Francisella novicida Mutant XWK4 Triggers Robust Inflammasome Activation Favoring Infection

Bacterial infection tendentiously triggers inflammasome activation, whereas the roles of inflammasome activation in host defense against diverse infections remain unclear. Here, we identified that an ASC-dependent inflammasome activation played opposite roles in host defense against Francisella novicida wild-type (WT) U112 and mutant strain XWK4. Comparing with U112, XWK4 infection induced robust cytokine production, ASC-dependent inflammasome activation, and pyroptosis. Both AIM2 and NLRP3 were involved and played independent roles in XWK4-induced inflammasome activation. Type II interferon was partially required for XWK4-triggered inflammasome activation, which was different from type I interferon dependency in U112-induced inflammasome activation. Distinct from F. novicida U112 and Acinetobacter baumannii infection, Asc–/– mice were more resistant than WT mice response to XWK4 infection by limiting bacterial burden in vivo. The excessive inflammasome activation triggered by XWK4 infection caused dramatical cell death and pathological damage. Our study offers novel insights into mechanisms of inflammasome activation in host defense and provides potential therapeutic approach against bacterial infections and inflammatory diseases.

Theoretical Estimation of Optimal Linear Cooling Rate for PK-15 Cell Suspension

Preservation of cells during crystallization of the cell suspension is influenced by two types of damaging factors. The first type of cryoinjury occurs during the crystallization of the extracellular environment and is caused by dehydration of cells, increasing the concentration and ionic strength of extracellular and intracellular solutions. As the cooling rate rises, the damage rate of the first type decreases as a result of the reduced time of action of damaging factors. The second type of cryoinjury is intracellular crystallization, the probability of which enhances at high cooling rates, is considered the most destructive to cells. The optimal linear cooling rate for PK-15 cells is determined using a physico-mathematical model, which describes the probability of cryoinjury of cells in the linear freezing mode and is based on the two-factor theory of cryoinjury, thermodynamic theory of homogeneous crystallization and general theory of activation-type processes. The findings have shown that within the range of cooling rates < 0.5 °C/min the cryoinjury of PK-15 cells occurs mainly due to the effects of the solution, and at cooling rates > 2.5 °C/min this was mainly resulted from an intracellular crystallization. The dependence of the percentage of damaged cells on the cooling rate has a relatively wide minimum within the range of cooling rates of 0.5 °C/min… 2.5 °C/min.

Examining Engagement With Sport Sponsor Activations on Twitter

Research on sport sponsors’ use of social media has begun to emerge, but, to date, limited research has examined how sponsors are using social media as an activation platform to engage with followers. Thus, the purpose of this research was to examine differences in follower engagement with regard to sponsored Twitter posts from North American professional sport organizations, based upon the focus, scope, and activation type of the sponsored messages. This manuscript consists of two related studies—Study 1 employed a deductive content analysis, followed by negative binomial regression modeling, to examine differences in engagement between message structures defined by focus and scope. Study 2 featured an inductive content analysis to investigate differences in engagement between different types of activations. The findings suggest that, in general, more passive (or less overt) forms of sponsor integration in social media messages drive more engagement among followers.

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Hydrolytic dehalogenation operon of 4-chlorobenzoate is transcriptionally regulated by the TetR-type repressor FcbR and its ligand 4-chlorobenzoyl-CoA

