Heterologous production of the D-cycloserine intermediate O-acetyl-L-serine in a human type II pulmonary cell model.

Tuberculosis (TB) is the second leading cause of death by a single infectious disease behind COVID-19. Despite a century of effort, the current TB vaccine does not effectively prevent pulmonary TB, promote herd immunity, or prevent transmission. Therefore, alternative approaches are needed.

The C terminus of the mycobacterium ESX-1 secretion system substrate ESAT-6 is required for phagosomal membrane damage and virulence.

SignificanceTuberculosis (TB), an ancient disease of humanity, continues to be a major cause of worldwide death. The causative agent of TB, , and its close pathogenic relative , initially infect, evade, and exploit macrophages, a major host defense against invading pathogens. Within macrophages, mycobacteria reside within host membrane-bound compartments called phagosomes.

Deep learning forecasting using time-varying parameters of the SIRD model for Covid-19.

Accurate epidemiological models are necessary for governments, organizations, and individuals to respond appropriately to the ongoing novel coronavirus pandemic. One informative metric epidemiological models provide is the basic reproduction number ([Formula: see text]), which can describe if the infected population is growing ([Formula: see text]) or shrinking ([Formula: see text]). We introduce a novel algorithm that incorporates the susceptible-infected-recovered-dead model (SIRD model) with the long short-term memory (LSTM) neural network that allows for real-time forecasting and time-dependent parameter estimates, including the contact rate, [Formula: see text], and deceased rate, [Formula: see text].

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions.

Mycobacterium tuberculosis and Mycobacterium marinum are thought to exert virulence, in part, through their ability to lyse host cell membranes. The type VII secretion system ESX-1 [6-kDa early secretory antigenic target (ESAT-6) secretion system 1] is required for both virulence and host cell membrane lysis. Both activities are attributed to the pore-forming activity of the ESX-1-secreted substrate ESAT-6 because multiple studies have reported that recombinant ESAT-6 lyses eukaryotic membranes.

Regulating the response to targeted MEK inhibition in melanoma: enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/β-catenin activation.

The limitations of revolutionary new mutation-specific inhibitors of BRAF(V600E) include the universal recurrence seen in melanoma patients treated with this novel class of drugs. Recently, our lab showed that simultaneous activation of the Wnt/β-catenin signaling pathway and targeted inhibition of BRAF(V600E) by PLX4720 synergistically induces apoptosis across a spectrum of BRAF(V600E) melanoma cell lines. As a follow-up to that study, treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 also induces apoptosis.

Bili inhibits Wnt/beta-catenin signaling by regulating the recruitment of axin to LRP6.

Background: Insights into how the Frizzled/LRP6 receptor complex receives, transduces and terminates Wnt signals will enhance our understanding of the control of the Wnt/ss-catenin pathway.

Methodology/principal Findings: In pursuit of such insights, we performed a genome-wide RNAi screen in Drosophila cells expressing an activated form of LRP6 and a beta-catenin-responsive reporter. This screen resulted in the identification of Bili, a Band4.

Bruton's tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling.

Wnts are secreted ligands that activate several receptor-mediated signal transduction cascades. Homeostatic Wnt signaling through beta-catenin is required in adults, because either elevation or attenuation of beta-catenin function has been linked to diverse diseases. To contribute to the identification of both protein and pharmacological regulators of this pathway, we describe a combinatorial screen that merged data from a high-throughput screen of known bioactive compounds with an independent focused small interfering RNA screen.

Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1.

Background: Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins.

Methodology: We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1.

A Wnt survival guide: from flies to human disease.

It has been two decades since investigators discovered the link between the Drosophila wingless (Wg) gene and the vertebrate oncogene int-1, thus establishing the family of signaling proteins known as Wnts. Since the inception of the Wnt signaling field, there have been 19 Wnt isoforms identified in humans. These secreted glycoproteins can activate at least two distinct signaling pathways in vertebrate cells, leading to cellular changes that regulate a vast array of biological processes, including embryonic development, cell fate, cell proliferation, cell migration, stem cell maintenance, tumor suppression, and oncogenesis.

Beta-catenin-independent Wnt pathways: signals, core proteins, and effectors.

Wnt signaling activates several distinct intracellular pathways, which are important for cell proliferation, differentiation, and polarity. Wnt proteins are secreted molecules that typically signal across the membrane via interaction with the transmembrane receptor Frizzled. Following interaction with Frizzled, the downstream effect of the most widely studied Wnt pathway is stabilization and nuclear translocation of the cytosolic protein, beta-catenin.