DAF-16/FoxO and DAF-12/VDR control cellular plasticity both cell-autonomously and via interorgan signaling

Many cell types display the remarkable ability to alter their cellular phenotype in response to specific external or internal signals. Such phenotypic plasticity is apparent in the nematodeCaenorhabditis eleganswhen adverse environmental conditions trigger entry into the dauer diapause stage. This entry is accompanied by structural, molecular, and functional remodeling of a number of distinct tissue types of the animal, including its nervous system. The transcription factor (TF) effectors of 3 different hormonal signaling systems, the insulin-responsive DAF-16/FoxO TF, the TGFβ-responsive DAF-3/SMAD TF, and the steroid nuclear hormone receptor, DAF-12/VDR, a homolog of the vitamin D receptor (VDR), were previously shown to be required for entering the dauer arrest stage, but their cellular and temporal focus of action for the underlying cellular remodeling processes remained incompletely understood. Through the generation of conditional alleles that allowed us to spatially and temporally control gene activity, we show here that all 3 TFs are not only required to initiate tissue remodeling upon entry into the dauer stage, as shown before, but are also continuously required to maintain the remodeled state. We show that DAF-3/SMAD is required in sensory neurons to promote and then maintain animal-wide tissue remodeling events. In contrast, DAF-16/FoxO or DAF-12/VDR act cell-autonomously to control anatomical, molecular, and behavioral remodeling events in specific cell types. Intriguingly, we also uncover non-cell autonomous function of DAF-16/FoxO and DAF-12/VDR in nervous system remodeling, indicating the presence of several insulin-dependent interorgan signaling axes. Our findings provide novel perspectives into how hormonal systems control tissue remodeling.

A Technical Approach to Safe Mode Management for a Smooth Transition from Automatic to Manual Drilling

Unexpected situations and system failures during well construction operations are always possible. In the context of drilling automation, or even autonomous drilling, proper automatic management of these situations is of critical importance as the situation awareness of the human operator is very much reduced. The proper management of the transition between automatic and manual modes is necessary to improve the safety of automation solutions. An important characteristic of drilling automation solutions is their ability to cope with unexpected situations. This also encompasses, placing the drilling system in a state that is easy and intuitive for the human operator when manual control is required. Our approach to safe mode management is dependent on a good state estimation of the current conditions of the process. If for any reason, manual control must be regained, then the automated function itself triggers the necessary actions that will ensure a stable current state. In case of a drilling problem or a system failure, the human operator may have to regain control when the context might be totally different from the one left when the automation or autonomous function was enabled. It may even be a different human operator that has to take control, if a crew change has taken place. To make the transition from the automated/autonomous context to manual control, the automation/autonomous system sets the drilling machines in a so-called safe transition state. A safe transition state is one for which leaving the current setpoints of drilling machines untouched for a reasonable amount of time, will not immediately jeopardize the safety of the drilling operation. A safe transition state is contextual as it is not necessarily the same sequence of actions that must be performed to reach the safe transition state every time. The novel safe modes management method is integrated into existing drilling automation solutions. In a drilling automation context, the situation awareness of the human operator is considerably reduced as the automated functions control the process and the human operator is not actively driving the drilling machines. Without active safe mode management, there is a risk that drilling automation solutions may lead to serious situations as the driller may be totally unprepared to regain control in the middle of a critical situation. When it is needed to return to manual mode in the middle of the execution of an automatic procedure, an adequate procedure is executed. The choice of the procedure and its parameters depend on the current state of the process and system.

Applications, challenges, and needs for employing synthetic biology beyond the lab

Synthetic biology holds great promise for addressing global needs. However, most current developments are not immediately translatable to ‘outside-the-lab’ scenarios that differ from controlled laboratory settings. Challenges include enabling long-term storage stability as well as operating in resource-limited and off-the-grid scenarios using autonomous function. Here we analyze recent advances in developing synthetic biological platforms for outside-the-lab scenarios with a focus on three major application spaces: bioproduction, biosensing, and closed-loop therapeutic and probiotic delivery. Across the Perspective, we highlight recent advances, areas for further development, possibilities for future applications, and the needs for innovation at the interface of other disciplines.

Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression

ABSTRACTImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.STATEMENT OF SIGNIFICANCEImmune evasion is a key property of PDAC, rendering it refractory to immunotherapy. Here we demonstrate that tumor-derived PGRN promotes autophagy-dependent MHCI degradation, while anti-PGRN increases intratumoral CD8 infiltration and blocks tumor progression. With recent advances in T cell-mediated approaches, PGRN represents a pivotal target to enhance tumor antigen-specific cytotoxicity.

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1−/− microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.

Gut microbiota And Human Body Interactions; Its Impact on Health: a review

: Gut microbiota (GM) as an organ of the human body has a particular and autonomous function that related to it. This review aimed to investigate human intestinal and gut microbiota interaction and its impact on health. As a creation referable database about this dynamic and complex organ, several comprehensive projects are implemented by using culture-dependent (culturomics), culture independent methods (e.g metagenomics, mathematics model), and Gnotobiological together. This study was done by searching PubMed, Scopus and Google scholar database in the gut, health microbiota and interaction keywords. The first acquired microbiota during pregnancy or childbirth is colonized in the gut by using specific and non-specific mechanisms. That`s structure and shape reach relative stability with selection pressure along with host development until adulthood and keep its resilience against external or internal variables depending on the host genetics and negative feedback. Due to several research individuals have 2 functional group microbiota including the core (common between vast majorities human) and flexible (transient population) microbiome. The most important role of the GM in the human body can be summarized in three basic landscapes: metabolic, immune system, and gut-brain axis interaction. So that loss of microbial population balance will lead to disorder and disease.

High expression level of serpin peptidase inhibitor clade E member 2 is associated with poor prognosis in lung adenocarcinoma

Background: Recent studies have revealed that serpin peptidase inhibitor clade E member 2 (SERPINE2) is associated with tumorigenesis. However, SERPINE2 expression and its role in lung adenocarcinomas are still unknown.Methods: The expression levels of SERPINE2 in 74 consecutively resected lung adenocarcinomas were analyzed by using immunostaining. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by quantitative PCR. Cell number assays and cell apoptosis assays were performed to clarify the cell-autonomous function of SERPINE2 in A549 and PC9 lung cancer cells.Results: The overall survival of patients with high SERPINE2 expression was significantly worse than that of patients with low SERPINE2 expression (P=0.0172). Multivariate analysis revealed that SERPINE2 expression was an independent factor associated with poor prognosis (P=0.03237). The interference of SERPINE2 decreased cell number and increased apoptosis in A549 and PC9 cellsConclusion: These results suggest that SERPINE2 can be used as a novel prognostic marker of lung adenocarcinoma.

High expression level of serpin peptidase inhibitor clade E member 2 is associated with poor prognosis in lung adenocarcinoma

Background Recent studies have revealed that serpin peptidase inhibitor clade E member 2 (SERPINE2) is associated with tumorigenesis. However, SERPINE2 expression and its role in lung adenocarcinomas are still unknown. Methods The expression levels of SERPINE2 in 74 consecutively resected lung adenocarcinomas were analyzed by using immunostaining. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by quantitative PCR. Cell number assays and cell apoptosis assays were performed to clarify the cell-autonomous function of SERPINE2 in A549 and PC9 lung cancer cells. Results The overall survival of patients with high SERPINE2 expression was significantly worse than that of patients with low SERPINE2 expression (P = 0.0172). Multivariate analysis revealed that SERPINE2 expression was an independent factor associated with poor prognosis (P = 0.03237). The interference of SERPINE2 decreased cell number and increased apoptosis in A549 and PC9 cells Conclusion These results suggest that SERPINE2 can be used as a novel prognostic marker of lung adenocarcinoma.

High Expression Level of Serpin Peptidase Inhibitor Clade E Member 2 is Associated with Poor Prognosis in Lung Adenocarcinoma

Background: Recent studies have revealed that serpin peptidase inhibitor clade E member 2 (SERPINE2) is associated with tumorigenesis. However, SERPINE2 expression and its role in non-small cell lung cancer are still unknown.Methods: The expression levels of SERPINE2 in 74 consecutively resected lung adenocarcinomas were analyzed by using immunostaining. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by quantitative PCR. Proliferation assays and cell apoptosis assays were performed to clarify the cell-autonomous function of SERPINE2 in A549 and PC9 lung cancer cells.Results: The overall survival of patients with high SERPINE2 expression was significantly worse than that of patients with low SERPINE2 expression (P=0.0172). Multivariate analysis revealed that SERPINE2 expression was an independent factor associated with poor prognosis (P=0.03237). The interference of SERPINE2 decreased proliferation and increased apoptosis in A549 and PC9 cellsConclusion: These results suggest that SERPINE2 can be used as a novel prognostic marker of lung adenocarcinoma.