Granulomatous inflammation in tuberculosis and sarcoidosis: does the lymphatic system contribute to disease?

A striking and unexplained feature of granulomatous inflammation is its anatomical association with the lymphatic system. Accumulating evidence suggests that lymphatic tracks and granulomas may alter the function of each other. The formation of new lymphatics, or lymphangiogenesis, is an adaptive response to tumor formation, infection, and wound healing. Granulomas also may induce lymphangiogenesis which, through a variety of mechanisms, could contribute to disease outcomes in tuberculosis and sarcoidosis. On the other hand, alterations in lymph node function and lymphatic draining may be primary events which attenuate the risk and severity of granulomatous inflammation. This review begins with an introduction of granulomatous inflammation and the lymphatic system. A role of the lymphatic system in tuberculosis and sarcoidosis is then hypothesized. With a focus on lymphangiogenesis in these diseases, and on the potential for this process to promote dissemination, parallels are established with the well‐established role of lymphangiogenesis in tumor biology

Macrophage-specific responses to human -and animal- adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process

Photoperiod affects the phenotype of mitochondrial complex I mutants

Plant mutants for genes encoding subunits of mitochondrial Complex I (CI, NADH:ubiquinone oxidoreductase), the first enzyme of the respiratory chain, display various phenotypes depending on growth conditions. Here, we examined the impact of photoperiod, a major environmental factor controlling plant development, on two Arabidopsis thaliana CI mutants: a new insertion mutant interrupted in both ndufs8.1 and ndufs8.2 genes encoding the NDUFS8 subunit, and the previously characterized ndufs4 CI mutant. In long day (LD) condition, both ndufs8.1 and ndufs8.2 single mutants were indistinguishable from Col-0 at phenotypic and biochemical levels, whereas the ndufs8.1 ndufs8.2 double mutant was devoid of detectable holo-CI assembly/activity, showed higher AOX content/activity and displayed a growth-retardation phenotype similar to that of the ndufs4 mutant. Although growth was more affected in ndufs4 than ndufs8.1 ndufs8.2 under short day (SD) condition, both mutants displayed a similar impairment of growth acceleration after transfer to LD as compared to the WT. Untargeted and targeted metabolomics showed that overall metabolism was less responsive to the SD-to-LD transition in mutants than in the WT. The typical LD acclimation of carbon, nitrogen-assimilation and redox-related parameters was not observed in ndufs8.1 ndufs8. Similarly, NAD(H) content, that was higher in SD condition in both mutants than in Col-0, did not adjust under LD. We propose that altered redox homeostasis and NAD(H) content/redox state control the phenotype of Complex I mutants and photoperiod acclimation in Arabidopsis

Indication for the disappearance of reactor electron antineutrinos in the Double Chooz experiment

The Double Chooz Experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. A ratio of 0.944 $\pm$ 0.016 (stat) $\pm$ 0.040 (syst) observed to predicted events was obtained in 101 days of running at the Chooz Nuclear Power Plant in France, with two 4.25 GW$_{th}$ reactors. The results were obtained from a single 10 m$^3$ fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 measurement as an anchor point. The deficit can be interpreted as an indication of a non-zero value of the still unmeasured neutrino mixing parameter \sang. Analyzing both the rate of the prompt positrons and their energy spectrum we find \sang = 0.086 $\pm$ 0.041 (stat) $\pm$ 0.030 (syst), or, at 90% CL, 0.015 $<$ \sang $\ <$ 0.16.Comment: 7 pages, 4 figures, (new version after PRL referee's comments

Differential Metabolisms of Green Leaf Volatiles in Injured and Intact Parts of a Wounded Leaf Meet Distinct Ecophysiological Requirements

Almost all terrestrial plants produce green leaf volatiles (GLVs), consisting of six-carbon (C6) aldehydes, alcohols and their esters, after mechanical wounding. C6 aldehydes deter enemies, but C6 alcohols and esters are rather inert. In this study, we address why the ability to produce various GLVs in wounded plant tissues has been conserved in the plant kingdom. The major product in completely disrupted Arabidopsis leaf tissues was (Z)-3-hexenal, while (Z)-3-hexenol and (Z)-3-hexenyl acetate were the main products formed in the intact parts of partially wounded leaves. 13C-labeled C6 aldehydes placed on the disrupted part of a wounded leaf diffused into neighboring intact tissues and were reduced to C6 alcohols. The reduction of the aldehydes to alcohols was catalyzed by an NADPH-dependent reductase. When NADPH was supplemented to disrupted tissues, C6 aldehydes were reduced to C6 alcohols, indicating that C6 aldehydes accumulated because of insufficient NADPH. When the leaves were exposed to higher doses of C6 aldehydes, however, a substantial fraction of C6 aldehydes persisted in the leaves and damaged them, indicating potential toxicity of C6 aldehydes to the leaf cells. Thus, the production of C6 aldehydes and their differential metabolisms in wounded leaves has dual benefits. In disrupted tissues, C6 aldehydes and their α,β-unsaturated aldehyde derivatives accumulate to deter invaders. In intact cells, the aldehydes are reduced to minimize self-toxicity and allow healthy cells to survive. The metabolism of GLVs is thus efficiently designed to meet ecophysiological requirements of the microenvironments within a wounded leaf

