Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors.

FMS-like tyrosine kinase 3 (FLT3) is an ideal drug target for the treatment of acute myeloid leukemia (AML). Although several FLT3 inhibitors have been approved or evaluated in clinical trials, selectivity over c-Kit kinase and FLT3 WT remains a major challenge. Herein, we report a series of 4-(2-fluorophenoxy)pyridine derivatives with potent inhibitory activities against FLT3 internal tandem duplication (FLT3-ITD).

Identification of novel components of the Ced and Ups systems in REY15A.

In cells, transcription of the Ups (UV-inducible pili of ) and Ced (Crenarchaeal system for exchange of DNA) genes is highly induced by DNA damage, and the two systems play key roles in pili-mediated cell aggregation and chromosomal DNA import, respectively. Ups is composed of UpsA, UpsB, UpsE, and UpsF, while Ced is composed of CedA, CedA1, CedA2, and CedB. So far, how DNA is transported by these systems is far from clear.

PerR functions as a redox-sensing transcription factor regulating metal homeostasis in the thermoacidophilic archaeon Saccharolobus islandicus REY15A.

Thermoacidophilic archaea thrive in environments with high temperatures and low pH where cells are prone to severe oxidative stress due to elevated levels of reactive oxygen species (ROS). While the oxidative stress responses have been extensively studied in bacteria and eukaryotes, the mechanisms in archaea remain largely unexplored. Here, using a multidisciplinary approach, we reveal that SisPerR, the homolog of bacterial PerR in Saccharolobus islandicus REY15A, is responsible for ROS response of transcriptional regulation.

A relay race of ESCRT-III paralogs drives cell division in a hyperthermophilic archaeon.

Unlabelled: Cell division is a fundamental process ensuring the perpetuation of all cellular life forms. Archaea of the order Sulfolobales divide using a simpler version of the eukaryotic endosomal sorting complexes required for transport (ESCRT) machinery, composed of three ESCRT-III homologs (ESCRT-III, -III-1, and -III-2), AAA+ ATPase Vps4 and an archaea-specific component CdvA. Here, we clarify how these components act sequentially to drive the division of the hyperthermophilic archaeon .

DeepPhylo: Phylogeny-Aware Microbial Embeddings Enhanced Predictive Accuracy in Human Microbiome Data Analysis.

Microbial data analysis poses significant challenges due to its high dimensionality, sparsity, and compositionality. Recent advances have shown that integrating abundance and phylogenetic information is an effective strategy for uncovering robust patterns and enhancing the predictive performance in microbiome studies. However, existing methods primarily focus on the hierarchical structure of phylogenetic trees, overlooking the evolutionary distances embedded within them.

Rational design of unrestricted pRN1 derivatives and their application in the construction of a dual plasmid vector system for .

REY15A represents one of the very few archaeal models with versatile genetic tools, which include efficient genome editing, gene silencing, and robust protein expression systems. However, plasmid vectors constructed for this crenarchaeon thus far are based solely on the pRN2 cryptic plasmid. Although this plasmid coexists with pRN1 in its original host, early attempts to test pRN1-based vectors consistently failed to yield any stable host-vector system for .

Machine Learning Reveals Impacts of Smoking on Gene Profiles of Different Cell Types in Lung.

Smoking significantly elevates the risk of lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. This risk is attributed to the harmful chemicals in tobacco smoke that damage lung tissue and impair lung function. Current research on the impact of smoking on gene expression in specific lung cells is limited.

Prediction of Acute Kidney Injury in Intracerebral Hemorrhage Patients Using Machine Learning.

Background: Acute kidney injury (AKI) is prevalent in patients with intracerebral hemorrhage (ICH) and is associated with mortality. This study aimed to verify the predictive accuracy of different machine learning algorithms for AKI in patients with ICH using a large dataset.

Methods: A total of 1366 ICH patients received treatments between 2001 and 2012 from the Medical Information Mart for Intensive Care-III (MIMIC-III) database were identified based on the ICD-9 code: 431.

The canonical single-stranded DNA-binding protein is not an essential replication factor but an RNA chaperon in .

Single-stranded DNA-binding proteins (SSBs) have been regarded as indispensable replication factors. Herein, we report that the genes encoding the canonical SSB (SisSSB) and the non-canonical SSB (SisDBP) in REY15A are not essential for cell viability. Interestingly, at a lower temperature (55°C), the protein level of SisSSB increases and the growth of Δ and ΔΔ is retarded.

Exploring the diversity of microbes and natural products from fungus-growing termite tripartite symbiosis.

The fungus-growing termite is considered a distinct ecological niche because it involves a tripartite symbiosis between the termite host, gut microflora, and the fungus , which has led to the expansion of highly organized and complex societies among termite colonies. Tripartite symbiosis in fungus-growing termites may promote unique microbes with distinctive metabolic pathways that may serve as valuable resources for developing novel antimicrobial therapeutic options. Recent research on complex tripartite symbioses has revealed a plethora of previously unknown natural products that may have ecological roles in signaling, communication, or defense responses.

The FHA domain protein ArnA functions as a global DNA damage response repressor in the hyperthermophilic archaeon .

Forkhead-associated (FHA) domain proteins specifically recognize phosphorylated threonine via the FHA domain and are involved in signal transduction in various processes especially DNA damage response (DDR) and cell cycle regulation in eukaryotes. Although FHA domain proteins are found in prokaryotes, archaea, and bacteria, their functions are far less clear as compared to the eukaryotic counterparts, and it has not been studied whether archaeal FHA proteins play a role in DDR. Here, we have characterized an FHA protein from the hyperthermophilic Crenarchaeon (SisArnA) by genetic, biochemical, and transcriptomic approaches.

