Impact of submarine groundwater discharge on biogeochemistry and microbial communities in pockmarks

The impact of submarine groundwater discharge (SGD) on coastal sea biogeochemistry has been demonstrated in many recent studies. However, only a few studies have integrated biogeochemical and microbiological analyses, especially at sites with pockmarks of different degrees of groundwater influence. This study investigated biogeochemical processes and microbial community structure in sediment cores from three pockmarks in Hanko, Finland, in the northern Baltic Sea. Pockmark data were supplemented by groundwater and seawater measurements. Two active pockmarks showed SGD rates of 0.02 cm d-1 and 0.31 cm d-1, respectively, based on porewater Cl- profiles, while a third pockmark had no SGD influence. Reactive transport modelling (RTM) established that the porewater systems of these active pockmarks are dominated by advection, resulting in the focusing of biogeochemical reactions and the microbial community into a thin zone at the sediment surface. The advection further reduces the accumulation of organic matter in the surface sediments, resulting in the absence of a sulfate-methane transition zone (SMTZ) at these pockmarks. Furthermore, the RTM estimated low rates of consumption of SO42-, and low rates of production of CH4, NH4+, DIC at the active pockmarks. Archaeal communities in the active pockmarks were dominated by ammonia-oxidizing archaea of predominantly groundwater origin. In contrast, at the inactive pockmark, the lack of SGD has permitted rapid deposition of organic-rich mud. The porewater system in the inactive pockmark is dominated by diffusion, leading to orders of magnitude higher metabolite concentrations at depth compared to the active pockmarks. The biogeochemical environment in the inactive pockmark resembles typical organic-rich mud seafloor in the area, with sulphate reduction and methanogenesis dominating organic matter remineralization. Accordingly, methanogens dominate the archaeal community, whereas sulfate reducers dominate the bacterial community. RTM results suggest that sulfate-mediated anaerobic oxidation of methane (S-AOM) also occurs at this site. Although depth-integrated fluxes of SO42-, CH4, NH4, DIC at the inactive pockmark are orders of magnitude higher compared to the active pockmarks, processes at the inactive pockmark represent internal recycling in the coastal sea. Fluxes observed at the active pockmarks, although comparatively small in magnitude, are partly influenced by external inputs to the sea through SGD. Hence, effluxes across the sediment-water interface at these sites partly represent direct external fluxes to the marine environment, in addition to diagenetic recycling at the benthic interface. The study highlights that SGD can result in significant spatial heterogeneity of biogeochemical processes and microbial community structure in the coastal zone, and that the overall effects of SGD and associated solute fluxes at an SGD site are a function of the number of pockmarks, the rate of SGD, and the ratio of active to inactive pockmarks.Peer reviewe

Exhausted CD4+ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4<sup>+</sup> T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4<sup>+</sup> T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (<i>Ag-exp</i>) CD4<sup>+</sup> T cell exhaustion during <i>Plasmodium yoelii</i> nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4<sup>+</sup> T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted <i>Ag-exp</i>CD4<sup>+</sup> T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4<sup>+</sup> T cells. Consistent with this, <i>Ag-exp</i>Th1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) <i>Ag-exp</i>T cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4<sup>+</sup> T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4<sup>+</sup> T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in <i>Ag-exp</i>CD4<sup>+</sup> T cells but that reduction in mTOR activity may not directly underpin <i>Ag-exp</i>Th1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4<sup>+</sup> T cells during malaria infection and other chronic conditions

EFFECTS OF CIMETIDINE AND RANUTIDINE ON HALOTHANE METABOLISM AND HEPATOTOXICITY IN AN ANIMAL MODEL

ABSTRACT: This study was undertaken to determine the effects of two Hrscsptor antagonists, cimetidine and ranitidine, on halothane metabolism and hepatotoxlclty In the hypoxic FlsMr 344 rat model for halothane he s

RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth

In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a −97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (−139 to −250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth

Does increasing treatment frequency address sub-optimal responses to ivermectin for the control and elimination of river blindness?

