Category: Nevin Manimala

BMC Cancer. 2023 Feb 10;23(1):138. doi: 10.1186/s12885-023-10559-1.

ABSTRACT

BACKGROUND: Rearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial cell-derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance.

METHODS: To gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Finally, we performed cell proliferation assays using rGDNF, tamoxifen (TAM), and Palbociclib treatments in TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR experiments were determined using a student’s paired t-test and statistical significance for the cell viability assay was a one-way ANOVA.

RESULTS: GDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of phospho-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels. We also show that inhibition of cyclin D1 with Palbociclib, in the presence of rGDNF, decreases cell proliferation and resensitizes cells to TAM.

CONCLUSION: Outcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer.

PMID:36765275 | DOI:10.1186/s12885-023-10559-1

BMC Cardiovasc Disord. 2023 Feb 10;23(1):80. doi: 10.1186/s12872-023-03072-7.

ABSTRACT

BACKGROUND: The home treatment of elderly patients with chronic heart failure (CHF) is often accompanied by malnutrition, which increases the risk of re-hospitalisation and affects the prognosis. Therefore, how to effectively improve the nutritional self-management of patients is a current focus of medical research. This study aims to test the effect of home-based nutritional intervention method on improving the nutritional status of elderly patients with CHF.

METHODS: A total of 90 hospitalised elderly patients with CHF were randomly divided into the experimental group (n = 45) and the control group (n = 45). The patients in both groups were given standardised drug therapy and their nutritional status was evaluated using a body composition analyser prior to discharge (protein, body fat percentage, visceral fat area, skeletal muscle, upper arm muscle circumference, left lower limb and right lower limb muscle mass), with the cardiopulmonary function evaluated using a six-minute walk test and the metabolic equivalents method. The control group was given general nutrition education and routine dietary guidance from cardiac rehabilitation nurses, while the experimental group was given an individualised nutrition prescription by dietitians based on the evaluation results, according to which one-to-one food exchange dietary intervention training was given until the patients mastered the process.

RESULTS: The nutritional indexes at the end of the study were significantly higher in the experimental group than in the control group and were higher than those before the intervention (P < 0.05). The muscle circumference of the upper arm, the muscle mass of the left lower limb and the right lower limb had no statistical significance following the intervention compared to the control group and before the intervention (P > 0.05). The cardiopulmonary function indexes were significantly better in the experimental group at the end of the study than before the intervention and were better than those in the control group, with statistically significant differences (P < 0.05), while no significant changes were observed in the control group before and after the intervention (P > 0.05).

CONCLUSION: The home-based nutritional intervention method of food exchange portions can effectively improve the nutritional status of elderly patients with CHF, with the distribution of visceral fat more reasonable and the cardiopulmonary function and exercise endurance improved.

PMID:36765270 | DOI:10.1186/s12872-023-03072-7

Sci Rep. 2023 Feb 10;13(1):2423. doi: 10.1038/s41598-023-29585-x.

ABSTRACT

Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of individual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I-IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan-Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.

PMID:36765262 | DOI:10.1038/s41598-023-29585-x

Sci Rep. 2023 Feb 10;13(1):2434. doi: 10.1038/s41598-023-29625-6.

ABSTRACT

Bazhong City is located on stratum dominated by red-bed conditions. This type of weak geological condition with sand and mudstone interbedding is very easily affected by climatic conditions to produce rainfall-type landslides. On the basis of landslide data statistics collected in Bazhong City from 2011 to 2019, this paper uses ERA5-Land rainfall data to statistically analyze the correlation between rainfall and landslide events in Bazhong City. The landslide events in Bazhong City are greatly affected by rainfall events lasting for 10 days. Considering the influence of rainfall seepage and other processes, an effective cumulative rainfall-duration threshold curve for Bazhong City is obtained via median nonlinear fitting. Then, on the basis of the prediction interval, the rainfall threshold formula under different landslide occurrence probabilities is obtained and the critical threshold curve with a non-exceeding probability of 1% in Bazhong City is calculated and verified. Subsequently, a continuous probability distribution fitting function of landslide occurrence is established and a continuous probability distribution surface with a good fitting effect in Bazhong City is obtained. This allows a definite probability of whether future rainfall events will induce landslides to be obtained, providing an important basis for engineering disaster prevention and mitigation.

