Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.

INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

Extracting individual characteristics from population data reveals a negative social effect during honeybee defence.

Honeybees protect their colony against vertebrates by mass stinging and they coordinate their actions during this crucial event thanks to an alarm pheromone carried directly on the stinger, which is therefore released upon stinging. The pheromone then recruits nearby bees so that more and more bees participate in the defence. However, a quantitative understanding of how an individual bee adapts its stinging response during the course of an attack is still a challenge: Typically, only the group behaviour is effectively measurable in experiment; Further, linking the observed group behaviour with individual responses requires a probabilistic model enumerating a combinatorial number of possible group contexts during the defence; Finally, extracting the individual characteristics from group observations requires novel methods for parameter inference. We first experimentally observed the behaviour of groups of bees confronted with a fake predator inside an arena and quantified their defensive reaction by counting the number of stingers embedded in the dummy at the end of a trial. We propose a biologically plausible model of this phenomenon, which transparently links the choice of each individual bee to sting or not, to its group context at the time of the decision. Then, we propose an efficient method for inferring the parameters of the model from the experimental data. Finally, we use this methodology to investigate the effect of group size on stinging initiation and alarm pheromone recruitment. Our findings shed light on how the social context influences stinging behaviour, by quantifying how the alarm pheromone concentration level affects the decision of each bee to sting or not in a given group size. We show that recruitment is curbed as group size grows, thus suggesting that the presence of nestmates is integrated as a negative cue by individual bees. Moreover, the unique integration of exact and statistical methods provides a quantitative characterisation of uncertainty associated to each of the inferred parameters.

Anti-Cancer Effects of Artesunate in Human 3D Tumor Models of Different Complexity.

The anti-malaria drug Artesunate (ART) shows strong anti-cancer effects in vitro; however, it shows only marginal treatment results in clinical cancer studies. In this study, ART was tested in preclinical 3D cancer models of increasing complexity using clinically relevant peak plasma concentrations to obtain further information for translation into clinical use. ART reduced cell viability in HCT-116 and HT-29 derived cancer spheroids (p < 0.001). HCT-116 spheroids responded dose-dependently, while HT-29 spheroids were affected more strongly by ART than by cytostatics (p < 0.001). HCT-116 spheroids were chemo-sensitized by ART (p < 0.001). In patient-derived cancer spheroids (PDCS), ART led to inhibition of cell viability in 84.62% of the 39 samples tested, with a mean inhibitory effect of 13.87%. Viability reduction of ART was 2-fold weaker than cytostatic monotherapies (p = 0.028). Meanwhile, tumor-stimulation of up to 16.30% was observed in six (15.38%) PDCS-models. In 15 PDCS samples, ART modulated chemotherapies in combined testing, eight of which showed chemo-stimulation (maximum of 36.90%) and seven chemo-inhibition (up to 16.95%). These results demonstrate that ART's anti-cancer efficacy depends on the complexity of the tumor model used. This emphasizes that cancer treatment with ART should be evaluated before treatment of the individual patient to ensure its benefits and prevent unwanted effects.

Warming has a minor effect on surface soil organic carbon in alpine meadow ecosystems on the Qinghai-Tibetan Plateau.

The alpine meadow ecosystem on the Qinghai-Tibetan Plateau (QTP) is very sensitive to warming and plays a key role in regulating global carbon (C) cycling. However, how warming affects the soil organic carbon (SOC) pool and related C inputs and outputs in alpine meadow ecosystems on the QTP remains unclear. Here, we combined two field experiments and a meta-analysis on field experiments to synthesize the responses of the SOC pool and related C cycling processes to warming in alpine meadow ecosystems on the QTP. We found that the SOC content of surface soil (0-10 cm) showed a minor response to warming, but plant respiration was accelerated by warming. In addition, the warming effect on SOC was not correlated with experimental and environmental variables, such as the method, magnitude and duration of warming, initial SOC content, mean annual temperature, and mean annual precipitation. We conclude that the surface SOC content is resistant to climate warming in alpine meadow ecosystems on the QTP.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Collaborative agent-based modeling for managing shrub encroachment in an Afroalpine grassland.