Chemical PARP Inhibition Enhances Growth of Arabidopsis and Reduces Anthocyanin Accumulation and the Activation of Stress Protective Mechanisms

Poly-ADP-ribose polymerase (PARP) post-translationally modifies proteins through the addition of ADP-ribose polymers, yet its role in modulating plant development and stress responses is only poorly understood. The experiments presented here address some of the gaps in our understanding of its role in stress tolerance and thereby provide new insights into tolerance mechanisms and growth. Using a combination of chemical and genetic approaches, this study characterized phenotypes associated with PARP inhibition at the physiological level. Molecular analyses including gene expression analysis, measurement of primary metabolites and redox metabolites were used to understand the underlying processes. The analysis revealed that PARP inhibition represses anthocyanin and ascorbate accumulation under stress conditions. The reduction in defense is correlated with enhanced biomass production. Even in unstressed conditions protective genes and molecules are repressed by PARP inhibition. The reduced anthocyanin production was shown to be based on the repression of transcription of key regulatory and biosynthesis genes. PARP is a key factor for understanding growth and stress responses of plants. PARP inhibition allows plants to reduce protection such as anthocyanin, ascorbate or Non-Photochemical-Quenching whilst maintaining high energy levels likely enabling the observed enhancement of biomass production under stress, opening interesting perspectives for increasing crop productivity

Drought Impact Is Alleviated in Sugar Beets (Beta vulgaris L.) by Foliar Application of Fullerenol Nanoparticles

Over the past few years, significant efforts have been made to decrease the effects of drought stress on plant productivity and quality. We propose that fullerenol nanoparticles (FNPs, molecular formula C-60(OH)(24)) may help alleviate drought stress by serving as an additional intercellular water supply. Specifically, FNPs are able to penetrate plant leaf and root tissues, where they bind water in various cell compartments. This hydroscopic activity suggests that FNPs could be beneficial in plants. The aim of the present study was to analyse the influence of FNPs on sugar beet plants exposed to drought stress. Our results indicate that intracellular water metabolism can be modified by foliar application of FNPs in drought exposed plants. Drought stress induced a significant increase in the compatible osmolyte proline in both the leaves and roots of control plants, but not in FNP treated plants. These results indicate that FNPs could act as intracellular binders of water, creating an additional water reserve, and enabling adaptation to drought stress. Moreover, analysis of plant antioxidant enzyme activities (CAT, APx and GPx), MDA and GSH content indicate that fullerenol foliar application could have some beneficial effect on alleviating oxidative effects of drought stress, depending on the concentration of nanoparticles applied. Although further studies are necessary to elucidate the biochemical impact of FNPs on plants; the present results could directly impact agricultural practice, where available water supplies are often a limiting factor in plant bioproductivity

Photosynthesis-dependent H₂O₂ transfer from chloroplasts to nuclei provides a high-light signalling mechanism

Chloroplasts communicate information by signalling to nuclei during acclimation to fluctuating light. Several potential operating signals originating from chloroplasts have been proposed, but none have been shown to move to nuclei to modulate gene expression. One proposed signal is hydrogen peroxide (H2O2) produced by chloroplasts in a light-dependent manner. Using HyPer2, a genetically encoded fluorescent H2O2 sensor, we show that in photosynthetic Nicotiana benthamiana epidermal cells, exposure to high light increases H2O2 production in chloroplast stroma, cytosol and nuclei. Critically, over-expression of stromal ascorbate peroxidase (H2O2 scavenger) or treatment with DCMU (photosynthesis inhibitor) attenuates nuclear H2O2 accumulation and high light-responsive gene expression. Cytosolic ascorbate peroxidase over-expression has little effect on nuclear H2O2 accumulation and high light-responsive gene expression. This is because the H2O2 derives from a sub-population of chloroplasts closely associated with nuclei. Therefore, direct H2O2 transfer from chloroplasts to nuclei, avoiding the cytosol, enables photosynthetic control over gene expression

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

A reversible light- and genotype-dependent acquired thermotolerance response protects the potato plant from damage due to excessive temperature

A powerful acquired thermotolerance response in potato was demonstrated and characterised in detail, showing the time course required for tolerance, the reversibility of the process and requirement for light. Potato is particularly vulnerable to increased temperature, considered to be the most important uncontrollable factor affecting growth and yield of this globally significant crop. Here, we describe an acquired thermotolerance response in potato, whereby treatment at a mildly elevated temperature primes the plant for more severe heat stress. We define the time course for acquiring thermotolerance and demonstrate that light is essential for the process. In all four commercial tetraploid cultivars that were tested, acquisition of thermotolerance by priming was required for tolerance at elevated temperature. Accessions from several wild-type species and diploid genotypes did not require priming for heat tolerance under the test conditions employed, suggesting that useful variation for this trait exists. Physiological, transcriptomic and metabolomic approaches were employed to elucidate potential mechanisms that underpin the acquisition of heat tolerance. This analysis indicated a role for cell wall modification, auxin and ethylene signalling, and chromatin remodelling in acclimatory priming resulting in reduced metabolic perturbation and delayed stress responses in acclimated plants following transfer to 40 °C