PMID:36765198 | DOI:10.1038/s41598-023-29625-6

Sci Rep. 2023 Feb 10;13(1):2414. doi: 10.1038/s41598-023-29635-4.

ABSTRACT

Clinical gait analysis is an important biomechanics field that is often influenced by subjectivity in time-varying analysis leading to type I and II errors. Statistical Parametric Mapping can operate on all time-varying joint dynamics simultaneously, thereby overcoming subjectivity errors. We present MovementRx, the first gait analysis modelling application that correctly models the deviations of joints kinematics and kinetics both in 3 and 1 degrees of freedom; presented with easy-to-understand color maps for clinicians with limited statistical training. MovementRx is a python-based versatile GUI-enabled movement analysis decision support system, that provides a holistic view of all lower limb joints fundamental to the kinematic/kinetic chain related to functional gait. The user can cascade the view from single 3D multivariate result down to specific single joint individual 1D scalar movement component in a simple, coherent, objective, and visually intuitive manner. We highlight MovementRx benefit by presenting a case-study of a right knee osteoarthritis (OA) patient with otherwise undetected postintervention contralateral OA predisposition. MovementRx detected elevated frontal plane moments of the patient’s unaffected knee. The patient also revealed a surprising adverse compensation to the contralateral limb.

PMID:36765193 | DOI:10.1038/s41598-023-29635-4

Sci Rep. 2023 Feb 10;13(1):2398. doi: 10.1038/s41598-023-29523-x.

ABSTRACT

Individuals of many animal populations exhibit idiosyncratic behaviors. One measure of idiosyncratic behavior is a behavior syndrome, defined as the stability of one or more behavior traits in an individual across different situations. While behavior syndromes have been described in various animal systems, their properties and the circuit mechanisms that generate them are poorly understood. We thus have an incomplete understanding of how circuit properties influence animal behavior. Here, we characterize olfactory behavior syndromes in the Drosophila larva. We show that larvae exhibit idiosyncrasies in their olfactory behavior over short time scales. They are influenced by the larva’s satiety state and odor environment. Additionally, we identified a group of antennal lobe local neurons that influence the larva’s idiosyncratic behavior. These findings reveal previously unsuspected influences on idiosyncratic behavior. They further affirm the idea that idiosyncrasies are not simply statistical phenomena but manifestations of neural mechanisms. In light of these findings, we discuss more broadly the importance of idiosyncrasies to animal survival and how they might be studied.

PMID:36765192 | DOI:10.1038/s41598-023-29523-x

Commun Med (Lond). 2023 Feb 10;3(1):21. doi: 10.1038/s43856-023-00250-8.

ABSTRACT

BACKGROUND: Patients with Type 2 diabetes mellitus (T2D) are at risk for micro- and macrovascular complications. Implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The epigenetic clock estimates an individual’s biological age using DNA methylation profiles.

METHODS: In this study, we examined older adults of the Berlin Aging Study II that were reexamined on average 7.4 years after baseline assessment as part of the GendAge study. DNA methylation age (DNAmA) and its deviation from chronological age DNAmA acceleration (DNAmAA) were calculated with the 7-CpG clock (available at both timepoints, n = 1,071), Horvath’s clock, Hannum’s clock, PhenoAge and GrimAge (available at follow-up only, n = 1,067). T2D associated complications were assessed with the Diabetes Complications Severity Index (DCSI).

RESULTS: We report on a statistically significant association between oral glucose tolerance test results and Hannum and PhenoAge DNAmAA. PhenoAge was also associated with fasting glucose. In contrast, we found no cross-sectional association after covariate adjustment between DNAmAA and a diagnosis of T2D. However, longitudinal analyses showed that every additional year of 7-CpG DNAmAA at baseline increased the odds for developing one or more additional complications or worsening of an already existing complication during the follow-up period by 11% in male participants with T2D. This association persisted after covariate adjustment (OR = 1.11, p = 0.045, n = 56).