We co-designed an agent-based model of an Afroalpine grassland in Ethiopia that is experiencing unwanted shrub encroachment. The goal was to enable managers of a community conservation area to better understand the drivers of shrub encroachment and to test possible management actions for controlling shrubs. Due to limited site-specific data, we parameterized this model using insights from published literature, remote sensing, and expert opinion from scientists and local managers. We therefore sought to explore potential future scenarios rather than make highly accurate predictions, focusing on facilitating discussions and learning among the diverse co-management team. We evaluated three social-ecological scenarios with our model, examining: (1) the impact of changing precipitation regimes on vegetation, (2) whether changing the frequency of guassa grass harvests would improve the long-term sustainability of the grassland, and (3) whether the combination of grass harvest and shrub removal would affect shrub encroachment. We found that the model was highly sensitive to the amount of grass harvested each year for local use. Our results indicate that the guassa grass was more resilient than shrubs during persistent dry climatic conditions, whereas a reduction in only the early spring rains (known as the "belg") resulted in considerable loss of grass biomass. While our modeling results lacked the quantitative specificity desired by managers, participants in the collaborative modeling process learned new approaches to planning and management of the conservation area and expanded their knowledge of the ecological complexity of the system. Several participants used the model as a boundary object, interpreting it in ways that reinforced their cultural values and goals for the conservation area. Our work highlights the lack of detailed scientific knowledge of Afroalpine ecosystems, and urges managers to reconnect with traditional ecological management of the conservation area in their pursuit of shrub encroachment solutions. The decline or absence of the belg rains is becoming increasingly common in the Ethiopian highlands, and our results underscore the need for more widespread understanding of how this changing climatic regime impacts local environmental management. This work lays a foundation for social-ecological research to improve both understanding and management of these highly threatened ecosystems.

Arylphosphonate-Tethered Porphyrins: Fluorescence Silencing Speaks a Metal Language in Living Enterocytes*.

We report the application of a highly versatile and engineerable novel sensor platform to monitor biologically significant and toxic metal ions in live human Caco-2 enterocytes. The extended conjugation between the fluorescent porphyrin core and metal ions through aromatic phenylphosphonic acid tethers generates a unique turn off and turn on fluorescence and, in addition, shifts in absorption and emission spectra for zinc, cobalt, cadmium and mercury. The reported fluorescent probes p-H8 TPPA and m-H8 TPPA can monitor a wide range of metal ion concentrations via fluorescence titration and also via fluorescence decay curves. Cu- and Zn-induced turn off fluorescence can be differentially reversed by the addition of common chelators. Both p-H8 TPPA and m-H8 TPPA readily pass the mammalian cellular membrane due to their amphipathic character as confirmed by confocal microscopic imaging of living enterocytes.

Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype.

Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABAAα1 subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABAAα1 subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor. Purkinje cell specific knockout of the GABAAα1 subunit abolished all GABAA-mediated inhibition in Purkinje cells, while leaving GABAA-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABAAα1 from Purkinje cells did not produce deficits on the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABAAα1 subunit, and, like essential tremor in patients, was responsive to ethanol. These findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells in tremor.NEW & NOTEWORTHY Animals with a global knockout of the GABAAα1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABAAα1 from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.

Identification of Chaoborus kairomone chemicals that induce defences in Daphnia.

Infochemicals play important roles in aquatic ecosystems. They even modify food web interactions, such as by inducing defenses in prey. In one classic but still not fully understood example, the planktonic freshwater crustacean Daphnia pulex forms specific morphological defenses (neckteeth) induced by chemical cues (kairomones) released from its predator, the phantom midge larva Chaoborus. On the basis of liquid chromatography, mass spectrometry, and chemical synthesis, we report here the chemical identity of the Chaoborus kairomone. The biologically active cues consist of fatty acids conjugated to the amino group of glutamine via the N terminus. These cues are involved in Chaoborus digestive processes, which explains why they are consistently released despite the disadvantage for its emitter. The identification of the kairomone may allow in-depth studies on multiple aspects of this inducible defense system.

Eutrophication weakens stabilizing effects of diversity in natural grasslands.

Studies of experimental grassland communities have demonstrated that plant diversity can stabilize productivity through species asynchrony, in which decreases in the biomass of some species are compensated for by increases in others. However, it remains unknown whether these findings are relevant to natural ecosystems, especially those for which species diversity is threatened by anthropogenic global change. Here we analyse diversity-stability relationships from 41 grasslands on five continents and examine how these relationships are affected by chronic fertilization, one of the strongest drivers of species loss globally. Unmanipulated communities with more species had greater species asynchrony, resulting in more stable biomass production, generalizing a result from biodiversity experiments to real-world grasslands. However, fertilization weakened the positive effect of diversity on stability. Contrary to expectations, this was not due to species loss after eutrophication but rather to an increase in the temporal variation of productivity in combination with a decrease in species asynchrony in diverse communities. Our results demonstrate separate and synergistic effects of diversity and eutrophication on stability, emphasizing the need to understand how drivers of global change interactively affect the reliable provisioning of ecosystem services in real-world systems.

Herbivores and nutrients control grassland plant diversity via light limitation.

Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.

Degradation of the Polymeric Brominated Flame Retardant "Polymeric FR" by Heat and UV Exposure.

Monomeric brominated flame retardants often pose risks to the environment. The new group of polymeric flame retardants is claimed to be a safer alternative due to their high molecular weight and persistence by design. Within this publication, the degradation of a commercially widely applied example of this group-the polymer "Polymeric FR"-was studied during UV irradiation and long-term exposure to heat (60 °C) for up to 36 weeks. Both treatments led to a variety of degradation products, which might have potentially adverse environmental effects and an increased mobility compared to the mother polymer. Besides identifying some of the possible degradation products (including for instance 2,4,6-tribromo-3-hydroxybenzoic acid), the degradation via UV irradiation, which yields 75 different degradation products, and via heat, which led to significantly less products, was compared. In addition, further parameters like TOC and the concentration of free bromine were studied and it was demonstrated that the used type of water (distilled, reconstituted, and rainwater) does not influence the outcome of the degradation experiments.

Capillary zone electrophoresis coupled to drift tube ion mobility-mass spectrometry for the analysis of native and APTS-labeled N-glycans.

Capillary zone electrophoresis (CZE) based on electrophoretic mobility in the liquid phase and ion mobility spectrometry (IMS) based on mobilities in the gas phase are both powerful techniques for the separation of complex samples. Protein glycosylation is one of the most common post-translational modifications associated with a wide range of biological functions and human diseases. Due to their high structural variability, the analysis of glycans still represents a challenging task. In this work, the first on-line coupling of CZE with drift tube ion mobility-mass spectrometry (DTIM-MS) has been perfomed to further improve separation capabilities for the analysis of native and 8-aminopyrene-1,3,6-trisulfonic acid (APTS)-labeled N-glycans. In this way, a complexity of glycan signals was revealed which could not be resolved by these techniques individually, shown for both native and APTS-labeled glycans. Each individual glycan signal separated in CZE exhibited an unexpectedly high number of peaks observed in the IMS dimension. This observation could potentially be explained by the presence of isomeric forms, including different linkages, and/or gas-phase conformers. In addition, the type of sialic acid attached to glycans has a significant impact on the obtained drift time profile. Furthermore, the application of α2-3 neuraminidase enabled the partial assignment of peaks in the arrival time distribution considering their sialic acid linkages (α2-3/α2-6). This work is a showcase for the high potential of CZE-DTIM-MS, which is expected to find various applications in the future. Graphical abstract ᅟ.

Comparison of CCS Values Determined by Traveling Wave Ion Mobility Mass Spectrometry and Drift Tube Ion Mobility Mass Spectrometry.

