Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric- and adult-type gliomas.

AIMS: The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker. METHODS: We performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult- and paediatric-type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative. RESULTS: OLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3-mutant, and EZHIP-overexpressed. However, in all DMG, EGFR-mutant, SOX10 was constantly negative. In diffuse paediatric-type high-grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH-wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1-altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2-activated. CONCLUSION: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult-type HGG.

Microsynt: Exploring the syntax of EEG microstates.

Microstates represent electroencephalographic (EEG) activity as a sequence of switching, transient, metastable states. Growing evidence suggests the useful information on brain states is to be found in the higher-order temporal structure of these sequences. Instead of focusing on transition probabilities, here we propose "Microsynt", a method designed to highlight higher-order interactions that form a preliminary step towards understanding the syntax of microstate sequences of any length and complexity. Microsynt extracts an optimal vocabulary of "words" based on the length and complexity of the full sequence of microstates. Words are then sorted into classes of entropy and their representativeness within each class is statistically compared with surrogate and theoretical vocabularies. We applied the method on EEG data previously collected from healthy subjects undergoing propofol anesthesia, and compared their "fully awake" (BASE) and "fully unconscious" (DEEP) conditions. Results show that microstate sequences, even at rest, are not random but tend to behave in a more predictable way, favoring simpler sub-sequences, or "words". Contrary to high-entropy words, lowest-entropy binary microstate loops are prominent and favored on average 10 times more than what is theoretically expected. Progressing from BASE to DEEP, the representation of low-entropy words increases while that of high-entropy words decreases. During the awake state, sequences of microstates tend to be attracted towards "A - B - C" microstate hubs, and most prominently A - B binary loops. Conversely, with full unconsciousness, sequences of microstates are attracted towards "C - D - E" hubs, and most prominently C - E binary loops, confirming the putative relation of microstates A and B to externally-oriented cognitive processes and microstate C and E to internally-generated mental activity. Microsynt can form a syntactic signature of microstate sequences that can be used to reliably differentiate two or more conditions.

GC-FTICR mass spectrometry with dopant assisted atmospheric pressure photoionization: application to the characterization of plastic pyrolysis oil.

Pyrolysis is a promising way to convert plastic waste into valuable resources. However, for downstream upgrading processes, many undesirable species, such as conjugated diolefins or heteroatom-containing compounds, can be generated during this pyrolysis. In-depth chemical characterization is therefore required to improve conversion and valorization. Because of the high molecular diversity found in these samples, advanced analytical instrumentation is needed to provide accurate and complete characterization. Generally, direct infusion Fourier transform mass spectrometry is used to gather information at the molecular level, but it has the disadvantage of limited structural insights. To overcome this drawback, gas chromatography has been coupled to Fourier transform ion cyclotron resonance mass spectrometry. By taking advantage of soft atmospheric pressure photoionization, which preserves molecular information, and the use of different dopants (pyrrole, toluene, and benzene), selective ionization of different chemical families was achieved. Differences in the ionization energy of the dopants will only allow the ionization of the molecules of the pyrolysis oil which have lower ionization energy, or which are accessible via specific chemical ionization pathways. With a selective focus on hydrocarbon species and especially hydrocarbon species having a double bond equivalent (DBE) value of 2, pyrrole is prone to better ionize low-mass molecules with lower retention times compared to the dopant benzene, which allowed better ionization of high-mass molecules with higher retention times. The toluene dopant presented the advantage of ionizing both low and high mass molecules.

Physics-based scintillations for outdoor sound auralization.

The sound propagating in a turbulent atmosphere fluctuates in amplitude and phase. This phenomenon, known as acoustic scintillation, is caused by random fluctuations in the acoustic refractive index of the air induced by atmospheric turbulence. Auralization techniques should consider this phenomenon to increase the realism of the synthetic sound. This paper proposes a physics-based formulation to model sequences of log-amplitude and phase fluctuations of a sound propagating in a turbulent atmosphere. This method applies to slanted and vertical propagation of the sound, which is useful for simulating elevated noise sources such as aircraft, drones, and wind turbines. The theoretical framework is based on the spatial correlation functions for the log-amplitude and phase fluctuations for spherical waves, the von Kármán spectrum, and similarity theories to model atmospheric turbulence. Two applications with audio files are presented to demonstrate the applicability of this method to tonal and broadband noise.

EEG microstate dynamics indicate a U-shaped path to propofol-induced loss of consciousness.

Evidence suggests that the stream of consciousness is parsed into transient brain states manifesting themselves as discrete spatiotemporal patterns of global neuronal activity. Electroencephalographical (EEG) microstates are proposed as the neurophysiological correlates of these transiently stable brain states that last for fractions of seconds. To further understand the link between EEG microstate dynamics and consciousness, we continuously recorded high-density EEG in 23 surgical patients from their awake state to unconsciousness, induced by step-wise increasing concentrations of the intravenous anesthetic propofol. Besides the conventional parameters of microstate dynamics, we introduce a new implementation of a method to estimate the complexity of microstate sequences. The brain activity under the surgical anesthesia showed a decreased sequence complexity of the stereotypical microstates, which became sparser and longer-lasting. However, we observed an initial increase in microstates' temporal dynamics and complexity with increasing depth of sedation leading to a distinctive "U-shape" that may be linked to the paradoxical excitation induced by moderate levels of propofol. Our results support the idea that the brain is in a metastable state under normal conditions, balancing between order and chaos in order to flexibly switch from one state to another. The temporal dynamics of EEG microstates indicate changes of this critical balance between stability and transition that lead to altered states of consciousness.

Disentangle genus microdiversity within a complex microbial community by using a multi-distance long-read binning method: example of Candidatus Accumulibacter.

Complete genomes can be recovered from metagenomes by assembling and binning DNA sequences into metagenome assembled genomes (MAGs). Yet, the presence of microdiversity can hamper the assembly and binning processes, possibly yielding chimeric, highly fragmented and incomplete genomes. Here, the metagenomes of four samples of aerobic granular sludge bioreactors containing Candidatus (Ca.) Accumulibacter, a phosphate-accumulating organism of interest for wastewater treatment, were sequenced with both PacBio and Illumina. Different strategies of genome assembly and binning were investigated, including published protocols and a binning procedure adapted to the binning of long contigs (MuLoBiSC). Multiple criteria were considered to select the best strategy for Ca. Accumulibacter, whose multiple strains in every sample represent a challenging microdiversity. In this case, the best strategy relies on long-read only assembly and a custom binning procedure including MuLoBiSC in metaWRAP. Several high-quality Ca. Accumulibacter MAGs, including a novel species, were obtained independently from different samples. Comparative genomic analysis showed that MAGs retrieved in different samples harbour genomic rearrangements in addition to accumulation of point mutations. The microdiversity of Ca. Accumulibacter, likely driven by mobile genetic elements, causes major difficulties in recovering MAGs, but it is also a hallmark of the panmictic lifestyle of these bacteria.

Visualization and identification of single meteoritic organic molecules by atomic force microscopy.

Using high-resolution atomic force microscopy (AFM) with CO-functionalized tips, we atomically resolved individual molecules from Murchison meteorite samples. We analyzed powdered Murchison meteorite material directly, as well as processed extracts that we prepared to facilitate characterization by AFM. From the untreated Murchison sample, we resolved very few molecules, as the sample contained mostly small molecules that could not be identified by AFM. By contrast, using a procedure based on several trituration and extraction steps with organic solvents, we isolated a fraction enriched in larger organic compounds. The treatment increased the fraction of molecules that could be resolved by AFM, allowing us to identify organic constituents and molecular moieties, such as polycyclic aromatic hydrocarbons and aliphatic chains. The AFM measurements are complemented by high-resolution mass spectrometry analysis of Murchison fractions. We provide a proof of principle that AFM can be used to image and identify individual organic molecules from meteorites and propose a method for extracting and preparing meteorite samples for their investigation by AFM. We discuss the challenges and prospects of this approach to study extraterrestrial samples based on single-molecule identification.

Three-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM): French translation and cultural adaptation.

PURPOSE: The routine use of validated diagnostic instruments is key to identifying delirious patients early and expediting care. The 3-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM) instrument is a brief, easy to use, sensitive, and specific delirium assessment tool for hospitalized patients. We aimed to translate the original English version into French, and then adapt it to older high-risk patients. METHODS: Translation and adaptation of the questionnaire were guided by an expert committee and the 3D-CAM instrument developer. During the translation phase, we achieved semantic and conceptual equivalence of the instrument by conducting forward and backward translations. During the adaptation phase, we assessed the face validity, clarity of wording, and ease of use of the translated questionnaire by administering it to 30 patients and their caregivers in peri-interventional and medical intermediate care units. During both phases, we used qualitative (goal and adequacy of the questionnaire) and quantitative (Sperber score, clarity score) criteria. RESULTS: Translation: four items were judged inadequate and were revised until all reached a Sperber score of < 3/7. Face validity: 91% of patients thought the questionnaire was designed to assess memory, thoughts, or reasoning. Clarity: eight items required adjustments until all scored ≥ 9/10 for clarity. Ease of use: all bedside caregivers reported that the questionnaire was easy to complete after receiving brief instructions. CONCLUSIONS: We produced a culturally adapted French version of the 3D-CAM instrument that is well understood and well-received by older high-risk patients and their caregivers.

