Next-generation sequencing shows marked rearrangements of BK polyomavirus that favor but are not required for polyomavirus-associated nephropathy

Background BKPyV is associated with polyomavirus-associated nephropathy (PVAN), a major cause of graft rejection in kidney transplant recipients (KTRs). Mutations occur in the transcriptional control region (TCR) of BKPyV, but whether they are required for the development of PVAN is not completely understood. To this end, we characterized BKPyV TCRs from KTRs to assess whether TCR mutations are associated with PVAN. Study design We analyzed urine and plasma samples of fifteen KTRs with biopsy-confirmed PVAN, presumptive PVAN, or probable PVAN in order to explore the contents of the BKPyV virome. BKPyV TCRs were amplified and deep sequenced to characterize the viral strains. Alterations in block structures and transcription factor binding sites were investigated. Results The majority of sequences in both urine and plasma samples represented archetype BKPyV TCR. Minor populations harboring rearranged TCRs were detected in all patient groups. In one biopsy-confirmed PVAN patient rearranged TCRs predominated, and in another patient half of all reads represented rearranged sequences. Conclusions Although archetype BKPyV predominated in most patients, highest proportions and highest numbers of rearranged strains were detected in association with PVAN. TCR mutations seem not necessary for the development of PVAN, but immunosuppression may allow increased viral replication giving rise to TCR variants with enhanced replication efficiency.Peer reviewe

A Period and a Prediction for the Of?p Spectrum Alternator HD 191612

The observational picture of the enigmatic O-type spectrum variable HD191612 has been sharpened substantially. A symmetrical, low-amplitude light curve with a period near 540 d has recently been reported from Hipparcos photometry. This period satisfies all of the spectroscopy since at least 1982, including extensive new observations during 2003 and 2004, and it has predicted the next transition during September--October 2004. Measurements of the H alpha equivalent width reveal a sharp emission peak in the phase diagram, in contrast to the apparently sinusoidal light curve. The He II absorption-line strength is essentially constant, while He I varies strongly, possibly filled in by emission in the O6 state, thus producing the apparent spectral-type variations. The O8 state appears to be the "normal" one. Two intermediate O7 observations have been obtained, which fall at the expected phases, but these are the only modern observations of the transitions so far. The period is too long for rotation or pulsation; although there is no direct evidence as yet for a companion, a model in which tidally induced oscillations drive an enhanced wind near periastron of an eccentric orbit appears promising. Further observations during the now predictable transitions may provide a critical test. Ultraviolet and X-ray observations during both states will likely also prove illuminating.Comment: 7 pages, 3 figures, 1 table; scheduled for the 2004 December 10 issue of ApJL, Vol. 617, No. 1. ApJ

Multiplex analysis of Human Polyomavirus diversity in kidney transplant recipients with BK virus replication

Background: While the pathogenicity of the two initially identified Human Polyomaviruses (HPyVs), BK Virus (BKPyV) and JC Virus (JCPyV) has been intensely studied, there is only limited data, on whether the occurrence of the recently discovered HPyVs correlates with high level BKPyV replication and progression towards Polyomavirus associated nephropathy (PVAN). Methods: Therefore, we performed a comprehensive longitudinal genoprevalence analysis of 13 HPyVs using a novel multiplex assay including 400 serum and 388 urine samples obtained from 99 kidney transplant recipients (KTRs), grouped by quantitative BKPyV DNA loads and evidence of manifest BKPyV associated disease (histologically verified PVAN, high urinary decoy cell levels and concurrent decrease of renal function). Results: In total, 3 different non-BKPyV/JCPyV HPyVs, Human Polyomavirus 9, Merkel Cell Polyomavirus (MCPyV) and Trichodysplasia Spinulosa associated Polyomavirus were detected in 11 blood and 21 urine samples from 21 patients. Although DNAemia of these viruses occurred more frequently during high level BKPyV DNAemia and PVAN, the increase of the detection frequency due to progression of BKPyV replication did not reach statistical significance for blood samples. The positive detection rate of MCPyV in urine, however, was significantly higher during BKPyV DNAemia in 19 KTRs of our cohort who suffered from histologically verified PVAN (p=0.005). In one individual with PVAN, continuous long-term shedding of MCPyV in urine was observed. Conclusion: In our cohort the recently discovered HPyVs HPyV9, TSPyV and MCPyV emerged in blood from KTRs with variable kinetics, while detection of MCPyV DNAuria occurred more frequently during BKPyV DNAemia in patients with PVAN.Peer reviewe

HD148937: a multiwavelength study of the third Galactic member of the Of?p class

Three Galactic O-type stars belong to the rare class of Of?p objects: HD108, HD191612, and HD148937. The first two stars show a wealth of phenomena, including magnetic fields and strong X-ray emission, light variability, and dramatic periodic spectral variability. We present here the first detailed optical and X-ray study of the third Galactic Of?p star, HD148937. Spectroscopic monitoring has revealed low-level variability in the Balmer and HeII4686 lines, but constancy at HeI and CIII4650. The Ha line exhibits profile variations at a possible periodicity of ~7d. Model atmosphere fits yield T_{eff}=41000+-2000K, log(g)=4.0+-0.1, Mdot_{sph}<~ 10^{-7}Msol/yr and a surabondance of nitrogen by a factor of four. At X-ray wavelengths, HD148937 resembles HD108 and HD191612 in having a thermal spectrum dominated by a relatively cool component (kT=0.2keV), broad lines (>1700km/s), and an order-of-magnitude overluminosity compared to normal O stars (log [L_X^unabs/L_BOL] ~ -6).Comment: accepted by AJ; 15p, 15fig available in jp