Collision cross section (CCS, Ω) values determined by ion mobility mass spectrometry (IM-MS) provide the study of ion shape in the gas phase and use of these as further identification criteria in analytical approaches. Databases of CCS values for a variety of molecules determined by different instrument types are available. In this study, the comparability of CCS values determined by a drift tube ion mobility mass spectrometer (DTIM-MS) and a traveling wave ion mobility mass spectrometer (TWIM-MS) was investigated to test if a common database could be used across IM techniques. A total of 124 substances were measured with both systems and CCS values of [M + H]+ and [M + Na]+ adducts were compared. Deviations <1% were found for most substances, but some compounds show deviations up to 6.2%, which indicate that CCS databases cannot be used without care independently from the instrument type. Additionally, it was found that for several molecules [2M + Na]+ ions were formed during electrospray ionization, whereas a part of them disintegrates to [M + Na]+ ions after passing through the drift tube and before reaching the TOF region, resulting in two signals in their drift spectrum for the [M + Na]+ adduct. Finally, the impact of different LC-IM-MS settings (solvent composition, solvent flow rate, desolvation temperature, and desolvation gas flow rate) were investigated to test whether they have an influence on the CCS values or not. The results showed that these conditions have no significant impact. Only for karbutilate changes in the drift spectrum could be observed with different solvent types and flow rates using the DTIM-MS system, which could be caused by the protonation at different sites in the molecule.

Warming and land use change concurrently erode ecosystem services in Tibet.

Alpine meadows on the Tibetan Plateau comprise the largest alpine ecosystem in the world and provide critical ecosystem services, including forage production and carbon sequestration, on which people depend from local to global scales. However, the provision of these services may be threatened by climate warming combined with land use policies that are altering if and how pastoralists can continue to graze livestock, the dominant livelihood practice in this region for millennia. We synthesized findings from a climate warming and yak grazing experiment with landscape-level observations in central Tibet to gain insight into the trajectories of change that Tibet's alpine meadows will undergo in response to expected changes in climate and land use. We show that within 5 years, experimental warming drove an alpine community with intact, sedge-dominated turfs into a degraded state. With removal of livestock, consistent with policy intended to reverse degradation, a longer-term shift to a more shrub-dominated community will likely occur. Neither degraded nor shrub meadows produce forage or sequester carbon to the same degree as intact meadows, indicating that climate warming and drying will reduce the ability of Tibet's alpine meadows to provide key ecosystem services, and that livestock reduction policies intended to counteract trajectories of land degradation instead endanger contemporary livelihoods on the Tibetan Plateau.

Late Diagnosis of Langerhans Cell Histiocytosis by Skin Biopsy in a Lung Transplant Candidate Patient.

We present the case of a lung transplant candidate under veno-venous membrane oxygenation assistance (VV ECMO) whose diagnosis of emphysema of undetermined etiology was redefined as Langerhans cell histiocytosis (LCH) due to a scalp skin biopsy performed years after the beginning of his respiratory symptoms. A 20-year-old patient started three years before his admission with progressive dyspnea leading to a diagnosis of bullous emphysema of undetermined cause, which evolved into respiratory failure and evaluation for bilateral lung transplant. Three years later, he developed bilateral pneumonia requiring mechanical ventilation. When refractory hypoxemia ensued, he had to be placed on VV ECMO. Under these conditions, he was transferred to our center and listed for a bilateral pulmonary transplantation. Forty-eight hours after admission, and due to intense polyuria, central diabetes insipidus was diagnosed. In this clinical context, the presence of cutaneous lesions on the scalp was reconsidered and biopsied under the presumption of possible LCH, with pathology analysis confirming the diagnosis. He continued to be assisted with VV ECMO for 66 more days as a bridge to transplantation, developing multi-organ failure and passing away before a donor organ was available. The diagnosis of LCH should be considered in any adult patient with bullous emphysema of undetermined cause. Given the possibility of early therapeutic interventions, the search for its clinical associations (e.g., diabetes insipidus and/or skin lesions) should be a systematic part of the etiologic workup. The availability of skin specimens to reach a diagnosis makes its thorough search an important part of the diagnostic approach.

A Modified Switching Procedure from Temporary to Tunneled Central Venous Dialysis Catheters.

Background: Tunneled central venous catheters are commonly used for dialysis in patients without a functional permanent vascular access. In an emergent setting, a non-tunneled, temporary central venous catheter is often placed for immediate dialysis. The most critical step in the catheter insertion is venipuncture, which is often a major cause for longer intervention times and procedure-related adverse events. To avoid this critical step when placing a more permanent tunneled catheter, an exchange over a previously placed temporary one can be considered. In this paper, we present a modified switching approach with a separate access site. Methods: In this retrospective analysis of a prospective database, we examined whether this modified technique is non-inferior to a de novo application. Therefore, we included all 396 patients who received their first tunneled dialysis catheter at our site from March 2018 to March 2023. Out of these, 143 patients received the modified approach and 253 the standard de novo ultrasound-guided puncture and insertion. Then, the outcomes of the two groups, including adverse events and infections, were compared by nonparametric tests and multivariable logistic regression. Results: In both groups, the implantations were 100% successful. Catheter explantation due to infection according to CDC criteria was necessary in 18 cases, with no difference between the groups (5.0% vs. 4.4% p = 0.80). The infection rate per 100 days was 0.113 vs. 0.106 in the control group, with a comparable spectrum of bacteria. A total of 12 catheters (3 vs. 9) had to be removed due to a periinterventional complication. An early-onset infection was the reason in two cases (1.3%) in the study group and five in the control group (1.9%). A total misplacement of the catheter occurred in two cases only in the control group. After adjustment for potential confounders via multivariable logistic regression there was not a significant difference in the complication rate (adjusted odds ratio, aOR = 0.53, 95% CI = 0.14-2.03, p = 0.351) but an estimated decreased risk overall based on the average treatment effect of -1.7% in favor of the study group. Conclusions: The present study shows that a catheter exchange leads to no more infections than a de novo placement; hence, it is a feasible method. Moreover, misplacements and control chest X-rays to exclude pneumothorax after venipuncture were completely avoided by exchanging. This approach yields a much lower infection rate than previous reports: 1.3% compared to 2.7% in all existing aggregated studies. The presented approach seems to be superior to existing switching methods. Overall, an exchange can also help to preserve veins for future access, since the same jugular vein is used.

Predicting invasion in grassland ecosystems: is exotic dominance the real embarrassment of richness?

Invasions have increased the size of regional species pools, but are typically assumed to reduce native diversity. However, global-scale tests of this assumption have been elusive because of the focus on exotic species richness, rather than relative abundance. This is problematic because low invader richness can indicate invasion resistance by the native community or, alternatively, dominance by a single exotic species. Here, we used a globally replicated study to quantify relationships between exotic richness and abundance in grass-dominated ecosystems in 13 countries on six continents, ranging from salt marshes to alpine tundra. We tested effects of human land use, native community diversity, herbivore pressure, and nutrient limitation on exotic plant dominance. Despite its widespread use, exotic richness was a poor proxy for exotic dominance at low exotic richness, because sites that contained few exotic species ranged from relatively pristine (low exotic richness and cover) to almost completely exotic-dominated ones (low exotic richness but high exotic cover). Both exotic cover and richness were predicted by native plant diversity (native grass richness) and land use (distance to cultivation). Although climate was important for predicting both exotic cover and richness, climatic factors predicting cover (precipitation variability) differed from those predicting richness (maximum temperature and mean temperature in the wettest quarter). Herbivory and nutrient limitation did not predict exotic richness or cover. Exotic dominance was greatest in areas with low native grass richness at the site- or regional-scale. Although this could reflect native grass displacement, a lack of biotic resistance is a more likely explanation, given that grasses comprise the most aggressive invaders. These findings underscore the need to move beyond richness as a surrogate for the extent of invasion, because this metric confounds monodominance with invasion resistance. Monitoring species' relative abundance will more rapidly advance our understanding of invasions.