RéSUMé: OBJECTIF: L'administration systématique d'instruments diagnostiques validés est essentielle pour identifier précocement les patients confus. Le questionnaire 3D-CAM (3 Minute Diagnostic Confusion Assessment Method) est un outil d'évaluation bref, facile à administrer en milieu hospitalier, sensible et spécifique pour l'état confusionnel. Notre objectif était de le traduire en français, puis de l'adapter à une population de patients âgés à haut risque. MéTHODE: La traduction et l'adaptation ont été guidées par un comité d'experts et le développeur de l'instrument. Nous avons atteint une équivalence sémantique et conceptuelle en menant des traductions antérogrades, puis rétrogrades. Nous avons évalué la validité de contenu, la clarté lexicale, et la facilité d'administration du questionnaire en le soumettant à 30 patients et 30 soignants dans des unités de soins intermédiaires médicaux et péri-interventionnels. Durant les phases de traduction et d'adaptation, nous avons utilisé des critères qualitatifs et quantitatifs. RéSULTATS: Traduction : quatre questions ont été jugées inadéquates et ont été révisées pour atteindre un score de Sperber < 3/7. Validité de contenu : 91% des patients pensaient que le questionnaire était conçu pour évaluer la mémoire, les pensées, ou le raisonnement. Clarté : huit questions ont dû être modifiées pour atteindre un score de clarté ≥ 9/10. Facilité d'administration : tous les soignants pensaient que le questionnaire était facile à utiliser après une brève formation. CONCLUSIONS: Nous avons produit une version française du questionnaire 3D-CAM qui est adaptée aux patients âgés à haut risque et aux soignants en milieu de soins aigus.

Exploring Complex Mixtures by Cyclic Ion Mobility High-Resolution Mass Spectrometry: Application Toward Petroleum.

The in-depth isomeric and isobaric description of ultra-complex organic mixtures remains one of the most challenging analytical tasks. In the last two decades, ion mobility coupled to high-performance mass spectrometry added an additional structural dimension. Despite tremendous instrumental improvements, commercial devices are still limited in ion mobility and mass spectrometric resolving power and struggle to resolve isobaric species and complex isomeric patterns. To overcome these limitations, we explored the capabilities of cyclic ion mobility high-resolution mass spectrometry with special emphasis on petrochemical applications. We could show that quadrupole-selected ion mobility mass spectrometry gives closer insights into the isomeric distribution. In combination with slicing the specific parts of the ion mobility dimension, isobaric interferences could be drastically removed. Collision-induced dissociation (CID) allowed separating structural groups of polycyclic aromatic hydrocarbons and heterocycles (PAH/PASH), deploying up to 10 passes in the cyclic ion mobility device. Finally, we introduce a data processing workflow to resolve the 3.4 mDa SH4/C3 mass split by combining ion mobility and mass spectrometric resolving power. Cyclic ion mobility with the intelligent design of experiments and processing routines will be a powerful approach addressing the isobaric and isomeric complexity of ultra-complex mixtures.

Structural analysis of petroporphyrins from asphaltene by trapped ion mobility coupled with Fourier transform ion cyclotron resonance mass spectrometry.

Molecular characterization of compounds present in highly complex mixtures such as petroleum is proving to be one of the main analytical challenges. Heavy fractions, such as asphaltenes, exhibit immense molecular and isomeric complexity. Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) with its unequalled resolving power, mass accuracy and dynamic range can address the isobaric complexity. Nevertheless, isomers remain largely inaccessible. Therefore, another dimension of separation is required. Recently, ion mobility mass spectrometry has revealed great potential for isomer description. In this study, the combination of trapped ion mobility and Fourier transform ion cyclotron resonance mass spectrometry (TIMS-FTICR) is used to obtain information on the structural features and isomeric diversity of vanadium petroporphyrins present in heavy petroleum fractions. The ion mobility spectra provided information on the isomeric diversity of the different classes of porphyrins. The determination of the collision cross section (CCS) from the peak apex allows us to hypothesize about the structural aspects of the petroleum molecules. In addition, the ion mobility signal full width at half maximum (FWHM) was used as a measure for isomeric diversity. Finally, theoretical CCS determinations were conducted first on core structures and then on alkylated petroporphyrins taking advantage of the linear correlation between the CCS and the alkylation level. This allowed the proposal of putative structures in agreement with the experimental results. The authors believe that the presented workflow will be useful for the structural prediction of real unknowns in highly complex mixtures.

Optimization of ion trajectories in a dynamically harmonized Fourier-transform ion cyclotron resonance cell using a design of experiments strategy.

RATIONALE: With the recent introduction of the dynamically harmonized Fourier-transform ion cyclotron resonance (FT-ICR) cell, the complexity of tuning has expanded drastically, and fine-tuning of the direct current voltages is required to optimize the ion cloud movement. As this adjustment must typically be performed manually, more reliable computational methods would be useful. METHODS: Here we propose a computational method based on a design of experiments (DoE) strategy to overcome the limits of classical manual tuning. This DoE strategy was exemplarily applied on a 12 T FT-ICR instrument equipped with a dynamically harmonized ICR cell. The chemometric approach, based on a central composite face (CCF) design, was first applied to a reference material (sodium trifluoroacetate) allowing for the evaluation of the primary cell parameters. Eight factors related to shimming and gating were identified. The summed intensity of the signal corresponding to the even harmonics was defined as one quality criterion. RESULTS: The DoE response allowed for rapid and complete mapping of cell parameters resulting in an optimized parameter set. The new set of cell parameters was applied to the study of an ultra-complex sample: Tholins, an ultra-complex mixture that mimics the haze present on Titan, was chosen. We observed a substantial improvement in mass spectrometric performance. The sum of signals related to harmonics was decreased by a factor of three (from 4% for conventional tuning to 1.3%). Furthermore, the dynamic range was also increased, which in turn led to an increase in attributed peaks by 13%. CONCLUSIONS: This computational procedure based on an experimental design can be applied to any other mass spectrometric parameter optimization problem. This strategy will lead to a more transparent and data-driven method development.

High-resolution mass spectrometry for future space missions: Comparative analysis of complex organic matter with LAb-CosmOrbitrap and laser desorption/ionization Fourier transform ion cyclotron resonance.

RATIONALE: Mass spectrometers are regularly boarded on spacecraft for the exploration of the Solar System. A better understanding of the origin, distribution and evolution of organic matter and its relationships with inorganic matter in different extra-terrestrial environments requires the development of innovative space tools, described as Ultra-High-Resolution Mass Spectrometry (UHRMS) instruments. METHODS: Analyses of a complex organic material simulating extraterrestrial matter (Titan's tholins) are performed with a homemade space-designed Orbitrap™ equipped with a laser ablation ionization source at 266 nm: the LAb-CosmOrbitrap. Mass spectra are obtained using only one laser shot and transient duration of 838 ms. A comparison is made on the same sample with a laboratory benchmark mass spectrometer: a Fourier Transform Ion Cyclotron Resonance equipped with a laser desorption ionization source at 355 nm (LDI-FTICR) allowing accumulation of 20,000 laser shots. RESULTS: Mass spectra and attributions of molecular formulae based on the peaks detected by both techniques show significant similarities. Detection and identification of the same species are validated. The formation of clusters ions with the LAb-CosmOrbitrap is also presented. This specific feature brings informative and unusual indirect detections about the chemical compounds constituting Titan's tholins. In particular, the detection of HCN confirms previous results obtained with laboratory Electrospray Ionization (ESI)-UHRMS studies about the understanding of polymeric patterns for the formation of tholins. CONCLUSIONS: The capabilities of the LAb-CosmOrbitrap to decipher complex organic mixtures using single laser shot and a short transient are highlighted. In agreement with results provided by a commercial FTICR instrument in the laboratory, we demonstrate in this work the relevance of a space laser-CosmOrbitrap instrument for future planetary exploration.

Prediction of long-term quality of life after severe traumatic brain injury based on variables at hospital admission.

