Constraints on Earth system functioning at the Paleocene-Eocene Thermal Maximum from the marine silicon cycle

The Paleocene‐Eocene Thermal Maximum (PETM, ca. 56 Ma) is marked by a negative carbon isotope excursion (CIE) and increased global temperatures. The CIE is thought to result from the release of 13C‐depleted carbon, although the source(s) of carbon and triggers for its release, its rate of release, and the mechanisms by which the Earth system recovered are all debated. Many of the proposed mechanisms for the onset and recovery phases of the PETM make testable predictions about the marine silica cycle, making silicon isotope records a promising tool to address open questions about the PETM. We analyzed silicon isotope ratios (δ30Si) in radiolarian tests and sponge spicules from the Western North Atlantic (ODP Site 1051) across the PETM. Radiolarian δ30Si decreases by 0.6‰ from a background of 1‰ coeval with the CIE, while sponge δ30Si remains consistent at 0.2‰. Using a box model to test the Si cycle response to various scenarios, we find the data are best explained by a weak silicate weathering feedback, implying the recovery was mostly driven by nondiatom organic carbon burial, the other major long‐term carbon sink. We find no resolvable evidence for a volcanic trigger for carbon release, or for a change in regional oceanography. Better understanding of radiolarian Si isotope fractionation and more Si isotope records spanning the PETM are needed to confirm the global validity of these conclusions, but they highlight how the coupling between the silica and carbon cycles can be exploited to yield insight into the functioning of the Earth system

Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21–26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3–24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-021-06314-4

Specific Human Astrocyte Subtype Revealed by Affinity Purified GFAP+1 Antibody; Unpurified Serum Cross-Reacts with Neurofilament-L in Alzheimer

The human GFAP splice variants GFAPΔ164 and GFAPΔexon6 both result in a GFAP protein isoform with a unique out-of-frame carboxy-terminus that can be detected by the GFAP+1 antibody. We previously reported that GFAP+1 was expressed in astrocytes and in degenerating neurons in Alzheimer's disease brains. In this study we aimed at further investigating the neuronal GFAP+1 expression and we started by affinity purifying the GFAP+1 antibody. The purified antibody resulted in a loss of neuronal GFAP+1 signal, although other antibodies directed against the amino- and carboxy-terminus of GFAPα still revealed GFAP-immunopositive neurons, as described before. With an in-depth analysis of a western blot, followed by mass spectrometry we discovered that the previously detected neuronal GFAP+1 expression was due to cross-reactivity of the antibody with neurofilament-L (NF-L). This was confirmed by double-label fluorescent immunohistochemistry and western blotting with the unpurified GFAP+1 antibody and an antibody against NF-L. Our data imply that NF-L can accumulate in some tangle-like structures in Alzheimer brains. More importantly, the purified GFAP+1 antibody clearly revealed a specific subtype of astrocytes in the adult human brain. These large astrocytes are present throughout the brain, e.g., along the subventricular zone, in the hippocampus, in the striatum and in the spinal cord of controls, Alzheimer, and Parkinson patients. The presence of a specific GFAP-isoform suggests a specialized function of these astrocytes

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function

The role of water fittings in intensive care rooms as reservoirs for the colonization of patients with Pseudomonas aeruginosa

International audienceOBJECTIVE: To assess the role of the water environment in the Pseudomonas aeruginosa colonization of patients in intensive care units in the absence of a recognized outbreak. DESIGN AND SETTING: Prospective, single-centre study over an 8-week period in two adult ICUs at a university hospital. Environmental samples were taken from the water fittings of rooms once per week, during a 8-week period. Patients were screened weekly for P. aeruginosa carriage. Environmental and humans isolates were genotyped by using pulsed-field gel electrophoresis. RESULTS: P. aeruginosa was detected in 193 (86.2%) of the 224 U-bend samples and 10 of the 224 samples taken from the tap (4.5%). Seventeen of the 123 patients admitted were colonized with P. aeruginosa. Only one of the 14 patients we were able to evaluate was colonized by a clone present in the water environment of his room before the patient's first positive sample was obtained. CONCLUSION: The role of the water environment in the acquisition of P. aeruginosa by intensive care patients remains unclear, but water fittings seem to play a smaller role in non-epidemic situations than expected by many operational hospital hygiene teams

The Population Genetics of Pseudomonas aeruginosa Isolates from Different Patient Populations Exhibits High-Level Host Specificity

Objective To determine whether highly prevalent P. aeruginosa sequence types (ST) in Dutch cystic fibrosis (CF) patients are specifically linked to CF patients we investigated the population structure of P. aeruginosa from different clinical backgrounds. We first selected the optimal genotyping method by comparing pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and multilocus variable number tandem-repeat analysis (MLVA). Methods Selected P. aeruginosa isolates (n = 60) were genotyped with PFGE, MLST and MLVA to determine the diversity index (DI) and congruence (adjusted Rand and Wallace coefficients). Subsequently, isolates from patients admitted to two different ICUs (n = 205), from CF patients (n = 100) and from non-ICU, non-CF patients (n = 58, of which 19 were community acquired) were genotyped with MLVA to determine distribution of genotypes and genetic diversity. Results Congruence between the typing methods was >79% and DIs were similar and all >0.963. Based on costs, ease, speed and possibilities to compare results between labs an adapted MLVA scheme called MLVA9-Utrecht was selected as the preferred typing method. In 363 clinical isolates 252 different MLVA types (MTs) were identified, indicating a highly diverse population (DI = 0.995; CI = 0.993–0.997). DI levels were similarly high in the diverse clinical sources (all >0.981) and only eight genotypes were shared. MTs were highly specific (>80%) for the different patient populations, even for similar patient groups (ICU patients) in two distinct geographic regions, with only three of 142 ICU genotypes detected in both ICUs. The two major CF clones were unique to CF patients. Conclusion The population structure of P. aeruginosa isolates is highly diverse and population specific without evidence for a core lineage in which major CF, hospital or community clones co-cluster. The two genotypes highly prevalent among Dutch CF patients appeared unique to CF patients, suggesting specific adaptation of these clones to the CF lung