Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master ...regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the ...tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.
Alzheimer's disease (AD) is the leading cause of dementia in older adults. There is currently a lot of interest in applying machine learning to find out metabolic diseases like Alzheimer's and ...Diabetes that affect a large population of people around the world. Their incidence rates are increasing at an alarming rate every year. In Alzheimer's disease, the brain is affected by neurodegenerative changes. As our aging population increases, more and more individuals, their families, and healthcare will experience diseases that affect memory and functioning. These effects will be profound on the social, financial, and economic fronts. In its early stages, Alzheimer's disease is hard to predict. A treatment given at an early stage of AD is more effective, and it causes fewer minor damage than a treatment done at a later stage. Several techniques such as Decision Tree, Random Forest, Support Vector Machine, Gradient Boosting, and Voting classifiers have been employed to identify the best parameters for Alzheimer's disease prediction. Predictions of Alzheimer's disease are based on Open Access Series of Imaging Studies (OASIS) data, and performance is measured with parameters like Precision, Recall, Accuracy, and F1-score for ML models. The proposed classification scheme can be used by clinicians to make diagnoses of these diseases. It is highly beneficial to lower annual mortality rates of Alzheimer's disease in early diagnosis with these ML algorithms. The proposed work shows better results with the best validation average accuracy of 83% on the test data of AD. This test accuracy score is significantly higher in comparison with existing works.
Rap1GAP is a critical tumor suppressor gene that is downregulated in multiple aggressive cancers, such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the ...mechanistic basis of rap1GAP downregulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb-mediated repression of rap1GAP that involves Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase in head and neck cancers. We further demonstrate that the loss of miR-101 expression correlates with EZH2 upregulation, and the concomitant downregulation of rap1GAP in head and neck cancers. EZH2 represses rap1GAP by facilitating the trimethylation of histone 3 at lysine 27, a mark of gene repression, and also hypermethylation of rap1GAP promoter. These results provide a conceptual framework involving a microRNA-oncogene-tumor suppressor axis to understand head and neck cancer progression.
Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization ...for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention 'very cost-effective' by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.
The Drosophila genome contains >13000 protein-coding genes, the majority of which remain poorly investigated. Important reasons include the lack of antibodies or reporter constructs to visualise ...these proteins. Here, we present a genome-wide fosmid library of 10000 GFP-tagged clones, comprising tagged genes and most of their regulatory information. For 880 tagged proteins, we created transgenic lines, and for a total of 207 lines, we assessed protein expression and localisation in ovaries, embryos, pupae or adults by stainings and live imaging approaches. Importantly, we visualised many proteins at endogenous expression levels and found a large fraction of them localising to subcellular compartments. By applying genetic complementation tests, we estimate that about two-thirds of the tagged proteins are functional. Moreover, these tagged proteins enable interaction proteomics from developing pupae and adult flies. Taken together, this resource will boost systematic analysis of protein expression and localisation in various cellular and developmental contexts.
Speech Dysarthria is a disorder in which speech muscles become weak, and it becomes difficult to articulate otherwise linguistically normal speech. This work is based on detection of speech ...dysarthria and how it can assist physicians, specialists, and doctors in its detection. The proposed work achieves higher accuracies on the TORGO dataset by using a transfer learning based convolutional neural network model (TL-CNN) and by converting the audio samples to Mel-spectrograms. The proposed work TL-CNN achieved better accuracy when compared with other machine learning models.
First-order radiomic features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are associated with disease progression in early-stage classical Hodgkin lymphoma (HL). We ...hypothesized that a model incorporating first- and second-order radiomic features would more accurately predict outcome than MTV or TLG alone. We assessed whether radiomic features extracted from baseline PET scans predicted relapsed or refractory disease status in a cohort of 251 patients with stage I-II HL who were managed at a tertiary cancer center. Models were developed and tested using a machine-learning algorithm. Features extracted from mediastinal sites were highly predictive of primary refractory disease. A model incorporating 5 of the most predictive features had an area under the curve (AUC) of 95.2% and total error rate of 1.8%. By comparison, the AUC was 78% for both MTV and TLG and was 65% for maximum standardize uptake value (SUV
). Furthermore, among the patients with refractory mediastinal disease, our model distinguished those who were successfully salvaged from those who ultimately died of HL. We conclude that our PET radiomic model may improve upfront stratification of early-stage HL patients with mediastinal disease and thus contribute to risk-adapted, individualized management.
Mammalian polynucleotide kinase (PNK) is a key component of both the base excision repair (BER) and nonhomologous end-joining (NHEJ) DNA repair pathways. PNK acts as a 5′-kinase/3′-phosphatase to ...create 5′-phosphate/3′-hydroxyl termini, which are a necessary prerequisite for ligation during repair. PNK is recruited to repair complexes through interactions between its N-terminal FHA domain and phosphorylated components of either pathway. Here, we describe the crystal structure of intact mammalian PNK and a structure of the PNK FHA bound to a cognate phosphopeptide. The kinase domain has a broad substrate binding pocket, which preferentially recognizes double-stranded substrates with recessed 5′ termini. In contrast, the phosphatase domain efficiently dephosphorylates single-stranded 3′-phospho termini as well as double-stranded substrates. The FHA domain is linked to the kinase/phosphatase catalytic domain by a flexible tether, and it exhibits a mode of target selection based on electrostatic complementarity between the binding surface and the phosphothreonine peptide.
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