Objectives: Variables collected early after severe traumatic brain injury (sTBI) could predict health-related quality of life (HRQoL). Our aim was to determine the prevalence of patients with a low HRQoL 4 years after sTBI and to develop a prediction model including early variables.Methods: Adult patients with both sTBI [abbreviated injury score of the head region (HAIS) >3] and disease-specific HRQoL assessments using the 'Quality of Life after Brain Injury' (QOLIBRI) were included. The outcome was the total score (TS) of QOLIBRI; cutoff for low HRQoL: <60 points. A multivariate logistic regression model and prediction model were performed.Results: One hundred-sixteen patients [median age 50.8 years (IQR 25.9-62.8; 21.6% >65 years)] were included; 68 (58.6%) with HAIS = 4, 48 (41.4%) with HAIS = 5. Median Glasgow Coma Scale (GCS) was 13 (IQR 3-15). Median TS was 77 (IQR 60-88). Low HRQoL was observed in 28 patients (24.1%). Two variables were associated with low HRQoL: GCS <13, working situation other than employed or retired. The prediction model had an AUROC of 0.765; calibration was moderate (Hosmer Lemeshow Chi2 6.82, p = .556).Conclusion: One in four patients had a low HRQoL after 4 years. A lower GCS and working situations were associated with low HRQoL.

Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavioral outcomes of PWS, an understanding of its effects on the development of hypothalamic circuits remains elusive. Here, we show that mice lacking Magel2, one of the genes responsible for the etiology of PWS, display an abnormal development of ARH axonal projections. Notably, the density of anorexigenic α-melanocyte-stimulating hormone axons was reduced in adult Magel2-null mice, while the density of orexigenic agouti-related peptide fibers in the mutant mice appeared identical to that in control mice. On the basis of previous findings showing a pivotal role for metabolic hormones in hypothalamic development, we also measured leptin and ghrelin levels in Magel2-null and control neonates and found that mutant mice have normal leptin and ghrelin levels. In vitro experiments show that Magel2 directly promotes axon growth. Together, these findings suggest that a loss of Magel2 leads to the disruption of hypothalamic feeding circuits, an effect that appears to be independent of the neurodevelopmental effects of leptin and ghrelin and likely involves a direct neurotrophic effect of Magel2.

Extending standard urban outdoor noise propagation models to complex geometries.

A hybrid method that combines a noise engineering method and the 2.5D boundary element method approximates outdoor sound propagation in large domains with complex objects more accurately than noise engineering methods alone and more efficiently than reference methods alone. Noise engineering methods (e.g., ISO 9613-2 or CNOSSOS-EU) efficiently approximate sound levels from roads, railways, and industrial sources in cities for simple, box-shaped geometries by first finding the propagation paths between the source and receiver, then applying attenuations (e.g., geometrical divergence and atmospheric absorption) to each path, and finally incoherently summing all of the path contributions. Standard engineering methods cannot model more complicated geometries but introducing an additional attenuation term quantifies the influence of complex objects. Calculating this extra attenuation term requires reference calculations but performing reference computations for each path is too computationally expensive. Thus, the extra attenuation term is linearly interpolated from a data table containing the corrections for many source/receiver positions and frequencies. The 2.5D boundary element method produces the levels for the real and simplified geometries and subtracting them yields a table of corrections. For a T-shaped barrier with two buildings, this approach reduces the mean error by approximately 2 dBA compared to a standard engineering method.

Use of Bacteria To Stabilize Archaeological Iron.

Iron artifacts are common among the findings of archaeological excavations. The corrosion layer formed on these objects requires stabilization after their recovery, without which the destruction of the item due to physicochemical damage is likely. Current technologies for stabilizing the corrosion layer are lengthy and generate hazardous waste products. Therefore, there is a pressing need for an alternative method for stabilizing the corrosion layer on iron objects. The aim of this study was to evaluate an alternative conservation-restoration method using bacteria. For this, anaerobic iron reduction leading to the formation of stable iron minerals in the presence of chlorine was investigated for two strains of Desulfitobacterium hafniense (strains TCE1 and LBE). Iron reduction was observed for soluble Fe(III) phases as well as for akaganeite, the most troublesome iron compound in the corrosion layer of archaeological iron objects. In terms of biogenic mineral production, differential efficiencies were observed in assays performed on corroded iron coupons. Strain TCE1 produced a homogeneous layer of vivianite covering 80% of the corroded surface, while on the coupons treated with strain LBE, only 10% of the surface was covered by the same mineral. Finally, an attempt to reduce iron on archaeological objects was performed with strain TCE1, which led to the formation of both biogenic vivianite and magnetite on the surface of the artifacts. These results demonstrate the potential of this biological treatment for stabilizing archaeological iron as a promising alternative to traditional conservation-restoration methods.IMPORTANCE Since the Iron Age, iron has been a fundamental material for the building of objects used in everyday life. However, due to its reactivity, iron can be easily corroded, and the physical stability of the object built is at risk. This is particularly true for archaeological objects on which a potentially unstable corrosion layer is formed during the time the object is buried. After excavation, changes in environmental conditions (e.g., higher oxygen concentration or lower humidity) alter the stability of the corrosion layer and can lead to the total destruction of the object. In this study, we demonstrate the feasibility of an innovative treatment based on bacterial iron reduction and biogenic mineral formation to stabilize the corrosion layer and protect these objects.