Background Several African countries have adopted a biannual ivermectin distribution strategy in some foci to control and eliminate onchocerciasis. In 2010, the Ghana Health Service started biannual distribution to combat transmission hotspots and sub-optimal responses to treatment. We assessed the epidemiological impact of the first 3 years of this strategy and quantified responses to ivermectin over two consecutive rounds of treatment in 10 sentinel communities. Methods We evaluated Onchocerca volvulus microfilarial intensity and prevalence in those aged +/-20 years before the first, second and fifth (or sixth) biannual treatment rounds using skin snip data from 956 participants. We used longitudinal regression modelling to estimate rates of microfilarial repopulation of the skin in a cohort of 217 participants who were followed-up over the first two rounds of biannual treatment. Results Biannual treatment has had a positive impact, with substantial reductions in infection intensity after 4 or 5 rounds in most communities. We identified three communities—all having been previously recognised as responding sub-optimally to ivermectin—with statistically significantly high microfilarial repopulation rates. We did not find any clear association between microfilarial repopulation rate and the number of years of prior intervention, coverage, or the community level of infection. Conclusions The strategy of biannual ivermectin treatment in Ghana has reduced O. volvulus microfilarial intensity and prevalence, but sub-optimal responses to treatment remain evident in a number of previously and consistently implicated communities. Whether increasing the frequency of treatment will be sufficient to meet the World Health Organization’s 2020 elimination goals remains uncertain

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers:A nationwide cohort study

AIM: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. RESULTS: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). CONCLUSION: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers

A Study of Muon Neutrino Disappearance Using the Fermilab Main Injector Neutrino Beam

We report the results of a search for muon-neutrino disappearance by the Main Injector Neutrino Oscillation Search. The experiment uses two detectors separated by 734 km to observe a beam of neutrinos created by the Neutrinos at the Main Injector facility at Fermi National Accelerator Laboratory. The data were collected in the first 282 days of beam operations and correspond to an exposure of 1.27e20 protons on target. Based on measurements in the Near Detector, in the absence of neutrino oscillations we expected 336 +/- 14 muon-neutrino charged-current interactions at the Far Detector but observed 215. This deficit of events corresponds to a significance of 5.2 standard deviations. The deficit is energy dependent and is consistent with two-flavor neutrino oscillations according to delta m-squared = 2.74e-3 +0.44/-0.26e-3 eV^2 and sin^2(2 theta) > 0.87 at 68% confidence level.Comment: In submission to Phys. Rev.

Measurement of the Atmospheric Muon Charge Ratio at TeV Energies with MINOS

The 5.4 kton MINOS far detector has been taking charge-separated cosmic ray muon data since the beginning of August, 2003 at a depth of 2070 meters-water-equivalent in the Soudan Underground Laboratory, Minnesota, USA. The data with both forward and reversed magnetic field running configurations were combined to minimize systematic errors in the determination of the underground muon charge ratio. When averaged, two independent analyses find the charge ratio underground to be 1.374 +/- 0.004 (stat.) +0.012 -0.010(sys.). Using the map of the Soudan rock overburden, the muon momenta as measured underground were projected to the corresponding values at the surface in the energy range 1-7 TeV. Within this range of energies at the surface, the MINOS data are consistent with the charge ratio being energy independent at the two standard deviation level. When the MINOS results are compared with measurements at lower energies, a clear rise in the charge ratio in the energy range 0.3 -- 1.0 TeV is apparent. A qualitative model shows that the rise is consistent with an increasing contribution of kaon decays to the muon charge ratio.Comment: 16 pages, 17 figure

Measurement of neutrino velocity with the MINOS detectors and NuMI neutrino beam

The velocity of a ~3 GeV neutrino beam is measured by comparing detection times at the near and far detectors of the MINOS experiment, separated by 734 km. A total of 473 far detector neutrino events was used to measure (v-c)/c=5.12.910-5 (at 68% C.L.). By correlating the measured energies of 258 charged-current neutrino events to their arrival times at the far detector, a limit is imposed on the neutrino mass of mnu<50 MeV/c2 (99% C.L.)

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution