conclude that these genes are poor prognosis biomarkers for GC and have the potential to be used as markers for future treatment monitoring.

PMID:36720664 | DOI:10.1016/j.ajg.2023.01.004

Eur Urol Oncol. 2023 Jan 29:S2588-9311(23)00028-7. doi: 10.1016/j.euo.2023.01.010. Online ahead of print.

ABSTRACT

BACKGROUND: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival.

OBJECTIVE: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups.

DESIGN, SETTING, AND PARTICIPANTS: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC.

INTERVENTION: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1.

RESULTS AND LIMITATIONS: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified.

CONCLUSIONS: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS.

PATIENT SUMMARY: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a “complete response” or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

PMID:36720658 | DOI:10.1016/j.euo.2023.01.010

Comput Methods Programs Biomed. 2023 Jan 23;231:107366. doi: 10.1016/j.cmpb.2023.107366. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Computer simulations of joint contact mechanics have great merit to improve our current understanding of articular ankle pathology. Owed to its computational simplicity, discrete element analysis (DEA) is an encouraging alternative to finite element analysis (FEA). However, previous DEA models lack subject-specific anatomy and may oversimplify the biomechanics of the ankle. The objective of this study was to develop and validate a personalized DEA framework that permits movement of the fibula and incorporates personalized cartilage thickness as well as ligamentous constraints.

METHODS: A linear and non-linear DEA framework, representing cartilage as compressive springs, was established, verified, and validated. Three-dimensional (3D) bony ankle models were constructed from cadaveric lower limb CT scans imaged during application of weight (85 kg) and/or torque (10 Nm). These 3D models were used to generate cartilage thickness and ligament insertion sites based on a previously validated statistical shape model. Ligaments were modelled as non-linear tension-only springs. Validation of contact stress prediction was performed using a simple, axially constrained tibiotalar DEA model against an equivalent FEA model. Validation of ligamentous constraints compared the final position of the ankle mortise to that of the cadaver after application of torque and sequential ligament sectioning. Finally, a combined ligamentous-constraining DEA model was validated for predicted contact stress against an equivalent ligament-constraining FEA model.

RESULTS: The linear and non-linear DEA model reproduced a mean articular contact stress within 0.36 MPa and 0.39 MPa of the FEA calculated stress, respectively. With respect to the ligamentous validation, the DEA ligament-balancing algorithm could reproduce the position of the distal fibula within the ankle mortise to within 0.97 mm of the experimental observed distal fibula. When combining the ligament-constraining and contact stress algorithm, DEA was able to reproduce a mean articular contact stress to within 0.50 MPa of the FEA calculated contact stress.

CONCLUSION: The DEA framework presented herein offers a computationally efficient alternative to FEA for the prediction of contact stress in the ankle joint, manifesting its potential to enhance the mechanical understanding of articular ankle pathologies on both a patient-specific and population-wide level. The novelty of this model lies in its personalized nature, inclusion of the distal tibiofibular joint and the use of non-linear ligament balancing to maintain the physiological ankle joint articulation.

PMID:36720186 | DOI:10.1016/j.cmpb.2023.107366