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Abstract The host limits Mycobacterium tuberculosis (Mtb) by enriching copper in high concentrations. This research investigates how Mtb escapes copper stress. The membrane protein encoded by Mtb Rv0102, when its homolog in M. smegmatis (MSMEG_4702) was knocked out, resulted in a fourfold decrease in intracellular copper levels and enhanced tolerance to elevated extracellular copper concentrations. Similarly, knockout mutants of its homolog in M. marinum (MMAR_0267) showed increased virulence in zebrafish and higher bacterial load within macrophages. In THP-1 cells infected with MMAR_0267 deletion mutants, the intracellular survival of these mutants increased, along with reduced THP-1 cell apoptosis. Deficiency in copper down-regulated the transcriptional level of the virulence factor CFP-10 in M. marinum, suppressed cytosolic signaling via the macrophage STING pathway, leading to decreased production of IFN-β and reduced cell apoptosis. In conclusion, these findings highlight the significant impact of copper on the survival and reproduction of mycobacteria, underscoring the importance of studying mycobacterial adaptation mechanisms in copper-rich environments.

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a serious threat to global public health. Fluoroquinolones (FQs) are effective against M. tuberculosis; however, resistant strains have limited their efficacy. M ycobacterium fluoroquinolone resistance protein A (MfpA) confers intrinsic resistance to FQs; however, its regulatory mechanisms remain largely unknown. Using M. smegmatis as a model, we investigated whether MfpC is necessary for FQ susceptibility. MfpC mutants were sensitive to moxifloxacin, indicating that MfpC is involved in FQ susceptibility. By testing the mfpC inactivation phenotype in different mutants and using mycobacterial protein fragment complementation, we demonstrated that the function of MfpC depends on its interactions with MfpB. Guanine nucleotide exchange assays and site-directed mutagenesis confirmed that MfpC acts as a guanine nucleotide exchange factor to regulate MfpB. We propose that MfpB influences MfpA at the translational level. In summary, we reveal the role of MfpC in regulating the function of MfpA in FQ resistance.

ABSTRACT The VII secretion system is the main channel for Mycobacterium tuberculosis (MTB) to secrete virulence proteins. The ESAT-like proteins EsxA/B and EsxW/V in the RD region of its genome have been used as targets for vaccine antigens. However, the function of EsxO/P has not been explored, although it was predicted to potentially induce Th1 cell responses as a vaccine development target. In this study, the VII secretion system effector molecule Rv2347c was heterologously expressed in Mycobacterium smegmatis and found to inhibit the expression of the early marker RAB5 of phagosomes, thus preventing the maturation process of phagosomes toward lysosomes, and activated the host cytoplasmic sensing pathway. It inhibited autophagy and activated IFNβ transcription through the STING/TBK1 pathway promoting the host’s survival. Therefore, Rv2347c plays an important role in the pathogenesis of MTB with the potential to be utilized as a new target for tuberculosis vaccine development.IMPORTANCEWe found that the ESAT-like protein Rv2347c (EsxP) can inhibit the maturation of phagosomes, leading to mycobacterium escape from phagosomes into the cytoplasm, which triggers the host’s cytoplasmic sensing pathway STING/TBK1, inhibiting autophagy and upregulating IFNβ transcription, which contributes to the survival of mycobacterium in the host cell. We also found that Rv2347c was able to activate host immunity by activating NF-κB via STING and promoting the transcription of downstream pro-inflammatory factors. Meanwhile, the host also produces IL-1β to repair phagosome maturation arrest via the STING-mediated non-NF-κB pathway.

The disposition effect is one of the most prominent and widely studied behavioral biases observed among investors. It describes the tendency to close out winning investments prematurely while holding on to losing ones for too long and is generally associated with reduced investment returns. Researchers have explored various debiasing strategies and interventions to mitigate the disposition effect and its detrimental impact on returns. We summarize a between-subject experiment with n = 132 UK participants testing the impact of an informational feedback-like intervention to mitigate the disposition effect, informing participants about the disposition effect. Moreover, we re-examine our intervention's impact in the follow-up measurements which are 2 weeks and again 3 months after the first measurement. We find our intervention to have a significant impact, reducing the disposition effect in the first measurement. In addition, we still find a significant impact of the intervention, reducing the disposition effect after 2 weeks, while no significant impact is observed at the 3-month point. While we find a higher disposition effect to be associated with lower returns for one measurement, the opposite is true for the other two measurements. Moreover, the intervention had a return reducing impact for one measurement and no significant impact for the other two. Overall, our study shows a promising intervention that may be readily deployed among retail investors with a somewhat lasting impact to mitigate the disposition effect. However, our study also shows that the relationship between the disposition effect and investment returns is nuanced.

Abstract High-temperature electromagnetic (EM) protection materials integrated of multiple EM protection mechanisms and functions are regarded as desirable candidates for solving EM interference over a wide temperature range. In this work, a novel microwave modulator is fabricated by introducing carbonyl iron particles (CIP)/resin into channels of carbonized wood (C-wood). Innovatively, the spaced arrangement of two microwave absorbents not only achieves a synergistic enhancement of magnetic and dielectric losses, but also breaks the translational invariance of EM characteristics in the horizontal direction to obtain multiple phase discontinuities in the frequency range of 8.2–18.0 GHz achieving modulation of reflected wave radiation direction. Accordingly, CIP/C-wood microwave modulator demonstrates the maximum effective bandwidth of 5.2 GHz and the maximum EM protection efficiency over 97% with a thickness of only 1.5 mm in the temperature range 298–673 K. Besides, CIP/C-wood microwave modulator shows stable and low thermal conductivities, as well as monotonic electrical conductivity-temperature characteristics, therefore it can also achieve thermal infrared stealth and working temperature monitoring in wide temperature ranges. This work provides an inspiration for the design of high-temperature EM protection materials with multiple EM protection mechanisms and functions.

The deleterious alteration of protein structure and function due to the oxidation of methionine residues has been studied extensively in age-associated neurodegenerative disorders such as Alzheimer’s and Parkinson’s Disease. Methionine sulfoxide reductases (MSR) have three well-characterized biological functions. The most commonly studied function is the reduction of oxidized methionine residues back into functional methionine thus, often restoring biological function to proteins. Previous studies have successfully overexpressed and silenced MSR activity in numerous model organisms correlating its activity to longevity and oxidative stress. In the present study, we have characterized in vivo effects of MSR deficiency in Drosophila. Interestingly, we found no significant phenotype in animals lacking either methionine sulfoxide reductase A (MSRA) or methionine sulfoxide reductase B (MSRB). However, Drosophila lacking any known MSR activity exhibited a prolonged larval third instar development and a shortened lifespan. These data suggest an essential role of MSR in key biological processes.