The bacterial hydrolytic dehalogenation of 4-chlorobenzoate (4CBA) is a CoA-activation type catabolic pathway that is usually a common part of the microbial mineralization of chlorinated aromatic compounds. Previous studies have shown that the transport and dehalogenation genes for 4CBA are typically clustered as an fcbBAT1T2T3C operon and are inducibly expressed in response to 4CBA. However, the associated molecular mechanism remains unknown. In this study, a gene (fcbR) adjacent to the fcb operon was predicted to encode a TetR-type transcriptional regulator in strain Comamonas sediminis CD-2. The fcbR knockout strain exhibited constitutive expression of the fcb cluster. In the host E. coli, the expression of the Pfcb-fused gfp reporter was repressed by the introduction of the fcbR gene, and genetic studies combining various catabolic genes suggest that the FcbR ligand may be an intermediate metabolite. Purified FcbR could bind to the Pfcb DNA probe in vitro, and the metabolite 4-chlorobenzyl-CoA (4CBA-CoA) prevented FcbR binding to the Pfcb DNA probe. Isothermal titration calorimetry (ITC) measurements showed that 4CBA-CoA could bind to FcbR at a 1:1 mole ratio. DNase I footprinting showed that FcbR protected a 42-bp DNA motif (5′-GGAAATCAATAGGTCCATAGAAAATCTATTGACTAATCGAAT-3′) that consists of two sequence repeats containing four pseudo-palindromic sequences (5’-TCNATNGA-3’). This binding motif overlaps with the -35 box of Pfcb and was proposed to prevent the binding of RNA polymerase. This study identified a transcriptional repressor and its ligand of the fcb operon, extending halogenated benzoyl-CoA as a member of known ligands of transcriptional regulators. Importance The bacterial hydrolytic dehalogenation of 4CBA is a special CoA-activation type catabolic pathway, which plays an important role in the biodegradation of polychlorinated biphenyls and many certain herbicides. With genetic and biochemical approaches, the present study identified the transcriptional repressor and its cognate effector of a 4CBA hydrolytic dehalogenation operon. This work extends halogenated benzoyl-CoA as a new member of CoA-derived effector compounds that mediate allosteric regulation of transcriptional regulators.

Author Correction: Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Calculation of the Radiation Dose for Some Hydrobionts of the River Yenisei During the Operation of the Nuclear Fuel Cycle Enterprise - Mining and Chemical Combine, Krasnoyarsk

The given work considers the accumulation levels of technogenic radionuclides by some components of the river Yenisei near the discharge area of the water containing a big number of technogenic radionuclides, this water being discharged from the Mining and Chemical Combine (MCC). The investigation was carried out during the operation of the nuclear reactor included into the facility of the given enterprise (2006-2009). The content of gamma-emitting technogenic and natural radionuclides was measured. Using the method of gamma spectrometry, a considerable amount of technogenic radionuclides of the activation type ( 24Na – up to 1950 Bq·kg-1 , 51Cr – up to 2860 Bq·kg-1) were detected in biological objects. Making some assumptions in calculating the dose rate, for the organisms under study the following largest doses were revealed (μGy·day-1): aquatic plants – up to 39, fish: grayling - 22,3 and pike - 36,4. These values are considerably lower than the accepted radiation dose for aquatic biota which amounts to 10 mGy·day-1 .

Presynaptic dysregulation of the paraventricular thalamic nucleus causes depression-like behavior

The paraventricular thalamic nucleus (PVT) is a part of epithalamus and sends outputs to emotion-related brain areas such as the medial prefrontal cortex, nucleus accumbens, and amygdala. Various functional roles of the PVT in emotion-related behaviors are drawing attention. Here, we investigated the effect of manipulation of PVT neurons on the firing patterns of medial prefrontal cortical (mPFC) neurons and depression-like behavior. Extracellular single-unit recordings revealed that acute activation of PVT neurons by hM3Dq, an activation type of designer receptors exclusively activated by designer drugs (DREADDs), and administration of clozapine N-oxide (CNO) caused firing rate changes in mPFC neurons. Moreover, chronic presynaptic inhibition in PVT neurons by tetanus toxin (TeTX) increased the proportion of interneurons among firing neurons in mPFC and shortened the immobility time in the forced swimming test, whereas long-term activation of PVT neurons by hM3Dq caused recurrent hypoactivity episodes. These findings suggest that PVT neurons regulate the excitation/inhibition balance in the mPFC and mood stability.

Колоссальное магнитосопротивление слоистого манганита La-=SUB=-1.2-=/SUB=-Sr-=SUB=-1.8-=/SUB=-Mn-=SUB=-2-=/SUB=-O-=SUB=-7-=/SUB=- и его описание "спин-поляронным" механизмом проводимости

The resistance of a La_1.2Sr_1.8Mn_2(1– z )O_7 single crystal has been studied in magnetic fields from 0 to 90 kOe. The magnetoresistance at temperature T = 75 K, near which a colossal magnetoresistance maximum is observed, has been successfully described in terms of the “spin–polaron” electric conduction mechanism. This value of the colossal magnetoresistance is due to a three-fold increase in the polaron size. The method of separating contributions of various conduction mechanisms to the magnetoresistance developed for materials with activation type of conduction is generalized to compounds in which a metal–insulator transition is observed. It is found that, at a temperature of 75 K, the contribution of the “orientation” mechanism is maximum (≈20%) in a magnetic field of 5 kOe and almost disappears in fields higher than 50 kOe.