Identification of fungus-growing termite-associated halogenated-PKS maduralactomycin a as a potential inhibitor of MurF protein of multidrug-resistant .

Multidrug-resistant infections have become a major public health concern globally. Inhibition of its essential MurF protein has been proposed as a potential target for broad-spectrum drugs. This study aimed to evaluate the potential of a novel ecological niche of 374 fungus-growing termite associated Natural Products (NPs).

Identification of potential natural products derived from fungus growing termite, inhibiting quorum sensing protein LasR using molecular docking and molecular dynamics simulation approach.

, the most common opportunistic pathogen, is becoming antibiotic-resistant worldwide. The fate of , a multidrug-resistant strain, can be determined by multidrug efflux pumps, enzyme synthesis, outer membrane protein depletion, and target alterations. Microbial niches have long used quorum sensing (QS) to synchronize virulence gene expression.

A novel RHH family transcription factor aCcr1 and its viral homologs dictate cell cycle progression in archaea.

Cell cycle regulation is of paramount importance for all forms of life. Here, we report that a conserved and essential cell cycle-specific transcription factor (designated as aCcr1) and its viral homologs control cell division in Sulfolobales. We show that the transcription level of accr1 reaches peak during active cell division (D-phase) subsequent to the expression of CdvA, an archaea-specific cell division protein.

The archaeal KEOPS complex possesses a functional Gon7 homolog and has an essential function independent of the cellular tA modification level.

Kinase, putative Endopeptidase, and Other Proteins of Small size (KEOPS) is a multisubunit protein complex conserved in eukaryotes and archaea. It is composed of Pcc1, Kae1, Bud32, Cgi121, and Gon7 in eukaryotes and is primarily involved in N-threonylcarbamoyl adenosine (tA) modification of transfer RNAs (tRNAs). Recently, it was reported that KEOPS participates in homologous recombination (HR) repair in yeast.

Dissection of Functional Domains of Orc1-2, the Archaeal Global DNA Damage-Responsive Regulator.

Orc1-2 is a non-initiator ortholog of archaeal/eukaryotic Orc1 proteins, which functions as a global regulator in DNA damage-responsive (DDR) expression. As for Orc1 initiators, the DDR regulator harbors an AAA+ ATPase domain, an Initiator-Specific Motif (ISM) and a winged-helix (wH) DNA-binding domain, which are also organized in a similar fashion. To investigate how Orc1-2 mediates the DDR regulation, the mutants inactivating each of these functional domains were constructed with and genetically characterized.

A Well-Conserved Archaeal B-Family Polymerase Functions as an Extender in Translesion Synthesis.

B-family DNA polymerases (PolBs) of different groups are widespread in , and different PolBs often coexist in the same organism. Many of these PolB enzymes remain to be investigated. One of the main groups that is poorly characterized is PolB2, whose members occur in many archaea but are predicted to be inactivated forms of DNA polymerase.

Enzymatic Switching Between Archaeal DNA Polymerases Facilitates Abasic Site Bypass.

Abasic sites are among the most abundant DNA lesions encountered by cells. Their replication requires actions of specialized DNA polymerases. Herein, two archaeal specialized DNA polymerases were examined for their capability to perform translesion DNA synthesis (TLS) on the lesion, including Dpo2 of B-family, and Dpo4 of Y-family.

Retracted article: Knockdown of long non-coding RNA AGAP2-AS1 suppresses the proliferation and metastasis of glioma by targeting microRNA-497-5p.

Yi Sun, Yulong Shen and Xing Li. Knockdown of long non-coding RNA AGAP2-AS1 suppresses the proliferation and metastasis of glioma by targeting microRNA-497-5p. Bioengineered.

TET3-mediated accumulation of DNA hydroxymethylation contributes to the activity-dependent gene expression of Rab3a in post-mitotic neurons.

Rab3a, a subtype protein in the Rab3 family amongst the small G proteins, is closely associated with the learning and memory formation process. Various neuronal stimuli can induce the expression of Rab3a; however, how DNA modification is involved in regulating its expression is not fully understood. Ten-eleven translocation (TET) proteins can oxidate methylcytosine to hydroxymethylcytosine, which can further activate gene expression.

A type III-A CRISPR-Cas system mediates co-transcriptional DNA cleavage at the transcriptional bubbles in close proximity to active effectors.

Many type III CRISPR-Cas systems rely on the cyclic oligoadenylate (cOA) signaling pathway to exert immunization. However, LdCsm, a type III-A lactobacilli immune system mediates efficient plasmid clearance in spite of lacking cOA signaling. Thus, the system provides a good model for detailed characterization of the RNA-activated DNase in vitro and in vivo.

Mobility-Aware Privacy-Preserving Mobile Crowdsourcing.

The increasing popularity of smartphones and location-based service (LBS) has brought us a new experience of mobile crowdsourcing marked by the characteristics of network-interconnection and information-sharing. However, these mobile crowdsourcing applications suffer from various inferential attacks based on mobile behavioral factors, such as location semantic, spatiotemporal correlation, etc. Unfortunately, most of the existing techniques protect the participant's location-privacy according to actual trajectories.

Archaeal extracellular vesicles are produced in an ESCRT-dependent manner and promote gene transfer and nutrient cycling in extreme environments.

Membrane-bound extracellular vesicles (EVs), secreted by cells from all three domains of life, transport various molecules and act as agents of intercellular communication in diverse environments. Here we demonstrate that EVs produced by a hyperthermophilic and acidophilic archaeon Sulfolobus islandicus carry not only a diverse proteome, enriched in membrane proteins, but also chromosomal and plasmid DNA, and can transfer this DNA to recipient cells. Furthermore, we show that EVs can support the heterotrophic growth of Sulfolobus in minimal medium, implicating EVs in carbon and nitrogen fluxes in extreme environments.