Combined immunodeficiency develops with age in immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2)

The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect

Antibiotic treatment-induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia.

Broad-spectrum antibiotics are widely used with patients in intensive care units (ICUs), many of whom develop hospital-acquired infections with Pseudomonas aeruginosa. Although preceding antimicrobial therapy is known as a major risk factor for P. aeruginosa-induced pneumonia, the underlying mechanisms remain incompletely understood. Here we demonstrate that depletion of the resident microbiota by broad-spectrum antibiotic treatment inhibited TLR-dependent production of a proliferation-inducing ligand (APRIL), resulting in a secondary IgA deficiency in the lung in mice and human ICU patients. Microbiota-dependent local IgA contributed to early antibacterial defense against P. aeruginosa. Consequently, P. aeruginosa-binding IgA purified from lamina propria culture or IgA hybridomas enhanced resistance of antibiotic-treated mice to P. aeruginosa infection after transnasal substitute. Our study provides a mechanistic explanation for the well-documented risk of P. aeruginosa infection following antimicrobial therapy, and we propose local administration of IgA as a novel prophylactic strategy

Potential links between surging ice sheets, circulation changes and the Dansgaard Oeschger cycles in the Irminger Sea, 60-18 kyr.

Surface and deepwater paleoclimate records in Irminger Sea core SO82-5 (59°N, 31°W) and Icelandic Sea core PS2644 (68°N, 22°W) exhibit large fluctuations in thermohaline circulation (THC) from 60 to 18 calendar kyr B.P., with a dominant periodicity of 1460 years from 46 to 22 calendar kyr B.P., matching the Dansgaard-Oeschger (D-O) cycles in the Greenland Ice Sheet Project 2 (GISP2) temperature record [Grootes and Stuiver, 1997]. During interstadials, summer sea surface temperatures (SST<inf>su</inf>) in the Irminger Sea averaged to 8°C, and sea surface salinities (SSS) averaged to ∼36.5, recording a strong Irminger Current and Atlantic THC. During stadials, SST<inf>su</inf> dropped to 2°-4°C, in phase with SSS drops by ∼1-2. They reveal major meltwater injections along with the East Greenland Current, which turned off the North Atlantic deepwater convection and hence the heat advection to the north, in harmony with various ocean circulation and ice models. On the basis of the IRD composition, icebergs came from Iceland, east Greenland, and perhaps Svalbard and other northern ice sheets. However, the southward drifting icebergs were initially jammed in the Denmark Strait, reaching the Irminger Sea only with a lag of 155-195 years. We also conclude that the abrupt stadial terminations, the D-O warming events, were tied to iceberg melt via abundant seasonal sea ice and brine water formation in the meltwater-covered northwestern North Atlantic. In the 1/1460-year frequency band, benthic δ18O brine water spikes led the temperature maxima above Greenland and in the Irminger Sea by as little as 95 years. Thus abundant brine formation, which was induced by seasonal freezing of large parts of the northwestern Atlantic, may have finally entrained a current of warm surface water from the subtropics and thereby triggered the sudden reactivation of the THC. In summary, the internal dynamics of the east Greenland ice sheet may have formed the ultimate pacemaker of D-O cycles

Controls on delta¹⁸O and delta¹³C profiles within the aragonite bivalve <em>Arctica islandic</em> <em/>

The geochemistry of Arctica islandica shells provides an opportunity to reconstruct intra-annual resolution climate records in temperate latitudes, and the annual banding allows close temporal constraint. Stable isotope analyses of carbon and oxygen from an Arctica islandica live-collected at 6 m depth from Irvine Bay, UK are presented. Seawater temperature ranges reconstructed from shell delta O-18 agree, within error, with instrumental sea surface temperature measurements. The saw-tooth profile of the seasonal delta O-18 signal (compared with the sinusoidal seawater temperature) indicates that shell accretion rate is not constant throughout the year. yodelling the expected delta O-18 profile from water temperature, salinity and shell growth rate suggest that A. islandica at this site has significant variation in the shell extension rate during the year. Material deposited during shell damage shows a positive shift in delta O-18 m strong ontogenetic effect is seen in delta C-13 and damage to the shell is associated with a significant (&gt;0.5 parts per thousand) and sustained shift of delta C-13.</p

Controls on delta¹⁸O and delta¹³C profiles within the aragonite bivalve <em>Arctica islandic</em> <em/>

The geochemistry of Arctica islandica shells provides an opportunity to reconstruct intra-annual resolution climate records in temperate latitudes, and the annual banding allows close temporal constraint. Stable isotope analyses of carbon and oxygen from an Arctica islandica live-collected at 6 m depth from Irvine Bay, UK are presented. Seawater temperature ranges reconstructed from shell delta O-18 agree, within error, with instrumental sea surface temperature measurements. The saw-tooth profile of the seasonal delta O-18 signal (compared with the sinusoidal seawater temperature) indicates that shell accretion rate is not constant throughout the year. yodelling the expected delta O-18 profile from water temperature, salinity and shell growth rate suggest that A. islandica at this site has significant variation in the shell extension rate during the year. Material deposited during shell damage shows a positive shift in delta O-18 m strong ontogenetic effect is seen in delta C-13 and damage to the shell is associated with a significant (&gt;0.5 parts per thousand) and sustained shift of delta C-13.</p

Moving beyond the age–depth model paradigm in deep-sea palaeoclimate archives: dual radiocarbon and stable isotope analysis on single foraminifera

Late-glacial palaeoclimate reconstructions from deep-sea sediment archives provide valuable insight into past rapid changes in ocean chemistry. Unfortunately, only a small proportion of the ocean floor with sufficiently high sediment accumulation rate (SAR) is suitable for such reconstructions using the long-standing age–depth model approach. We employ ultra-small radiocarbon (14C) dating on single microscopic foraminifera to demonstrate that the long-standing age–depth model method conceals large age uncertainties caused by post-depositional sediment mixing, meaning that existing studies may underestimate total geochronological error. We find that the age–depth distribution of our 14C-dated single foraminifera is in good agreement with existing bioturbation models only after one takes the possibility of Zoophycos burrowing into account. To overcome the problems associated with the age–depth paradigm, we use the first ever dual 14C and stable isotope (δ18O and δ13C) analysis on single microscopic foraminifera to produce a palaeoclimate time series independent of the age–depth paradigm. This new state of the art essentially decouples single foraminifera from the age–depth paradigm to provide multiple floating, temporal snapshots of ocean chemistry, thus allowing for the successful extraction of temporally accurate palaeoclimate data from low-SAR deep-sea archives. This new method can address large geographical gaps in late-glacial benthic palaeoceanographic reconstructions by opening up vast areas of previously disregarded, low-SAR deep-sea archives to research, which will lead to an improved understanding of the global interaction between oceans and climate

Using simulations of the last millennium to understand climate variability seen in palaeo-observations: similar variation of Iceland–Scotland overflow strength and Atlantic Multidecadal Oscillation

International audienceA recent palaeo-reconstruction of the strength of the Iceland–Scotland overflow during the last 600 years suggests that its low-frequency variability exhibits strong similarity with palaeo-reconstructions of the Atlantic Multidecadal Oscillation (AMO). The underlying mechanism of the similar variation remains unclear, however, based on palaeo-reconstructions alone. In this study we use simulations of the last millennium driven by external forcing reconstructions with three coupled climate models in order to investigate possible mechanisms underlying the similar variation of Iceland–Scotland overflow strength and AMO index. Similar variation of the two time series is also largely found in the model simulations. Our analysis indicates that the basin-wide AMO index in the externally forced simulations is dominated by the low-latitude sea surface temperature (SST) variability and is not predominantly driven by variations in the strength of the Atlantic meridional overturning circulation (MOC). This result suggests that a large-scale link through the strength of the MOC is not sufficient to explain the (simulated) similar variation of Iceland–Scotland overflow strength and AMO index. Rather, a more local link through the influence of the Nordic seas surface state and density structure, which are positively correlated with the AMO index, on the pressure gradient across the Iceland–Scotland ridge is responsible for the (simulated) similar variation. In the model simulation showing a weaker correlation between the Iceland–Scotland overflow strength and the AMO index, the wind stress in the Nordic seas also influences the overflow strength. Our study demonstrates that palaeo-climate simulations provide a useful tool to understand mechanisms and large-scale connections associated with the relatively sparse palaeo-observations

Periplasmic vestibule plays an important role for solute recruitment, selectivity, and gating in the Rh/Amt/MEP superfamily

AmtB, a member of the Rh/Amt/MEP superfamily, is responsible for ammonia transport in Escherichia coli. The ammonia pathway in AmtB consists of a narrow hydrophobic lumen in between hydrophilic periplasmic and cytoplasmic vestibules. A series of molecular dynamics simulations (greater than 0.4 μs in total) were performed to determine the mechanism of solute recruitments and selectivity by the periplasmic vestibule. The results show that the periplasmic vestibule plays a crucial role in solute selectivity, and its solute preferences follow the order of . Based on our results, recruitment is initiated by its interaction with either E70 or E225, highly conserved residues located at the entrance of the vestibule. Subsequently, the backbone carbonyl groups at the periplasmic vestibule direct to the conserved aromatic cage at the bottom of the vestibule (known as the Am1 site). The umbrella sampling simulations suggest that the conserved residue D160 is not directly involved in the ammonia conduction; rather its main function is to keep the structure of periplasmic vestibule intact. The MD simulations also revealed that two partially stacked phenyl rings of F107 and F215, separating the periplasmic vestibule from the hydrophobic lumen, flip open and closed simultaneously with a frequency of approximately 108 flipping events per second. These results show how the periplasmic vestibule selectively recruits to the Am1 site, and also that the synchronized flipping of two phenyl rings potentially facilitates the solute transition from the periplasmic vestibule to the hydrophobic lumen in the Rh/Amt/MEP superfamily