CONCLUSION: Although our results remain to be independently validated, this study shows promising evidence of utility of the 7-CpG clock in identifying patients with diabetes who are at high risk for developing complications.

PMID:36765171 | DOI:10.1038/s43856-023-00250-8

Nat Methods. 2023 Feb;20(2):259-267. doi: 10.1038/s41592-022-01750-6. Epub 2023 Feb 10.

ABSTRACT

Single-molecule localization microscopy (SMLM) generates data in the form of coordinates of localized fluorophores. Cluster analysis is an attractive route for extracting biologically meaningful information from such data and has been widely applied. Despite a range of cluster analysis algorithms, there exists no consensus framework for the evaluation of their performance. Here, we use a systematic approach based on two metrics to score the success of clustering algorithms in simulated conditions mimicking experimental data. We demonstrate the framework using seven diverse analysis algorithms: DBSCAN, ToMATo, KDE, FOCAL, CAML, ClusterViSu and SR-Tesseler. Given that the best performer depended on the underlying distribution of localizations, we demonstrate an analysis pipeline based on statistical similarity measures that enables the selection of the most appropriate algorithm, and the optimized analysis parameters for real SMLM data. We propose that these standard simulated conditions, metrics and analysis pipeline become the basis for future analysis algorithm development and evaluation.

PMID:36765136 | DOI:10.1038/s41592-022-01750-6

Sci Rep. 2023 Feb 10;13(1):2435. doi: 10.1038/s41598-023-28752-4.

ABSTRACT

One clear aspect of behaviour in the COVID-19 pandemic has been people’s focus on, and response to, reported or observed infection numbers in their community. We describe a simple model of infectious disease spread in a pandemic situation where people’s behaviour is influenced by the current risk of infection and where this behavioural response acts homeostatically to return infection risk to a certain preferred level. This homeostatic response is active until approximate herd immunity is reached: in this domain the model predicts that the reproduction rate R will be centred around a median of 1, that proportional change in infection numbers will follow the standard Cauchy distribution with location and scale parameters 0 and 1, and that high infection numbers will follow a power-law frequency distribution with exponent 2. To test these predictions we used worldwide COVID-19 data from 1st February 2020 to 30th June 2022 to calculate [Formula: see text] confidence interval estimates across countries for these R, location, scale and exponent parameters. The resulting median R estimate was [Formula: see text] (predicted value 1) the proportional change location estimate was [Formula: see text] (predicted value 0), the proportional change scale estimate was [Formula: see text] (predicted value 1), and the frequency distribution exponent estimate was [Formula: see text] (predicted value 2); in each case the observed estimate agreed with model predictions.

PMID:36765110 | DOI:10.1038/s41598-023-28752-4

Sci Data. 2023 Feb 10;10(1):86. doi: 10.1038/s41597-023-01961-2.

ABSTRACT

Understanding the fine scale and subnational spatial distribution of reproductive, maternal, newborn, child, and adolescent health and development indicators is crucial for targeting and increasing the efficiency of resources for public health and development planning. National governments are committed to improve the lives of their people, lift the population out of poverty and to achieve the Sustainable Development Goals. We created an open access collection of high resolution gridded and district level health and development datasets of India using mainly the 2015-16 National Family Health Survey (NFHS-4) data, and provide estimates at higher granularity than what is available in NFHS-4, to support policies with spatially detailed data. Bayesian methods for the construction of 5 km × 5 km high resolution maps were applied for a set of indicators where the data allowed (36 datasets), while for some other indicators, only district level data were produced. All data were summarised using the India district administrative boundaries. In total, 138 high resolution and district level datasets for 28 indicators were produced and made openly available.

PMID:36765058 | DOI:10.1038/s41597-023-01961-2