Summary
Apoptosis modulation is a procedure amply utilized by intracellular pathogens to favour the outcome of the infection. Nevertheless, the role of apoptosis during infection with Mycobacterium ...tuberculosis, the causative agent of human tuberculosis, is subject of an intense debate and still remains unclear. In this work, we describe that apoptosis induction in host cells is clearly restricted to virulent M. tuberculosis strains, and is associated with the capacity of the mycobacteria to secrete the 6 kDa early secreted antigenic target ESAT‐6 bothunder in vitro and in vivo conditions. Remarkably, only apoptosis‐inducing strains are able to propagate infection into new cells, suggesting that apoptosis is used by M. tuberculosis as a colonization mechanism. Finally, we demonstrate that in vitro modulation of apoptosis affects mycobacterial cell‐to‐cell spread capacity, establishing an unambiguous relationship between apoptosis and propagation of M. tuberculosis. Our data further indicate that BCG and MTBVAC vaccines are inefficient in inducing apoptosis and colonizing new cells, correlating with the strong attenuation profile of these strains previously observed in vitro and in vivo.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Because of Klein tunneling, electrostatic potentials are unable to confine Dirac electrons. We show that it is possible to confine massless Dirac fermions in a monolayer graphene sheet by ...inhomogeneous magnetic fields. This allows one to design mesoscopic structures in graphene by magnetic barriers, e.g., quantum dots or quantum point contacts.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
In a greenhouse pot experiment, lettuce plants (
Lactuca sativa
L.) were grown in a Hg-contaminated sandy soil with and without inoculation with arbuscular mycorrhizal fungi (AMF) (a commercial ...inoculum containing infective propagules of
Rhizophagus irregularis
and
Funneliformis mosseae
) amended with different rates of a humic acid (0, 1, and 2 g kg
−1
of soil), with the objective of verifying the synergistic effects of the two soil treatments on the Hg tolerance of lettuce plants. Our results indicated that the plant biomass was significantly increased by the combined effect of AMF and humic acid treatments. Addition of humic matter to soil boosted the AMF effect on improving the nutritional plant status, enhancing the pigment content in plant leaves, and inhibiting both Hg uptake and Hg translocation from the roots to the shoots. This was attributed not only to the Hg immobilization by stable complexes with HA and with extraradical mycorrhizal mycelium in soil and root surfaces but also to an improved mineral nutrition promoted by AMF. This work indicates that the combined use of AMF and humic acids may become a useful practice in Hg-contaminated soils to reduce Hg toxicity to crops.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type ...1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models.
An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments.
89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models.
A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among ...elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe.
Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excluding the Russian and Turkish parts of Europe, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures.
Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths.
The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of the article is to evaluate the temporal change in the effect of heat on mortality in Italy in the last 12 years after the introduction of the national heat plan.
Time series analysis.
...Distributed lag non-linear models were used to estimate the association between maximum apparent temperature and mortality in 23 Italian cities included in the national heat plan in four study periods (before the introduction of the heat plan and three periods after the plan was in place between 2005 and 2016). The effect (relative risks) and impact (attributable fraction AF and number of heat-related deaths) were estimated for mild summer temperatures (20th and 75th percentile maximum apparent temperature Tappmax) and extreme summer temperatures (75th and 99th percentile Tappmax) in each study period. A survey of the heat preventive measures adopted over time in the cities included in the Italian heat plan was carried out to better describe adaptation measures and response.
Although heat still has an impact on mortality in Italian cities, a reduction in heat-related mortality is observed progressively over time. In terms of the impact, the heat AF related to extreme temperatures declined from 6.3% in the period 1999–2002 to 4.1% in 2013–2016. Considering the entire temperature range (20th vs 99th percentile), the total number of heat-related deaths spared over the entire study period was 1900.
Considering future climate change and the health burden associated to heat waves, it is important to promote adaptation measures by showing the potential effectiveness of heat prevention plans.
•The impact of heat on mortality varies over time.•In Italy, after the introduction of national heat plan, the impact of extreme heat has declined.•Heat prevention plans help improve local population adaptation and response to heat waves.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Since December 2016, excess all-cause mortality was observed in many European countries, especially among people aged ≥ 65 years. We estimated all-cause and influenza-attributable mortality in 19 ...European countries/regions. Excess mortality was primarily explained by circulation of influenza virus A(H3N2). Cold weather snaps contributed in some countries. The pattern was similar to the last major influenza A(H3N2) season in 2014/15 in Europe, although starting earlier in line with the early influenza season start.
Abstract
Background
Antibiotic use is associated with collateral damage to the healthy microbiota. Afabicin is a first-in-class prodrug inhibitor of the FabI enzyme that, when converted to the ...pharmacologically active agent afabicin desphosphono, demonstrates a staphylococcal-specific spectrum of activity. An expected benefit of highly targeted antibiotics such as afabicin is microbiome preservation.
Objectives
To compare the effects of oral treatment with afabicin and standard-of-care antibiotics upon the murine gut microbiota, and to assess the effects of oral afabicin treatment on the human gut microbiota.
Methods
Gut microbiota effects of a 10 day oral course of afabicin treatment were monitored in mice and compared with clindamycin, linezolid and moxifloxacin at human-equivalent dose levels using 16S rDNA sequencing. Further, the gut microbiota of healthy volunteers was longitudinally assessed across 20 days of oral treatment with afabicin 240 mg twice daily.
Results
Afabicin treatment did not significantly alter gut microbiota diversity (Shannon H index) or richness (rarefied Chao1) in mice. Only limited changes to taxonomic abundances were observed in afabicin-treated animals. In contrast, clindamycin, linezolid and moxifloxacin each caused extensive dysbiosis in the murine model. In humans, afabicin treatment was not associated with alterations in Shannon H or rarefied Chao1 indices, nor relative taxonomic abundances, supporting the findings from the animal model.
Conclusions
Oral treatment with afabicin is associated with preservation of the gut microbiota in mice and healthy subjects.
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