Type I IFN-mediated NET release promotes Mycobacterium tuberculosis replication and is associated with granuloma caseation.

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication.

Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses.

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms.

Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to M.

Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses.

Benthic foraminifera in Gulf of Mexico show temporal and spatial dynamics of microplastics.

Microplastics have accumulated in the environment since plastic production began, with present-day observations that range from marine trenches to mountains. However, research on microplastics has only recently begun so it is unclear how they have changed over time in many oceanic regions. Our study addressed this gap by quantifying the temporal and spatial dynamics of microplastics in two deep-water regions of the Gulf of Mexico (GOM).

Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant .

Of the approximately 10 million cases of () infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism.

Design principles for inflammasome inhibition by pyrin-only-proteins.

Inflammasomes are filamentous signaling platforms essential for host defense against various intracellular calamities such as pathogen invasion and genotoxic stresses. However, dysregulated inflammasomes cause an array of human diseases including autoinflammatory disorders and cancer. It was recently identified that endogenous pyrin-only-proteins (POPs) regulate inflammasomes by directly inhibiting their filament assembly.

FOXO1 regulates expression of Neurod4 in the pituitary gland.

Pituitary gland function is regulated by the activity of various transcription factors that control cell fate decisions leading to cellular differentiation and hormone production. FOXO1 is necessary for normal somatotrope differentiation and function. Recent in vivo data implicate FOXO1 in the regulation of genes important for somatotrope differentiation including Gh1, Neurod4, and Pou1f1.

Type I IFN signaling in the absence of IRGM1 promotes replication in immune cells by suppressing T cell responses.

Polymorphisms in the gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of , , is also essential for controlling (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting .

The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of () growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against .

Design, Synthesis, and Evaluation of Novel Δ-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mutant.

() drug resistance poses an alarming threat to global tuberculosis control. We previously reported that , a ring-fused thiazolo-2-pyridone, inhibits respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant isolates. This discovery revealed a new strategy to address INH resistance.

Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated.

Starvation sensing by mycobacterial RelA/SpoT homologue through constitutive surveillance of translation.

The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner.

Transcription regulation by CarD in mycobacteria is guided by basal promoter kinetics.

Bacterial pathogens like Mycobacterium tuberculosis (Mtb) employ transcription factors to adapt their physiology to the diverse environments within their host. CarD is a conserved bacterial transcription factor that is essential for viability in Mtb. Unlike classical transcription factors that recognize promoters by binding to specific DNA sequence motifs, CarD binds directly to the RNA polymerase to stabilize the open complex intermediate (RP) during transcription initiation.

Beclin-1-dependent autophagy, but not apoptosis, is critical for stem-cell-mediated endometrial programming and the establishment of pregnancy.

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period.

Transcription regulation by CarD in mycobacteria is guided by basal promoter kinetics.

Bacterial pathogens like ( ) employ transcription factors to adapt their physiology to the diverse environments within their host. CarD is a conserved bacterial transcription factor that is essential for viability in . Unlike classical transcription factors that recognize promoters by binding to specific DNA sequence motifs, CarD binds directly to the RNA polymerase (RNAP) to stabilize the open complex intermediate (RP ) during transcription initiation.

Evaluation of DNA metabarcoding for identifying fish eggs: a case study on the West Florida Shelf.

A critical factor in fisheries management is the protection of spawning sites for ecologically and economically important fish species. DNA barcoding (., amplification and sequencing of the mitochondrial cytochrome c oxidase I (COI) gene) of fish eggs has emerged as a powerful technique for identifying spawning sites.

Diverse Mechanisms of Helicase Loading during DNA Replication Initiation in Bacteria.

Initiation of DNA replication is required for cell viability and passage of genetic information to the next generation. Studies in Escherichia coli and Bacillus subtilis have established TPases ssociated with diverse cellular ctivities (AAA+) as essential proteins required for loading of the replicative helicase at replication origins. AAA+ ATPases DnaC in E.

Filament assembly underpins the double-stranded DNA specificity of AIM2-like receptors.

Upon sensing cytosolic- and/or viral double-stranded (ds)DNA, absent-in-melanoma-2 (AIM2)-like-receptors (ALRs) assemble into filamentous signaling platforms to initiate inflammatory responses. The versatile yet critical roles of ALRs in host innate defense are increasingly appreciated; however, the mechanisms by which AIM2 and its related IFI16 specifically recognize dsDNA over other nucleic acids remain poorly understood (i.e.

Trophic ontogeny of a generalist predator is conserved across space.

Consumers can influence ecological patterns and processes through their trophic roles and contributions to the flow of energy through ecosystems. However, the diet and associated trophic roles of consumers commonly change during ontogeny. Despite the prevalence of ontogenetic variation in trophic roles of most animals, we lack an understanding of whether they change consistently across local populations and broad geographic gradients.

Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug resistant .

Of the approximately 10 million cases of () infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism.

Gut microbiota and microbiota-derived metabolites promotes endometriosis.

Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis.

Understanding the contribution of metabolism to drug tolerance.

Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is due to multiple reasons, including inadequate drug concentrations reaching at the site of infection and physiological changes of in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of that promotes drug tolerance in the host.

Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes.

ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.

DciA Helicase Operators Exhibit Diversity across Bacterial Phyla.

A fundamental requirement for life is the replication of an organism's DNA. Studies in Escherichia coli and Bacillus subtilis have set the paradigm for DNA replication in bacteria. During replication initiation in E.