Arsenic Methylation Dynamics in a Rice Paddy Soil Anaerobic Enrichment Culture.

Methylated arsenic (As) species represent a significant fraction of the As accumulating in rice grains, and there are geographic patterns in the abundance of methylated arsenic in rice that are not understood. The microorganisms driving As biomethylation in paddy environments, and thus the soil conditions conducive to the accumulation of methylated arsenic, are unknown. We tested the hypothesis that sulfate-reducing bacteria (SRB) are key drivers of arsenic methylation in metabolically versatile mixed anaerobic enrichments from a Mekong Delta paddy soil. We used molybdate and monofluorophosphate as inhibitors of sulfate reduction to evaluate the contribution of SRB to arsenic biomethylation, and developed degenerate primers for the amplification of arsM genes to identify methylating organisms. Enrichment cultures converted 63% of arsenite into methylated products, with dimethylarsinic acid as the major product. While molybdate inhibited As biomethylation, this effect was unrelated to its inhibition of sulfate reduction and instead inhibited the methylation pathway. Based on arsM sequences and the physiological response of cultures to media conditions, we propose that amino acid fermenting organisms are potential drivers of As methylation in the enrichments. The lack of a demethylating capacity may have contributed to the robust methylation efficiencies in this mixed culture.

IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy.

IgA nephropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure worldwide. IgAN pathogenesis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is available for IgAN. The absence of IgA1 and CD89 homologs in the mouse has precluded in vivo proof-of-concept studies of specific therapies targeting IgA1. However, the α1KI­CD89Tg mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombinant IgA1 protease (IgA1­P), a bacterial protein that selectively cleaves human IgA1. Mice injected with IgA1­P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease in IgA1-sCD89 complexes. Levels of mesangial IgA1 deposits and the binding partners of these deposits (sCD89, transferrin receptor, and transglutaminase 2) decreased markedly 1 week after treatment, as did the levels of C3 deposition, CD11b(+) infiltrating cells, and fibronectin. Antiprotease antibodies did not significantly alter IgA1­P activity. Moreover, hematuria consistently decreased after treatment. In conclusion, IgA1­P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibrosis, and hematuria in a mouse IgAN model, and therefore may be a plausible treatment for patients with IgAN.

Preoperative and early postoperative quality of life after major surgery - a prospective observational study.

BACKGROUND: Changes in health-related quality of life (HRQoL) several days after surgery have rarely been investigated. We aimed to estimate the perioperative change of HRQoL, to identify patients with clinically relevant decrease in postoperative HRQoL and to establish factors associated with this decrease in HRQoL at day 30 after major surgery. METHODS: Patients scheduled for major surgery at a university hospital were enrolled. Based on the HRQoL SF-12 questionnaire, the preoperative physical component summary (PCS) score, preoperative mental component summary (MCS) score, and postoperative PCS and MCS scores at day 30 were recorded. Minimal clinically important difference (MCID) was defined as those with a decrease of at least one half of the standard deviation (SD) of preoperative PCS or MCS scores. Differences between the groups with or without decreased HRQoL were investigated using univariate comparisons. A multiple logistic regression model was performed to evaluate the predictive value of potential perioperative variables. RESULTS: The mean ± SD preoperative PCS score was 38.5 ± 10.6, postoperative score was 35.1 ± 7.8 (p = .004) in 85 patients. Thirty-five patients (41.2%) had a clinically relevant decrease of the postoperative PCS score. A normal to high preoperative exercise metabolic capacity measured with metabolic equivalent of task (MET) (p = .01) was a predictor of the decrease in postoperative PCS. The mean preoperative MCS scores (p = .395) were 42.2 (SD 12.8) preoperative, and 43.45 (SD 12.4) postoperative, respectively. CONCLUSIONS: Major surgery decreases postoperative PCS scores of HRQoL at 30 days. A normal to high exercise capacity was a predictor of a clinically relevant decrease of postoperative PCS scores. TRIAL REGISTRATION: 07-107 (Ethical Committee NAC of Geneva University Hospitals).