Functional analysis of the methylerythritol phosphate pathway terminal enzymes IspG and IspH from .

Unlabelled: Isoprenoids are a diverse family of compounds that are synthesized from two isomeric compounds, isopentenyl diphosphate and dimethylallyl diphosphate. In most bacteria, isoprenoids are produced from the essential methylerythritol phosphate (MEP) pathway. The terminal enzymes of the MEP pathway IspG and IspH are [4Fe-4S] cluster proteins, and in the substrates of IspG and IspH accumulate in cells in response to O, suggesting possible lability of their [4Fe-4S] clusters.

Brain dynamics and spatiotemporal trajectories during threat processing.

In the past decades, functional MRI research has investigated task processing in largely static fashion based on evoked responses during blocked and event-related designs. Despite some progress in naturalistic designs, our understanding of threat processing remains largely limited to those obtained with standard paradigms with limited dynamics. In the present paper, we applied Switching Linear Dynamical Systems to uncover the dynamics of threat processing during a continuous threat-of-shock paradigm.

Allosteric Modulation of the YAP/TAZ-TEAD Interaction by Palmitoylation and Small-Molecule Inhibitors.

The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, it translocates into the nucleus, where it associates with TEAD transcription factors.

Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.

Diverse environmental insults induce the integrated stress response (ISR), which features eIF2 phosphorylation and translational control that serves to restore protein homeostasis. The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other stresses not directly related to nutrients. Two mechanisms are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes.

Stress and Liver Fibrogenesis: Understanding the Role and Regulation of Stress Response Pathways in Hepatic Stellate Cells.

Stress response pathways are crucial for cells to adapt to physiological and pathologic conditions. Increased transcription and translation in response to stimuli place a strain on the cell, necessitating increased amino acid supply, protein production and folding, and disposal of misfolded proteins. Stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), allow cells to adapt to stress and restore homeostasis; however, their role and regulation in pathologic conditions, such as hepatic fibrogenesis, are unclear.

Geo-sentiment trends analysis of tweets in context of economy and employment during COVID-19.

To effectively design policies and implement measures for addressing problems faced by people during these difficult times of pandemic, it is critical to have a clear vision of the problems people are freely talking about. One of the ways is to analyze social media feeds e.g.

Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity.

The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which plays a critical role in cell proliferation, survival and cell fate specification. They are frequently deregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention.

Asparagine bioavailability regulates the translation of MYC oncogene.

Amino acid restriction has recently emerged as a compelling strategy to inhibit tumor growth. Recent work suggests that amino acids can regulate cellular signaling in addition to their role as biosynthetic substrates. Using lymphoid cancer cells as a model, we found that asparagine depletion acutely reduces the expression of c-MYC protein without changing its mRNA expression.

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis.

A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier () genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels.

The persistence of neoliberal logics in faculty evaluations amidst Covid-19: Recalibrating toward equity.

In this paper, we theorize the intersectional gendered impacts of COVID-19 on faculty labor, with a particular focus on how institutions of higher education in the United States evaluate faculty labor amidst the COVID-19 transition and beyond. The pandemic has disrupted faculty research, teaching, and service in differential ways, having larger impacts on women faculty, faculty of color, and caregiving faculty in ways that further reflect the intersections of these groups. Universities have had to reconsider how evaluation occurs, given the impact of these disruptions on faculty careers.

Emerging Mechanisms of Growth and Patterning Regulation by Dachsous and Fat Protocadherins.

Dachsous (Ds) and Fat are evolutionarily conserved cell adhesion molecules that play a critical role in development of multiple organ systems, where they coordinate tissue growth and morphogenesis. Much of our understanding of Ds-Fat signaling pathway comes from studies in , where they initiate a signaling pathway that regulate growth by influencing Hippo signaling and morphogenesis by regulating Planar Cell Polarity (PCP). In this review, we discuss recent advances in our understanding of the mechanisms by which Ds-Fat signaling pathway regulates these critical developmental processes.

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers.

YAP/TAZ are transcriptional coactivators that function as the key downstream effectors of Hippo signaling. They are commonly misregulated in most human cancers, which exhibit a higher level of expression and nuclear localization of YAP/TAZ, and display addiction to YAP-dependent transcription. In the nucleus, these coactivators associate with TEA domain transcription factors (TEAD1-4) to regulate the expression of genes that promote cell proliferation and inhibit cell death.

Analysis of Translational Control in the Integrated Stress Response by Polysome Profiling.

Translational control provides a strategy for rapid optimization of gene expression and restoration of protein homeostasis in response to cellular stresses. An important mechanism for translational control involves phosphorylation of eIF2, which invokes the integrated stress response (ISR). In the ISR, initiation of bulk protein synthesis is lowered coincident with enhanced translation efficiency of select gene transcripts that serve critical functions in stress adaptation.

Detection of human papillomavirus high-risk genotypes in rural women of Lucknow, North India.

Background: Human papilloma virus (HPV) has been widely implicated in cervical carcinogenesis and 90% of carcinoma cervix cases are due to high-risk HPV infection. This study was done to find the high-risk HPV genotypes in the rural women of Lucknow, North India.

Materials And Methods: HPV-DNA testing has been carried out in 130 cases of squamous intraepithelial lesions (SILs) of the cervix to find HPV status and type of high-risk HPV genotype infecting the rural women.

The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing.

Learning brain dynamics for decoding and predicting individual differences.

Insights from functional Magnetic Resonance Imaging (fMRI), as well as recordings of large numbers of neurons, reveal that many cognitive, emotional, and motor functions depend on the multivariate interactions of brain signals. To decode brain dynamics, we propose an architecture based on recurrent neural networks to uncover distributed spatiotemporal signatures. We demonstrate the potential of the approach using human fMRI data during movie-watching data and a continuous experimental paradigm.

Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress.

Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling.

Dual solutions in biomagnetic fluid flow and heat transfer over a nonlinear stretching/shrinking sheet: Application of lie group transformation method.

Of concern in the paper is a theoretical investigation of boundary layer flow of a biomagnetic fluid and heat transfer on a stretching/shrinking sheet in the presence of a magnetic dipole. The problem has been treated mathematically by using Lie group transformation. The governing nonlinear partial differential equations are thereby reduced to a system of coupled nonlinear ordinary differential equations subject to associated boundary conditions.

Assessment of micronuclei counts as tumour marker in cervical carcinogenesis: A follow-up study.

Objective: Micronuclei counts were performed in cervical smears with low-grade squamous intraepithelial lesions of the cervix (LSIL) to assess its potentiality as tumour marker in cervical carcinogenesis.

Methods: The cases studied were from the ongoing rural cervical cancer screening in west Lucknow, India. Micronuclei counts were performed in the cervical smears of 100 LSIL cases, and the number of cells with micronuclei was defined as micronucleated cells (MNC) and the number of micronuclei per 1000 cells as MNC score.

ASCUS (Atypical Squamous Cells of Undetermined Significance) in the Cervical Smears of Women from Rural Population of Lucknow West.

Background: Though Atypical squamous cells of undetermined significance (ASCUS) are not always precursors of cervical pre-malignancy but they need timely diagnosis and careful periodical follow-up.

Aim: The present study was carried out to investigate the incidence of ASCUS and SIL (squamous intraepithelial lesion of cervix) in women under rural setting.

Materials And Methods: Cervical cancer screening is in progress in rural population of West Lucknow, India, since May 2013 under auspices of Era's Lucknow Medical College and Hospital, Lucknow, and a total of 2478 women have been cytologically examined till October 2017.

AgNOR Pleomorphic Count as a Tumor Marker in Cervical Carcinogenesis and Feasibility of Its Introduction in Cervical Cancer Screening Programs to Discriminate High-Risk Cases of Squamous Intraepithelial Lesions of the Cervix.

Background: AgNOR pleomorphism has been widely used for its diagnostic importance in differentiating premalignant and malignant lesions of different human neoplasms. However, an evaluation of its potential for discriminating cases of high-risk squamous intraepithelial lesions of the cervix (SIL) has been rarely attempted.

Aim: The tumor marker potential of AgNOR pleomorphism counts was assessed by correlating high and low mean counts in low-grade SIL (LSIL) cases with persistence or regression of the lesion and HPV positivity.

Cervical cancer screening in rural India: Status & current concepts.

Cervical carcinoma is one of the most common and dreaded diseases of women, and in India, it accounts for 16 per cent of total cervical cancer cases occurring globally. The situation is more alarming in the rural areas where the majority of women are illiterate and ignorant about the hazards of cervical cancer. Different screening strategies such as rural cancer registries and camp approach for cancer detection have been found useful in minimizing the problem of cervical cancer in the villages.

Early girl is a novel component of the Fat signaling pathway.

The Drosophila protocadherins Dachsous and Fat regulate growth and tissue polarity by modulating the levels, membrane localization and polarity of the atypical myosin Dachs. Localization to the apical junctional membrane is critical for Dachs function, and the adapter protein Vamana/Dlish and palmitoyl transferase Approximated are required for Dachs membrane localization. However, how Dachs levels are regulated is poorly understood.