Longitudinal assessment of the CXCL10 blood and urine concentration in kidney transplant recipients with BK polyomavirus replication—a retrospective study

In kidney transplant recipients (KTRs), BK polyomavirus (BKPyV) replication may progress to polyomavirus-associated nephropathy (PVAN). In this retrospective study, we assessed the chemokine CXCL10 in urine and blood samples consecutively acquired from 85 KTRs who displayed different stages of BKPyV replication and eventually developed PVAN. In parallel to progression toward PVAN, CXCL10 gradually increased in blood and urine, from baseline (prior to virus replication) to BKPyV DNAuria (median increase in blood: 42.15 pg/ml, P = 0.0156), from mere DNAuria to low- and high-level BKPyV DNAemia (median increase: 52.60 and 87.26 pg/ml, P = 0.0010 and P = 0.0002, respectively) and peaked with histologically confirmed PVAN (median increase: 145.00 pg/ml, P <0.0001). CXCL10 blood and urine levels significantly differed among KTRs with respect to simultaneous presence of human cytomegalovirus (P <0.001) as well as in relation to the clinical severity of respective BKPyV DNAemia episodes (P = 0.0195). CXCL-10 concentrations were particularly lower in KTRs in whom BKPyV DNAemia remained without clinical evidence for PVAN, as compared to individuals who displayed high decoy cell levels, decreased renal function and/or biopsy-proven PVAN (median blood concentration: 266.97 vs. 426.42 pg/ml, P = 0.0282). In conclusion, in KTRs CXCL10 rises in parallel to BKPyV replication and correlates with the gradual development of PVAN.Peer reviewe

Allograft rejection is associated with development of functional IgE specific for donor MHC antigens.

BACKGROUND: Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. OBJECTIVE: This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. METHODS: Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcεRI). RESULTS: Donor MHC class I- and MHC class II-specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcεRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. CONCLUSION: These results demonstrate that MHC/HLA-specific IgE develops during an alloresponse and is functional in mediating effector mechanisms

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation:TTVguideIT

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.</p

Impact of atmospheric CO₂ and galactic cosmic radiation on Phanerozoic climate change and the marine d18O record

[1] A new model is developed and applied to simulate the Phanerozoic evolution of seawater composition (dissolved Ca, Sr, dissolved inorganic carbon, alkalinity, pH, δ18O), marine carbonates (Sr/Ca, 87Sr/86Sr, δ13C, δ18O), atmospheric CO2 and surface temperature. The marine carbonate records (Sr/Ca, 87Sr/86Sr, δ13C) are used to reconstruct changes in volcanic/tectonic activity and organic carbon burial over the Phanerozoic. Seawater pH is calculated assuming saturation with respect to calcite and considering the changing concentration of dissolved Ca documented by brine inclusion data. The depth of calcite saturation is allowed to vary through time and the effects of changing temperature and pressure on the stability constants of the carbonate system are considered. Surface temperatures are calculated using the GEOCARB III approach considering also the changing flux of galactic cosmic radiation (GCR). It is assumed that GCR cools the surface of the Earth via enhanced cloud formation at low altitudes. The δ18O of marine carbonates is calculated considering the changing isotopic composition of seawater, the prevailing surface temperatures and seawater pH. Repeated model runs showed that the trends observed in the marine δ18O record can only be reproduced by the model if GCR is allowed to have a strong effect on surface temperature. The climate evolution predicted by the model is consistent with the geological record. Warm periods (Cambrian, Devonian, Triassic, Cretaceous) are characterized by low GCR levels. Cold periods during the late Carboniferous to early Permian and the late Cenozoic are marked by high GCR fluxes and low pCO2 values. The major glaciations occurring during these periods are the result of carbon cycling processes causing a draw-down of atmospheric CO2 and a coevally prevailing dense cloud cover at low-altitudes induced by strong GCR fluxes. The two moderately cool periods during the Ordovician - Silurian and Jurassic - early Cretaceous are characterized by both high pCO2 and GCR levels so that greenhouse warming compensated for the cooling effect of low-altitude clouds. The very high Jurassic δ18O values observed in the geological record are caused by low pH values in surface waters rather than cold surface conditions

IgG1 Fc N-glycan galactosylation as a biomarker for immune activation.

Immunoglobulin G (IgG) Fc N-glycosylation affects antibody-mediated effector functions and varies with inflammation rooted in both communicable and non-communicable diseases. Worldwide, communicable and non-communicable diseases tend to segregate geographically. Therefore, we studied whether IgG Fc N-glycosylation varies in populations with different environmental exposures in different parts of the world. IgG Fc N-glycosylation was analysed in serum/plasma of 700 school-age children from different communities of Gabon, Ghana, Ecuador, the Netherlands and Germany. IgG1 galactosylation levels were generally higher in more affluent countries and in more urban communities. High IgG1 galactosylation levels correlated with low total IgE levels, low C-reactive protein levels and low prevalence of parasitic infections. Linear mixed modelling showed that only positivity for parasitic infections was a significant predictor of reduced IgG1 galactosylation levels. That IgG1 galactosylation is a predictor of immune activation is supported by the observation that asthmatic children seemed to have reduced IgG1 galactosylation levels as well. This indicates that IgG1 galactosylation levels could be used as a biomarker for immune activation of populations, providing a valuable tool for studies examining the epidemiological transition from communicable to non-communicable diseases

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives