We evaluated antibiotic activity against the intracellular bacterium Coxiella burnetii using an activated THP-1 cell model of infection. At clinically relevant concentrations, the intracellular ...bacterial load was reduced 300-fold by levofloxacin and finafloxacin, 40-fold by doxycycline, and 4-fold by ciprofloxacin and was unaffected by azithromycin. Acidification of the culture medium reduced antibiotic activity, with the exceptions of doxycycline (no change) and finafloxacin (slight improvement). This model may be used to select antibiotics to be evaluated
.
Two multiplex PCR screening capabilities (TaqMan Array Cards and FilmArray) were evaluated for their ability to detect Bacillus anthracis, Francisella tularensis and Yersinia pestis in blood samples ...obtained from respective murine infection models. Blood samples were obtained from infected mice at 24 h intervals after exposure. Multiplex PCR results were compared with standard blood culture and singleplex real-time PCR. Across all three models, 71 mice were tested in total, within which a subset of 43 samples was shown to contain an infecting agent by at least one of the detection technologies. Within this subset of positive samples, for each model studied, the detection rates of each technology were compared. The B. anthracis model blood culture (14 of 15 agent-containing samples tested) and FilmArray PCR (12 of 15) were shown to have equivalent detection rates, which were significantly higher (at the 95 % confidence level) than singleplex (five of 14) or Array Card (two of 14) PCRs. The F. tularensis model blood culture (12 of 12) was shown to have a significantly higher (at 95 % confidence level) detection rate than all PCR technologies, with FilmArray (seven of 11) and singleplex (seven of 12) PCRs shown to have significantly higher (at 95 % confidence level) detection rates than the Array Card PCR (two of 11). Within the Y. pestis model, there was no significant difference in detection rates between blood culture (10 of 16), singleplex PCR (14 of 16), Array Card PCR (10 of 16) and FilmArray PCR (10 of 13).
Megaloblastic anaemia in childhood usually occurs as a result of dietary folate deficiency or, rarely, congenital disorders of vitamin B
12
metabolism.
We present a 2-year-old girl with megaloblastic ...anaemia and insulin-dependent diabetes mellitus, both of which proved responsive to pharmacological doses of thiamine. She was also found to have sensorineural hearing loss.
Also known as Rogers' syndrome, thiamine-responsive megaloblastic anaemia is the result of inactivating mutations in a gene encoding a thiamine transporter.
A clinical diagnosis is supported by characteristic bone marrow findings and can be confirmed by demonstrating apoptosis in skin fibroblasts cultured in thiamine-depleted medium. Where available, DNA sequencing is definitive.
There is rapid reticulocytosis after thiamine administration. We recommend a trial of therapy for megaloblastic anaemia not responding to folate and vitamin B
12
, especially in a deaf and/or diabetic child.
The valence state of Fe plays a vital role in setting and recording the oxidation state of magmas, commonly expressed in terms of oxygen fugacity (
f
O
2
). However, our knowledge of how and why
f
O
...2
varies within and between magmatic systems remains patchy because of diverse challenges associated with estimating the valence state of Fe in glasses and minerals routinely. Here we investigate Fe valence systematics in magmatic clinopyroxene crystals from ocean island basalts (OIBs) erupted in Iceland and the Azores to explore whether they record information about magma Fe
3
+
contents and magmatic
f
O
2
conditions. Although many studies assume that all Fe in augitic clinopyroxene crystals from OIBs occurs as Fe
2
+
, we find that up to half of the total Fe present can occur as Fe
3
+
, with crystals from alkali systems typically containing more Fe
3
+
than those from tholeiitic systems. Thus, Fe
3
+
is a major if under-appreciated constituent of augitic clinopyroxene crystals erupted from ocean island volcanoes. Most Fe
3
+
in these crystals is hosted within esseneite component (CaFe
3
+
AlSiO
6
), though some may be hosted in aegirine component (NaFe
3
+
Si
2
O
6
) in crystals from alkali systems. Observations from samples containing quenched matrix glasses suggest that the incorporation of Fe
3
+
is related to the abundance of tetrahedrally coordinated Al (
IV
Al), implying some steric constraints over Fe
3
+
partitioning between clinopyroxene and liquid (i.e.,
D
Fe
2
O
3
cpx
-
liq
values), though this may not be an equilibrium relationship. For example,
IV
Al-rich
{
h
k
0
}
prism sectors of sector-zoned crystals contain more Fe
3
+
than
IV
Al-poor
{
1
¯
11
}
hourglass sectors. Moreover,
IV
Al-rich compositions formed during disequilibrium crystallisation are enriched in Fe
3
+
. Apparent clinopyroxene-liquid Fe
2
+
–Mg exchange equilibria (i.e.,
K
D
,
Fe
2
+
-
Mg
cpx
-
liq
values) are similarly affected by disequilibrium crystallisation in our samples. Nonetheless, it is possible to reconcile our observed clinopyroxene compositions with glass Fe valence systematics estimated from olivine-liquid equilibria if we assume that
K
D
,
Fe
2
+
-
Mg
cpx
-
liq
values lies closer to experimentally reported values of 0.24
-
0.26 than values of
∼
0.28 returned from a general model. In this case, olivine-liquid and clinopyroxene-liquid equilibria record equivalent narratives, with one of our glassy samples from Iceland recording evolution under
f
O
2
conditions about one log unit above fayalite-magnetite-quartz (FMQ) equilibrium (i.e.,
∼
FMQ+1) and our glassy Azorean sample recording evolution under significantly more oxidising conditions (
≥
FMQ+2.5) before experiencing syn-eruptive reduction, likely as a result of SO
2
degassing; our other glassy sample from Iceland was also affected by reductive SO
2
degassing. Overall, our findings demonstrate that the Fe valence systematics of clinopyroxene crystals can record information about the conditions under which OIBs evolve, but that further experimental work is required to properly disentangle the effects of magma composition, disequilibrium and
f
O
2
conditions on clinopyroxene-liquid equilibria involving Fe
2
+
and Fe
3
+
.
Clinopyroxene is a major rock forming mineral capable of incorporating diverse metal cations. As a consequence, clinopyroxene preserves valuable archives of magmatic processes. Understanding ...clinopyroxene is thus essential for understanding Earth’s wider chemical evolution. However, knowledge about the relative abundances of ferrous and ferric iron in magmatic clinopyroxene remains sparse because it is not currently possible to routinely measure the valence of iron in clinopyroxene crystals without either separating single crystals for bulk analysis or securing access to Mössbauer spectroscopy or a synchrotron radiation source to perform in-situ microanalysis. This is despite magmatic clinopyroxene crystals often containing appreciable quantities of ferric iron that affect its stability and behaviour in currently ill-constrained ways and limit our ability to exploit its chemistry to robustly reconstruct conditions of magma storage and evolution. Here we integrate optimised electron probe microanalysis and Mössbauer spectroscopy on endmember and single-crystal clinopyroxene samples to re-evaluate previously discredited approaches for estimating clinopyroxene ferric iron contents by stoichiometry. By ensuring that we measured all major and minor elements in clinopyroxene crystals with sufficient precision, we show that it is possible to readily obtain stoichiometric estimates of clinopyroxene ferric-to-total iron ratios with similar precisions to those derived from Mössbauer spectroscopy (1
σ
∼
3.5% absolute). Being able to robustly determine clinopyroxene ferric iron contents enables us to propose a new empirical scheme for assigning clinopyroxene components that explicitly accounts for ferric iron, which is primarily hosted within esseneite component (CaFe
3
+
AlSiO
6
) in clinopyroxenes dominated by quadrilateral components and aegirine component (NaFe
3
+
Si
2
O
6
) in alkali clinopyroxenes. Our new scheme provides a framework for documenting the full spectrum of clinopyroxene compositions in both natural and experimental systems when analyses are performed with sufficient precision.
Interactions between B and T cells are essential for most antibody responses, but the dynamics of these interactions are poorly understood. By two-photon microscopy of intact lymph nodes, we show ...that upon exposure to antigen, B cells migrate with directional preference toward the B-zone-T-zone boundary in a CCR7-dependent manner, through a region that exhibits a CCR7-ligand gradient. Initially the B cells show reduced motility, but after 1 d, motility is increased to approximately 9 microm/min. Antigen-engaged B cells pair with antigen-specific helper T cells for 10 to more than 60 min, whereas non-antigen-specific interactions last less than 10 min. B cell-T cell conjugates are highly dynamic and migrate extensively, being led by B cells. B cells occasionally contact more than one T cell, whereas T cells are strictly monogamous in their interactions. These findings provide evidence of lymphocyte chemotaxis in vivo, and they begin to define the spatiotemporal cellular dynamics associated with T cell-dependent antibody responses.
The mass of volatiles emitted during volcanic eruptions is often estimated by comparing the volatile contents of undegassed melt inclusions, trapped in crystals at an early stage of magmatic ...evolution, with that of the degassed matrix glass. Here we present detailed characterisation of magmatic volatiles (H
2
O, CO
2
, S, Fl and Cl) of crystal-hosted melt and fluid inclusions from the 2014–2015 Holuhraun eruption of the Bárðarbunga volcanic system, Iceland. Based on the ratios of magmatic volatiles to similarly incompatible trace elements, the undegassed primary volatile contents of the Holuhraun parental melt are estimated at 1500–1700 ppm CO
2
, 0.13–0.16 wt% H
2
O, 60–80 ppm Cl, 130–240 ppm F and 500–800 ppm S. High-density fluid inclusions indicate onset of crystallisation at pressures ≥ 0.4 GPa (~ 12 km depth) promoting deep degassing of CO
2
. Prior to the onset of degassing, the melt CO
2
content may have reached 3000–4000 ppm, with the total magmatic CO
2
budget estimated at 23–55 Mt. SO
2
release commenced at 0.12 GPa (~ 3.6 km depth), eventually leading to entrapment of SO
2
vapour in low-density fluid inclusions. We calculate the syn-eruptive volatile release as 22.2 Mt of magmatic H
2
O, 5.9–7.7 Mt CO
2
, and 11.3 Mt of SO
2
over the course of the eruption; F and Cl release were insignificant. Melt inclusion constraints on syn-eruptive volatile release are similar to estimates made during in situ field monitoring, with the exception of H
2
O, where field measurements may be heavily biased by the incorporation of meteoric water.
Sea-level rise (SLR) is predicted to elevate water depths above coral reefs and to increase coastal wave exposure as ecological degradation limits vertical reef growth, but projections lack data on ...interactions between local rates of reef growth and sea level rise. Here we calculate the vertical growth potential of more than 200 tropical western Atlantic and Indian Ocean reefs, and compare these against recent and projected rates of SLR under different Representative Concentration Pathway (RCP) scenarios. Although many reefs retain accretion rates close to recent SLR trends, few will have the capacity to track SLR projections under RCP4.5 scenarios without sustained ecological recovery, and under RCP8.5 scenarios most reefs are predicted to experience mean water depth increases of more than 0.5 m by 2100. Coral cover strongly predicts reef capacity to track SLR, but threshold cover levels that will be necessary to prevent submergence are well above those observed on most reefs. Urgent action is thus needed to mitigate climate, sea-level and future ecological changes in order to limit the magnitude of future reef submergence.
Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of ...GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.
We performed deep phenotyping of 20 GACI survivors.
Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.
GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
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